19th Expert Committee on the Selection and Use of Essential Medicines

Proposal for the inclusion

(as an additional purpose)

on the

WHO Model List of Essential Medicines of

DEXAMETHASONE FOR ACCELERATING LUNG MATURATION

IN PRETERM BABIES

Joy Lawn MB BS MRCP (Paeds) MPH, PhD

Director Global Evidence and Policy
Saving Newborn Lives/Save the Children
London
joylawn@yahoo.co.uk
Fernando Althabe MD, MSc
Instituto de Efectividad Clnica y Sanitaria (IECS)
Ravignani 2024
Buenos Aires 1414
Argentina
Tel: +5411 47778767 ext. 17
falthabe@gmail.com
falthabe@iecs.org.ar

Table of Contents
1. Summary................................................................................................................................. 2
2. Focal points in WHO submitting or supporting the application ..................... 3
3. Organizations consulted and/or supporting the application ........................... 3
4. International Nonproprietary Name (INN) of the medicine................................ 3
5. Formulation proposed for inclusion........................................................................... 3
6. International availability sources, manufacturers, and trade names ....... 4
7. Listing requested as an individual medicine .......................................................... 4
8. Information supporting the public health relevance ........................................... 4
9. Treatment details ............................................................................................................. 12
10. Summary of comparative effectiveness .............................................................. 15
11. Summary of comparative evidence on safety................................................... 21
12. Summary of available data on comparative cost and cost-effectiveness
within the pharmacological class or therapeutic group ...................................... 23
13. Summary of regulatory status of the medicine ................................................ 27
14. Availability of pharmacopoeial standards .......................................................... 27
15. Proposed adapted text for the WHO Model Formulary ................................. 28
Appendix A. Dexamethasone Injection Manufacturers and Trade Names ........ 33
Appendix B. National and Regional Guidelines Recommending Antenatal
Dexamethasone for Preterm Labor ..................................................................................... 34

1. Summary
This report demonstrates that dexamethasone injection given to women in preterm labour is a
safe, effective, and low-cost measure for reducing death and disability in preterm infants. Hence
we propose the inclusion of dexamethasone injection (4 mg/mL) on the WHO Model List of
Essential Medicines (EML) for use when preterm birth is anticipated. Dexamethasone has the
potential to greatly impact the over 1.1 million annual neonatal deaths directly due to preterm
birth complications, the majority of which occur in low and middle income countries.
Dexamethasone for preterm labour appears on the WHO list of Priority Life-Saving Medicines for
Women and Children 2012 and is recommended for inclusion on national EMLs and in national
treatment guidelines (WHO 2012), as well as widely recommended in WHO global clinical
guidelines such as Managing Complications in Pregnancy and Childbirth: a guide for midwives
and doctors (WHO 2000).
Antenatal corticosteroids (ACS), specifically dexamethasone and betamethasone, are the only
Priority Medicines not already included on the list of Essential Medicines for indications related
to preterm birth.
Dexamethasone injection in the same formulation proposed here is already included in the current
EML because of its proven safety and cost-effectiveness for three other indications (section 3
Antiallergics and medicines used in anaphylaxis, subsection 8.4 Medicines used in palliative
care, and subsection 17.2 Antiemetic medicines). The same formulation also appears on the
complementary list under subsection 8.3 Hormones and antihormones. Inclusion on the EML of
dexamethasone for antenatal use would help to increase the reach of this intervention into lowincome countries where it is most urgently needed.
The proposal for inclusion of dexamethasone for antenatal use is based on the following evidence
and considerations, detailed further in this document:

Preterm birth is the leading cause of neonatal deaths and the second most common cause of
under-5 mortality, as well as a leading contributor to the global burden of disease, due to a
significant risk of disability.
Each year an estimated 15 million babies are born preterm, three-quarters in South Asia and
Sub-Saharan Africa, and over 85% are moderate or late preterm, likely to survive without
intensive care, and yet still lacking basic care, ACS would be expected to make considerable
difference in mortality and morbidity, primarily though reducing the risk of respiratory
distress syndrome (RDS).
Antenatal corticosteroids have high-quality evidence of effect on all cause neonatal
mortality, based on a Cochrane review and meta-analysis of 18 trials (3956 infants) giving an
effect size of RR 0.69, 95% CI 0.58 to 0.81 (Roberts and Dalziel 2006). The same metaanalysis found reduced incidence of RDS (RR 0.66, 95% CI 0.59 to 0.73, 21 studies, 4038
infants) and cerebroventricular hemorrhage (RR 0.54, 95% CI 0.43 to 0.69, 13 studies, 2872
infants).
A meta-analysis of 4 RCTs (672 infants) from middle-income countries found an effect of
RR 0.47, 95% CI 0.35 to 0.64, suggesting that the effect size may be higher in settings with
lower levels of intensive care. No studies were found from low-income settings (Mwansa et
al. 2010).

Of the two main ACS drugs (dexamethasone and betamethasone), neither has been
definitively shown to be superior to the other. A large trial powered to detect a difference is
ongoing but results are not expected until 2015 (Brownfoot et al. 2008).
Dexamethasone is safe. It is already listed on the EML in the same formulation, with no
safety concerns on the existing listings. Meta-analysis of six trials where dexamethasone was
used in preterm labour demonstrated low risks to the mother, to the fetus/neonate, and to the
childs long-term development.
Dexamethasone is inexpensive (< US $1 per four-injection course) and widely available,
making it the lowest-cost and most accessible means of preventing RDS and deaths due to
preterm birth.
Dexamethasone treatment is highly cost-effective at an estimated cost per case treated of US
$16.25 and cost per life saved of US $634.

2. Focal points in WHO submitting or supporting the application

Dr. Matthews Matthai
Department of Maternal, Newborn, Child & Adolescent Health
mathaim@who.int
Dr. Metin Glmezoglu
Department of Reproductive Health and Research
gulmezoglum@who.int

3. Organizations consulted and/or supporting the application

Eunice Kennedy Shriver National Institute of Child Health and Human Development
(NICHD)
Global Network for Womens and Childrens Health Research (NICHD)
International Federation of Gynecology and Obstetrics (FIGO)
International Pediatric Association (IPA)
International Confederation of Midwives (ICM)
Maternal and Child Health Integrated Program (MCHIP)
Save the Children/Saving Newborn Lives
The Bill & Melinda Gates Foundation
United States Agency for International Development (USAID)

4. International Nonproprietary Name (INN) of the medicine

Dexamethasone

5. Formulation proposed for inclusion

Injection: 4 mg/ml in 1-ml ampoule (as disodium phosphate salt)
Note that since each dose is 6 mg, the 1-ml packaging may involve waste of ml (2 mg) per
dose, or 2 ml (8 mg) per 4-dose treatment (see 9.1. Dosage regimen and duration).

In order to avoid this wastage, the Committee may wish to consider multi-dose vials, which are
available at 4 mg/ml concentration in sizes ranging from 2 ml to 30 ml. However, it should be
noted that multi-dose vials carry increased risk of contamination and infection.
The ideal package size of 1.5 ml or 6 mg (one dose) is unfortunately not currently produced.

6. International availability sources, manufacturers, and trade names

Dexamethasone injection is widely available at low cost throughout the developed and
developing world. The International Drug Price Indicator Guide, published in collaboration with
the WHO, lists suppliers including the United Nations Population Fund and Mission Pharma, a
major supplier of essential medicines to NGOs. The product is also available via the UNICEF
catalog. A partial list of additional vendors and trade names is given in Appendix A.

7. Listing requested as an individual medicine

We request listing of dexamethasone as an individual medicine with therapeutic antenatal use in
preventing complication such as RDS and mortality or subsequent morbidity in preterm babies.
Dexamethasone is currently included in the 17th WHO EML under section 3 Antiallergics and
medicines used in anaphylaxis, subsection 8.4 Medicines used in palliative care, and subsection
17.2 Antiemetic medicines, as well as on the complementary list under subsection 8.3 Hormones
and antihormones.
Antenatal dexamethasone for the prevention of RDS could be included in section 29. Specific
medicines for neonatal care or section 25. Medicines acting on the respiratory tract, or in a new
section.

8. Information supporting the public health relevance

8.1. Disease burden
Preterm birth
In 2010, there were an estimated 14.9 million preterm births, or 11.1% of live births worldwide.
Preterm birth is a global problem, with a rate ranging from 5% in some European countries to
18% in some African countries. Over 60% of preterm births occurred in Southern Asia and subSaharan Africa, which contribute 52% of global live births. Table 1 presents estimated preterm
birth rates and numbers by region. Rates of preterm birth are increasing in all regions for which
reliable data are available (Blencowe et al. 2012).

Table 1. Estimated preterm birth rates and total number of preterm births for 2010, by
UN Millennium Development Goal region (from Blencowe et al. 2012).

*Uncertainty ranges derived using a bootstrap approach.

Preterm birth complications are the leading cause of neonatal death. In 2010, complications of
preterm birth were responsible for over one millions deaths, comprising roughly 35% of neonatal
deaths. Neonatal deaths make up 40% of all deaths in children under 5 years old, with preterm
birth contributing 14% of all under-5 deaths (see Figure 1). Preterm birth is thus the second
leading cause of death in children under 5, after pneumonia, and is projected to become the
leading cause before 2015 if coverage of available interventions does not increase (Liu et al.
2012).
Between 2000 and 2010, deaths from preterm birth decreased at a rate of 2% annually (Liu et al.
2012), or less than 20% over the decade. This rate is far from sufficient to meet UN Millennium
Development Goal (MDG) 4, which aims to reduce the under-5 mortality rate by two-thirds
between 1990 and 2015. As of 2010, child mortality had fallen by only 38%, and the UN MDG
Report identified neonatal mortality as a lagging area and an increasing proportion of child deaths
(UN 2012). Neonatal mortality rate is reducing one third more slowly than for deaths for children
aged 1-59 months, and at half the speed of maternal deaths (Lawn et al, 2012).

Figure 1. Global causes of childhood deaths in 2010 (from Liu et al. 2012)
Causes that lead to less than 1% of deaths are not shown.

Preterm birth further contributes to neonatal, child, and adult morbidity and disability due to the
effects of prematurity on neurodevelopmental functioning. Surviving preterm infants face
increased risk of cerebral palsy, learning impairment, visual disorders, and chronic disease in
adulthood (Howson et al. 2012).
Equity gap in the burden of preterm birth
The equity gap for survival of preterm babies is over 20-fold between the richest and poorest
countries, and has increased over the last decade. While babies born at 25 weeks gestation in
Europe or the North America have a 50% chance of survival, babies even in hospitals in the
poorest countries may have less than 50% survival at 32 weeks gestation (Howson et al. 2012).
Between 1990 and 2010, under-5 mortality dropped by over 50% in developed regions but only
35% in developing regions. As interventions progress more rapidly elsewhere, Southern Asia and
sub-Saharan Africa contribute an increasing share of under-5 deaths, with the highest neonatal
mortality rate occurring in sub-Saharan Africa (UN 2012).
Respiratory distress syndrome (RDS)
RDS is a common complication of preterm birth, and is widely considered the primary cause of
death among preterm babies (Roberts and Dalziel 2006, Liu et al. 2012, Vidyasagar et al. 2011).

Among survivors, RDS is also associated with long-term neurological disability (Roberts and
Dalziel 2006).
RDS in preterm birth is a consequence of underdeveloped lungs deficient in surfactant. The
incidence of RDS decreases with increasing gestational age and birthweight, reflecting increasing
lung maturity (Roberts and Dalziel 2006, Whitsett et al. 2005).
Detailed global data on the incidence of RDS are not available (Vidyasagar et al. 2011).
However, RDS is estimated to affect up to one-fifth of babies weighing under 2500 g and twothirds of babies under 1500 g (Roberts and Dalziel 2006). Weights of 1500 g and 2500 g
correspond to median fetal weights at 30 weeks and 33-34 weeks gestation, respectively, in the
United States (Oken et al. 2003), and would be expected to correspond to higher gestational ages
in developing countries, where birthweights are lower.
8.2. Prevention of RDS
Antenatal corticosteroids (ACS)
Antenatal corticosteroid treatment for women at risk of preterm delivery is considered to be the
most effective intervention for reducing incidence of RDS and resultant death and disability.
Fluorinated glucocorticoid hormones cross the placenta and trigger fetal lung maturation,
including the production of surfactant. This enables babies to establish regular breathing with
reduced requirements for mechanical respiratory support.
In the 30 years since the first study in 1972 (Liggins and Howie 1972), numerous randomized
clinical trials (RCTs) have established ACS as a standard of care recommended by the WHO and
the United States National Institutes of Health, among other organizations (see section 9.2 of this
document.)
A 2006 Cochrane review including 21 studies found that betamethasone and dexamethasone are
by far the most-studied ACS and the only two with proven efficacy (Roberts and Dalziel 2006).
Meta-analysis of 6 RCTs using dexamethasone and 12 RCTs using betamethasone showed a
reduction of 31% in neonatal mortality (18 studies, 3956 infants, RR 0.69, 95% CI 0.58 to 0.81,
see figure 2). The review also found substantial reductions in RDS (RR 0.66, 95% CI 0.59 to
0.73, 21 studies, 4038 infants), moderate to severe RDS (RR 0.55, 95% CI 0.43 to 0.71, 6 studies,
1686 infants), cerebroventricular hemorrhage (RR 0.54, 95% CI 0.43 to 0.69, 13 studies, 2872
infants), necrotising enterocolitis (RR 0.46, 95% CI 0.29 to 0.74, eight studies, 1675 infants),
need for mechanical ventilation/CPAP (RR 0.69, 95% CI 0.53 to 0.90, 4 studies, 569 infants),
need for intensive care admissions (RR 0.80, 95% CI 0.65 to 0.99, two studies, 277 infants), and
systemic infections in the rst 48 hours of life (RR 0.56, 95% CI 0.38 to 0.85, ve studies, 1319
infants).

Figure 2. A meta-analysis of 18 RCTs showing effect of an antenatal course of

dexamethasone or betamethasone on neonatal mortality following preterm birth (Mwansa
et al. 2010 using data from Roberts and Dalziel 2006).
Risk ratio
(95% CI)

Study

% Weight

Liggins 1972

0.87 (0.63,1.19)

24.3

Block 1977

0.19 (0.02,1.54)

1.8

Taeusch 1979

1.02 (0.43,2.41)

3.0

Doran 1980

0.27 (0.09,0.81)

4.3

Schutte 1980

0.23 (0.07,0.79)

4.2

Collaborative 1981

1.06 (0.67,1.68)

10.9

Nelson 1985

1.00 (0.07,15.00)

0.3

Parsons 1988

0.32 (0.01,7.45)

0.5

Gamsu 1989

0.84 (0.43,1.63)

5.8

Morales 1989

0.78 (0.30,2.06)

2.9

Garite 1992

0.99 (0.47,2.10)

3.4

Kari 1994

0.64 (0.19,2.21)

2.1

Lewis 1996

1.03 (0.07,15.82)

0.3

Silver 1995

0.68 (0.27,1.73)

3.1

Amorim 1999

0.50 (0.28,0.89)

9.6

Dexiprom 1999

0.48 (0.15,1.55)

2.8

Qublan 2001

0.45 (0.29,0.70)

13.8

Fekih 2002

0.46 (0.23,0.93)

6.9

Overall (95% CI)

0.69 (0.58,0.81)

.1

10
Risk ratio

Control arm received either placebo or no treatment. Total events = 491 neonatal deaths
Heterogeneity chi-squared = 21.54 (d.f. = 17) p = 0.203
Test of RR=1 : z= 4.50 p = 0.000
Fixed effect meta-analysis
(Source: Roberts and Dalziel 2006)

Generaliseability of ACS impact across regional and income settings

While the studies included in the Cochrane review compared ACS to antenatal placebo or no
antenatal treatment, all infants in both treatment and control arms received available neonatal
care, including ventilation and surfactant in some cases. This level of care is often unavailable in
low- and middle-income countries (Mwansa et al. 2010).
Of the 18 RCTs reporting on neonatal mortality outcomes, 14 were conducted in countries
classified as high-income (HICs) by the World Bank. The remaining 4 were conducted in uppermiddle-income countries (UMICs): Brazil, Jordan, South Africa, and Tunisia (Roberts and
Dalziel 2006, World Bank 2012). An independent meta-analysis of these 4 upper middle income
RCTs (Mwansa et al. 2010) found an elevated effect, with 53% reduction in neonatal mortality
(RR 0.47, 95% CI 0.35 to 0.64, 4 studies, 672 infants). Some of these UMIC studies mention
availability and use of mechanical ventilation, CPAP, surfactant, and neonatal intensive care units
(NICU).
Figure 3 shows the results of these four trials, while Figure 4 shows results from HICs. A
comparison suggests a greater impact of ACS in UMICs. If this difference in impact is related to
differing standards of neonatal care, it could be still greater in lower-middle-income and low-

income countries, though further study is needed. In addition, Mwansa et al. identified two
observational studies in UMICs (Brazil, Meneguel 2003; and Iran, Nayeri et al. 2005) which,
while weaker design, the risk reduction for neonatal death was consistent (RR 0.55, 95% CI 0.40
to 0.76, 2 studies, 692 infants).
Figure 3. Meta-analysis of 4 RCTs from middle-income countries comparing neonatal mortality
following administration of antenatal corticosteroids for preterm labor to placebo or not treatment
(from Mwansa et al. 2010).
*Erratum: Amorium 1999 refers to Amorim 1999.
Risk ratio
(95% CI)

Study

% Weight

Amorium 1999

0.50 (0.28,0.89)

28.9

Dexiprom 1999

0.48 (0.15,1.55)

8.4

Qublan 2001

0.45 (0.29,0.70)

41.8

Fekih 2002

0.46 (0.23,0.93)

20.9

Overall (95% CI)

0.47 (0.35,0.64)

.1

10
Risk ratio

Total events = 142

Heterogeneity 2 = 0.08 (d.f. = 3) P = 0.994
Test of RR = 1 : z = 4.87 P = 0.000
Fixed effect meta-analysis
Source: Mwansa J et al. 2010

Figure 4. Meta-analysis of 14 RCTs from high-income countries comparing neonatal mortality

following administration of antenatal steroids for preterm labor with placebo or no treatment
(from Mwansa et al. 2010).

Total events = 349

Heterogeneity 2 = 12.48 (df = 13) P = 0.489
Test of RR = 1 : z = 2.33 P = 0.020
Fixed effect meta-analysis
Source: Mwansa J et al. 2010
Quality of evidence on ACS
Mwansa et al. assessed the quality of evidence used the Child Health Epidemiology Reference
Group (CHERG) adaptation of the Grading of Recommendations Assessment, Development and
Evaluation (GRADE) Working Group methodology, which is aligned to the WHO use of
GRADE (Walker et al. 2010). This review considered the evidence for the effect of ACS on
neonatal mortality in all studies meeting inclusion criteria (18 RCTs, Figure 2) as well as in
UMICs only (4 RCTs, Figure 3), along with evidence on RDS outcomes for 21 RCTs including 4
in UMICs. Table 2 shows the result of the assessment, which graded the evidence as high quality.

10

Table 2. Quality assessment GRADE table of the effect of antenatal steroids for preterm labor on neonatal mortality due to direct complications of
preterm birth (from Mwansa et al. 2010).

11

8.3. Assessment of current use

Coverage and equity gap in the use of ACS
In high-income countries, coverage remained low for over a decade after publication of clear
evidence of effectiveness for ACS but rapidly increased following a 1994 NIH Consensus
Statement supporting use (NIH, Mwansa et al. 2010). Widespread use in North America and
Western Europe has since greatly reduced RDS incidence and severity (Mwansa et al. 2010).
ACS are used in nearly 90% of cases of preterm labor in HICs. (Stoll et al. 2010)
Middle-income countries (MICs) have highly variable coverage. One assessment of 4 Southeast
Asian countries found 9-73% coverage across 9 hospitals (Pattanittum et al. 2008), while another
survey found baseline coverage of 19% in Mexico City (22 hospitals) and 23% in NE Thailand
(18 hospitals, Gulmezoglu et al. 2007). In low-income countries (LICs), coverage rates are
estimated at 10% for 75 high-priority countries, but data are sparse (McClure et al. 2011).
Use of dexamethasone
Due to supply limitations and higher costs of betamethasone (discussed in section 10 and section
12 of this document), dexamethasone is much more widely available in LICs and MICs.
Both betamethasone and dexamethasone use may be limited due their lack of registration for
antenatal use in most countries. This may limit its inclusion in national formularies for fetal
indications, but it appears frequently for other indications. Off-label use of ACS is strongly
supported by current guidelines, evidence of effectiveness and safety, and consideration of
potential impact (discussed further in section 13).
8.4. Target population
Preterm birth is a global problem, and antenatal dexamethasone is aimed at reducing RDS and
neonatal mortality and morbidity in all preterm deliveries. However, low- and middle-income
countries with limited coverage and limited resources for neonatal care are of particular concern.

9. Treatment details
9.1. Dosage regimen and duration
For prevention of RDS in cases of anticipated preterm birth (including elective caesarean section)
within 7 days, the recommended regimen is a single course of 4 doses of 6 mg dexamethasone,
administered to the mother by intramuscular injections 12 hours apart.
9.2. Reference to existing WHO and other clinical guidelines
The organizations listed below recommend a course of antenatal corticosteroids for mothers at
risk of preterm labor. Each document lists both dexamethasone (4 doses of 6 mg IM, 12 hours
apart) and betamethasone as acceptable treatments for prevention of RDS.

WHO: Managing Complications in Pregnancy and Childbirth: a guide for midwives and
doctors, published in 2000 and reprinted in 2007
United States National Institute of Health (NIH): Consensus Statements in 1994 and 2000
American College of Obstetrics and Gynecology (ACOG): Committee Opinion, 2011

12

Royal College of Obstetrics and Gynecology (RCOG): Guideline, 2010

World Association of Perinatal Medicine (WAPM): Guideline (Miracle et al. 2008)
International Federation of Gynecology and Obstetrics (FIGO) and International Pediatric
Association (IPA): Joint statement on Prevention and Treatment of Preterm Births (2012)

A list of other national and regional guidelines is shown in Appendix B.

WHO Priority Medicines List
Dexamethasone is included on the WHO Priority Life-Saving Medicines for Women and Children
2012 for improvement of fetal lung maturity as part of management for preterm labor. This list is
an update of the first list of Priority Medicines for Mothers and Children 2011, which listed
dexamethasone as an alternative to betamethasone without comparative comment. The update
includes dexamethasone and betamethasone as separate entries.
The Priority Medicines list was developed collaboratively by groups including the WHO
Department of Essential Medicines and Health Products; Maternal, Newborn, Child and
Adolescent Health; and Reproductive Health and Research. Medicines were selected on the basis
of global disease burden and evidence of efficacy and safety. The antenatal corticosteroids
dexamethasone and betamethasone are the only Priority Medicines not already included on the
WHO Model List of Essential Medicines.
According to the WHO, Priority Medicines are those medicines that will have the biggest impact
on reducing maternal, newborn and child morbidity and mortality
and should be . . . [o]n National Essential Medicines lists and [p]art of national standard
treatment guidelines (WHO 2012b).
9.3. Repeat courses
A second course of antenatal corticosteroids is sometimes administered if the woman has not
given birth 7 or 14 days after the initial course. However, this treatment is non-standard and
according to guidelines should be reserved for rare cases.
A Cochrane meta-analysis (Crowther and Harding 2007) examined the safety and efficacy of
repeat courses of either betamethasone or dexamethasone and found reduced risk in incidence and
severity of neonatal lung disease as well as in serious infant morbidity. There was no statistically
significant difference in other primary outcomes including perinatal mortality or mean
birthweight. However, three individual studies reported reductions in birthweight or some
measures of size at birth.
Concerns about potential impact on long-term development combined with a lack of data have led
the NIH, ACOG, RCOG, and WPAM to recommend against routine use of repeat courses of
ACS. ACOG and RCOG guidelines allow for single repeated rescue course in very limited cases,
while NIH and WPAM recommend against any repeat courses except for women enrolled in
RCTs.
Of the five studies analyzed by Crowther and Harding, some included women enrolled after a
first course of dexamethasone, but all used betamethasone for repeat courses. Data specific to
antenatal dexamethasone use is not available. However, the WHO Model Formulary 2008, which
lists the same formulation of dexamethasone for other indications, notes a risk of intrauterine
growth retardation on prolonged or repeated systemic treatment though [b]enefit of treatment . .
. outweighs risk for indications listed in section 3 Antiallergics and medicines used in

13

anaphylaxis, subsection 8.3 Hormones and antihormones, and subsection 18.1 Adrenal hormones
and synthetic substitutes.
9.4. Gestational age at treatment
The following table summarizes the gestational age range for which antenatal dexamethasone is
recommended in the guidelines listed in section 9.2. The ACOG guideline follows the NIH
position on gestational age.
Table 3. Gestational age at which antenatal dexamethasone is recommended for anticipated
preterm labor
Guideline
WHO
NIH/ACOG

All cases (except contraindication)

Special cases

< 37 weeks
24-34 weeks

RCOG

24-34+6 weeks

WPAM

24-34 weeks

May be considered with caution at

23+0-23+6 weeks
All elective caesarean sections
< 38+6 weeks
24-35+6 weeks in cases of fetal
growth restriction
> 34 weeks with indication of
pulmonary immaturity

While the lower boundary is based on a lack of studies (Roberts and Dalziel 2006, RCOG 2010,
NIH 1994), upper limits are based on inadequate evidence of effectiveness for ACS at higher
gestational ages (NIH 1994, > 35 weeks; Roberts and Dalziel 2006, > 34+6 weeks). The recent
Mwansa et al. meta-analysis (2010) also indicated no effect of ACS on neonatal death after 36
weeks, as indicated in the note in Table 2.
However, all data on gestational ages above 34 weeks come from HICs. As fetuses at same
gestational age may be smaller and less developed in LICs and MICs, ACS may have broader
applicability in the regions which carry the greatest burden of mortality due to preterm birth.
The single dexamethasone study which included pregnancies at over 34 weeks reported an
inconclusive effect on RDS (RR 0.57, 95% CI 0.19 to 1.72, 374 infants).
9.5. Need for special diagnostics, treatment, or monitoring facilities and skills
Use of dexamethasone for fetal maturation requires the ability of the caregiver to roughly
determine gestational age and to diagnose preterm labor. Even in high-income settings, this can
be difficult to establish with certainty unless early ultrasound data are available. In the absence of
such data, guidelines support that obstetricians should err on the side of overuse rather than
underuse. The need for skilled evaluation means that antenatal dexamethasone treatment requires
a facility setting and is currently not recommended at the community level.
ACS reduces the overall need for special facilities by reducing need for mechanical
ventilation/CPAP as well as NICU admissions (section 8.2). Though the single dexamethasone
study contributing to this result from the Cochrane meta-analysis (Roberts and Dalziel 2006) does
not provide conclusive data by itself (RR 0.90, 95% CI 0.47 to 1.73, 206 infants) and no
dexamethasone-specific data are available for NICU admissions, some degree of reduction could
be expected considering reductions in morbidity requiring such treatment. One dexamethasone

14

study similarly suggests a lesser need for surfactant (RR 0.70, 95% CI 0.43 to 1.13, 179 infants;
all ACS, RR 0.72, 95% CI 0.51 to 1.03, 3 studies, 456 infants). Prophylactic dexamethasone
intervention is thus especially pertinent to lower-income settings with limited resources.
The related WHO guide provides detailed information on diagnosis of preterm labor and
administration of antenatal dexamethasone (2000).

10. Summary of comparative effectiveness

10.1. Identification of clinical evidence (search strategy, systematic reviews identified,
reasons for selection/exclusion of particular data)
Meta-analyses of efficacy and effectiveness
A 2006 Cochrane review (Roberts and Dalziel) considered all randomized controlled ACS
administration prior to anticipated preterm delivery, as compared with placebo or no antenatal
treatment. Published, unpublished, and ongoing trials with reported data were considered. The
Cochrane review excluded quasi-randomized trials as well as trials comparing effect of
corticosteroids bundled with co-interventions other than standard care. The reviewers identified
relevant studies by searching the Cochrane Pregnancy and Childbirth Group Trials Register as of
30 October 2005. The register drew from quarterly searches of the Cochrane Central Register of
Controlled Trials (CENTRAL), monthly searches of MEDLINE, hand searches of 30 journals and
proceedings of major conferences, and weekly current awareness search of an additional 37
journals. Language was not restricted.
A 2010 meta-analysis (Mwansa et al.) searched for studies through September 2009 in databases
including the Cochrane Libraries, PubMed, LILACS, African Medicus, EMRO, and all WHO
Regional Databases. Language was not restricted. Through this search, the authors did not
identify any randomized controlled trials not already included in the Cochrane review.
These previous reviews included 6 dexamethasone studies: Collaborative 1981, Dexiprom 1999
(Pattinson et al. 1999), Kari 1994, Qublan 2001, Silver 1996, and Taeusch 1979).
Meta-analysis of comparative efficacy
A 2008 Cochrane review (Brownfoot et al.) considered all randomized and quasi-randomized
controlled trials of ACS comparing any two corticosteroids or any two different dosage regimens
for preterm birth. Studies were identified through the Cochrane Pregnancy and Childbirth Group
Trials Register as of January 2008.
Search strategy for further clinical evidence on antenatal dexamethasone
To identify any studies since the Mwansa et al. (2010) search to September 2009, we repeated the
search strategy for September 2009 through October 2, 2012 in the following databases: PubMed,
the Cochrane CENTRAL trials register, and WHO regional databases with search terms
dexamethasone and any one of antenatal, prenatal, or preterm. Searches were limited to
human trials where possible, but were not restricted by language. Search results and screening are
summarized in Figure 5.

15

Figure 5. Identification of new evidence (since Mwansa et al. meta-analysis) on dexamethasone

for preterm birth.

Studies were screened following the PICO format (Patient, Intervention, Comparison, and
Outcome) using definitions adapted from Mwansa et al. (2010):
Population: neonates
Intervention: administration of antenatal dexamethasone to women with anticipated preterm
labor
Comparison: placebo or suitable control group differing from the experimental group except
only by absence of the intervention
Outcomes: primary efficacy outcomes (RDS and mortality), safety outcomes (long-term
developmental impact and adverse effects)
The initial search produced 82 results from PubMed, 13 from CENTRAL, 6 from Western Pacific
Region Index Medicus (WPRIM), 2 from Index Medicus for the South-East Asian Region
(IMSEAR), 2 from Index Medicus for the Eastern Mediterranean Region (IMEMR), and none
from either Latin American and Caribbean Health Sciences Literature (LILACS) or African Index
Medicus (AIM).
An initial screen of title and abstract for Population and Intervention reduced these 105 results to
17 after excluding publications not related to human clinical trials as well as interventions
including postnatal dexamethasone and prenatal administration of dexamethasone for conditions
unrelated to preterm birth. We further excluded 3 non-systematic reviews presenting no new data
or analysis and two trials presenting combined data for betamethasone and dexamethasone.

16

Screening for comparator further removed 5 studies that did not compare dexamethasone to a
control. Three secondary subgroup analyses examined fetal sex, race, and maternal body mass
index. A trial comparing single vs repeat courses of ACS (either dexamethasone or
betamethasone) found evidence against repeated courses due to reduced size at birth (PubMed
2010), consistent with prior studies. The fifth exclusion was a small descriptive study reporting
on neonatal cardiac function with no comparator (Tarunotai 2009).
Four studies did not report on primary efficacy outcomes or adverse or long-term effects. One
cohort study followed developmental outcomes which are summarized in section 11.1 (Liu et al.
2012).
The remaining publications included two foreign-language articles, one RCT (Helji et al. 2009)
and one observational study (Behrooz et al. 2010). Though neither article could be obtained in
full, main results provided in the abstracts confirmed previous findings on dexamethasone
efficacy. The RCT by Helji et al. reported 49% reduction in RDS (RR 0.51, 95% CI 0.35 to
0.74, 172 infants) and 60% reduction in severe RDS (RR 0.39, 95% CI 0.19 to 0.80, 77 infants).
Behrooz et al. reported a 23% reduction in RDS (RR 0.77, 95% CI 0.51 to 1.15, 235 infants).
10.2. Summary of available data
Six RCTs of antenatal dexamethasone showed improved neonatal outcomes, with a 28%
reduction in neonatal deaths and 20% reduction in RDS compared to placebo or no treatment (see
Table 4).
Table 4. Characteristics and outcomes of 6 RCTs of antenatal dexamethasone for preterm labor,
and meta-analysis
OUTCOME
compared to placebo or no treatment
Study

Taeusch 1979
Collaborative 1981
Kari 1994
Silver 1996
Dexiprom 1999
Qublan 2001

Dosage regimen

Neonates in
treatment arm

6 x 4mg
8 hrs apart
4 x 5mg
12 hrs apart
4 x 6mg
12 hrs apart
4 x 5mg
12 hrs apart (weekly
until delivery)
2 x 12mg
24 hrs apart
4 x 6mg
12 hrs apart
(+ 2nd course after 1
week)
POOLED

RDS

Neonatal death

RR

95% CI

RR

95% CI

54

0.64

[0.28, 1.47]

1.02

[0.43, 2.41]

378

0.70

[0.50, 1.00]

1.06

[0.67, 1.68]

95

0.73

[0.52, 1.02]

0.64

[0.19, 2.21]

54

0.98

[0.81, 1.20]

0.68

[0.27, 1.73]

105

1.16

[0.75, 1.79]

0.48

[0.15, 1.55]

72

0.54

[0.31, 0.95]

0.45

[0.29, 0.70]

758

0.80

[0.68, 0.93]

0.72

[0.55, 0.94]

Total events: 76(Treatment), 103(Control)

Test for heterogeneity chi-square=8.29 df=5 p=0.14 I =39.7%
Test for overall effect z=2.43 p=0.02
Source: Roberts and Dalziel 2006

17

While no optimal dosage regimen has conclusively been found, it is clear that dexamethasone is
effective in improving neonatal outcomes at various doses (Roberts and Dalziel 2006), including
the standard recommended by WHO and other guidelines (see section 9.2 Reference to existing
WHO and other clinical guidelines). As more evidence becomes available, recommendations on
optimal dose could be re-evaluated.
Table 5 shows reductions in two other adverse neonatal outcomes.
Table 5. Meta-analysis of additional outcomes of antenatal dexamethasone for preterm labor
(Roberts and Dalziel 2006).
Outcome

RR

95% CI

# of studies

Cerebroventricular hemorrhage
Necrotizing enterocolitis

0.63
0.46

[0.43, 0.91]
[0.27, 0.80]

5
4

Neonates in treatment
arm
360
574

Note that while all trials compared antenatal dexamethasone to placebo or no antenatal treatment,
babies in both groups received standard neonatal care. Mwansa et al. (2010) suggest that the
impact of ACS may be greater in LICs and MICs where standards and resources for neonatal care
are lower (see also 8.3 Prevention of RDS).
Variety of settings
All studies were conducted in hospital settings.
Four of the 6 dexamethasone RCTs were from HICs, while two (Dexiprom 1999 and Qublan
2001) were from UMICs. In keeping with the trend found by Mwansa et al. (2010) for all ACS
studies, impact on neonatal deaths was greater in UMICs (RR 0.46, 95% CI 0.30 to 0.73, 2
studies, 341 infants) than in HICs (RR 0.94, 95% CI 0.66 to 1.35, 4 studies, 1127 infants). Of the
two observational studies conducted in UMICs, one addressed antenatal dexamethasone (Nayeri
2005), and one considered outcomes from any ACS treatment, including both betamethasone and
dexamethasone. The observational study on dexamethasone similarly showed highly reduced
neonatal mortality (RR 0.39, 95% CI 0.18 to 0.84, 282 infants) and a greater effect than the
observational study of any ACS treatment (RR 0.61, 95% CI 0.43-0.85, 410 infants).
The trend between HICs and UMICs suggest that the impact of antenatal dexamethasone could be
even greater in lower-middle-income and low-income countries. If a correlation does exist
between low income and increased effect, it may again reflect the reduction in need for additional
and expensive resources (e.g., mechanical ventilation and surfactant) to treat rather than prevent
RDS, as well as lower fetal weights for gestational age.
Quality of evidence and basis for recommendation
Table 6 presents a GRADE analysis of the efficacy of antenatal dexamethasone for reducing
neonatal death and RDS. The overall quality of evidence for efficacy as well for safety (section
11.1), the Cochrane meta-analysis finding comparable outcomes and overall safety for
dexamethasone and betamethasone (sections 10.3 and 11.2), low cost and comparative cost
(sections 12.1 and 12.2), and widespread availability and comparative availability (sections 6 and
12.2) all provide strong support for use of antenatal dexamethasone.

18

Table 6. GRADE analysis of evidence for the efficacy and safety of antenatal dexamethasone for anticipated preterm labor.
Date: November 2012
Question: Should antenatal dexamethasone be used for preterm labor?
Settings: hospital, high-income (4) and middle-income (2) countries
Bibliography: Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2006; CD004454.

Quality assessment

No of patients

Effect
Quality

No of
studies

Design

Risk of
bias

Inconsistency Indirectness Imprecision

Other
Antenatal
Relative
Control
considerations dexamethasone
(95% CI)

Importance

Absolute

Neonatal death
6

Randomised no serious no serious

trials
risk of
inconsistency
bias1

no serious
indirectness

serious2

none

76/739
(10.3%)

103/729 RR 0.72
(14.1%) (0.55 to
0.94)

40 fewer per
CRITICAL

1000 (from 8 MODERATE

fewer to 64
fewer)

no serious
indirectness

no serious
imprecision

none

176/732
(24%)

210/725 RR 0.80
(29%) (0.68 to
0.93)

58 fewer per
1000 (from 20
fewer to 93
fewer)

no serious
indirectness

serious2,4

none

26/706
(3.7%)

31/714
(4.3%)

RR 0.92
(0.56 to
1.5)

3 fewer per
CRITICAL

1000 (from 19 MODERATE

fewer to 22
more)

no serious
indirectness

serious6

none

0/28
(0%)

0/18
(0%)

Respiratory distress syndrome

6

Randomised no serious no serious

trials
risk of
inconsistency
bias1

HIGH

CRITICAL

Fetal death
5

Randomised no serious no serious

trials
risk of
inconsistency
bias3

Maternal death
1

Randomised serious5
trials

no serious
inconsistency

19

LOW

CRITICAL

Chorioamnionitis
4

Randomised no serious no serious

trials
risk of
inconsistency
bias

no serious
indirectness

serious7

none

43/290
(14.8%)

31/285 RR 1.35
(10.9%) (0.89 to
2.05)

38 more per
IMPORTANT

1000 (from 12 MODERATE

fewer to 114
more)

no serious
indirectness

serious2

none

35/265
(13.2%)

21/271
(7.7%)

57 more per
IMPORTANT

1000 (from 3 MODERATE

more to 146
more)

Puerperal sepsis
4

Randomised no serious no serious

trials
risk of
inconsistency
bias

RR 1.74
(1.04 to
2.89)

One study with inadequate and 3 with unclear allocation concealment as assessed by Roberts and Dalziel, but overall low risk of bias
Sample size below optimal information size (OIS)
3
Unclear allocation concealment not likely to bias this outcome
4
95% confidence interval includes both appreciable harm and appreciable benefit
5
Inadequate allocation concealment
6
Small sample size
7
95% confidence interval includes both appreciable harm and no effect
2

20

10.3. Summary of available estimates of comparative effectiveness between dexamethasone

and betamethasone
Dexamethasone and betamethasone are the only ACS used in prevention of RDS that have been
extensively studied and recommended by WHO and other guidelines. Two Cochrane reviews
concluded that neither steroid can be clearly recommended over the other from an efficacy
perspective without further study. Most guidelines echo this conclusion in that they recommend
either ACS equivalently (ACOG 2011, Miracle et al. 2008, NIH 2004, RCOG 2010; see section
9.2 of this document).
Roberts and Dalziels 2006 Cochrane review showed a greater reduction of both RDS and
neonatal death for betamethasone compared to control than for dexamethasone compared to
control, with a reduction in RDS of 44% (RR 0.56, 95% CI 0.48 to 0.65, 14 studies, 2563 infants)
vs 20% (RR 0.80, 95% CI 0.68 to 0.93, 6 studies, 1457 infants) and a reduction in neonatal
mortality of 33% (RR 0.67, 95% CI 0.54 to 0.82, 12 studies, 2488 infants) vs 28% (RR 0.72, 95%
CI 0.55 to 0.94, 6 studies, 1468 infants).
The Brownfoot et al. 2008 Cochrane review included nine studies (919 women and 973 infants)
comparing dexamethasone regimens to betamethasone regimens. Dexamethasone was
substantially more effective in reducing intraventricular hemorrhage (RR 0.44, 95% CI 0.21 to
0.92, 4 studies, 549 infants). There were no statistically significant differences for other primary
outcomes including RDS (RR 1.06, 95% CI 0.88 to 1.27, 5 studies, 753 infants) and perinatal
death (RR 1.28, 95% CI 0.46 to 3.52, 2 studies, 596 infants).

11. Summary of comparative evidence on safety

11.1 Estimate of total patient exposure to ACS
Adoption of ACS in developed regions escalated quickly following an NIH statement in 1994,
and became a standard of care in much of the developed world. HICs currently see over 1.2
million preterm births annually (Blencowe et al. 2012). Simplifying to a decade of full coverage
for one million births a year gives an order-of-magnitude estimate of 10 million children exposed.
11.1 Safety of dexamethasone
For the mother
Of the six dexamethasone studies included in the 2006 Cochrane review, only one reported
number of maternal deaths, of which there were none in either the treatment or control arm.
Roberts and Dalziels subgroup analysis on dexamethasone showed a possibly elevated risk of
chorioamnionitis (RR 1.35, 95% CI 0.89 to 2.05, 4 studies, 575 women), puerperal sepsis (RR
1.74, 95% CI 1.04 to 2.89, 4 studies, 536 women), and fever requiring the use of antibiotics (RR
2.05, 95% CI 1.14 to 3.69, 1 study, 118 women).
Maternal pulmonary edema can occur when antenatal corticosteroids are used in combination
with tocolytic agents. This complication is more commonly associated with maternal infection,
fluid overload and multiple gestations. Pulmonary edema has not been reported when antenatal
corticosteroids are used alone (NIH 1994).
Safety for the fetus
No increase was seen in fetal deaths (RR 0.92, 95% CI 0.56 to 1.50, 5 studies, 1420 fetuses).

21

The WHO Model Formulary 2008, which includes information on use of dexamethasone during
pregnancy for several other indications, notes only a risk of intrauterine growth retardation on
prolonged or repeated systemic treatment. Antenatal dexamethasone treatment should consist of
a single course.
Safety for the child
No short-term adverse effects were identified in any study. Long-term data are sparse on
dexamethasone, but two follow-ups found no increased risk of death in childhood (RR 1.00, 95%
CI 0.38 to 2.63, 2 studies, 586 children).
A recent observational study evaluated development of prenatally exposed children compared to
control at 1 year (1554 infants), 3 years (1328 children), and 6 years (1297 children). The study
found no statistically significant adverse effect of dexamethasone treatment on verbal (VIQ) or
performance intelligence quotient (PIQ); or physical, mental (MDI), or psychomotor (PDI)
development indices (Liu et al. 2012).
Quality of evidence
Table 6 shows the output of a GRADE analysis of Cochrane-reviewed studies reporting safety
outcomes for antenatal dexamethasone.
Other risks
The mismatch between dosage and available vial size results in either wasted medicine from a
smaller ampoule, or heightened risk of infection due to contamination of multi-dose vials.
11.2. Comparative safety
Betamethasone is the only other ACS used in prevention of RDS that has been extensively
studied and recommended in WHO and other guidelines.
For the mother
In the 2006 Cochrane review, neither dexamethasone nor betamethasone influenced maternal
death or incidence of postnatal fever. Dexamethasone showed potentially higher risk of
chorioamnionitis, puerperal sepsis, and fever requiring the use of antibiotics, whereas an effect
was not detected for betamethasone.
No maternal outcomes were reported in any study included in the 2008 Cochrane review.
For the fetus or child
In the 2006 review, neither dexamethasone nor betamethasone showed an increase in fetal deaths.
No short-term adverse effects were identified for either dexamethasone or betamethasone, and
neither showed an increase in childhood deaths.
The 2008 review considered fetal deaths and neonatal deaths together as perinatal deaths, which
showed no statistically significant difference. The review also found no difference of occurrence
of neonatal sepsis. No other outcomes potentially related to safety were reported.
Summary of comparative safety
Dexamethasone may carry greater risk to mother, particularly of puerperal sepsis. Nonetheless,
evidence is insufficient to recommend one ACS over the other from a safety perspective without
further study (Roberts and Dalziel 2006, Brownfoot et al. 2008).

22

12. Summary of available data on comparative cost and cost-effectiveness

within the pharmacological class or therapeutic group
Dexamethasone is inexpensive and the most cost-effective ACS for prevention of RDS.
Note that dexamethasone is already on the WHO list for other indications.
12.1. Range of costs of the proposed medicine
The International Drug Price Indicator Guide (MSH 2010) was used to find current prices for
dexamethasone. Table 7 shows prices for 7 suppliers (a) and 8 buyers (b). The average supplier
price was US $0.77 per course of treatment (4 doses of 6 mg dexamethasone, totaling 24 mg
dexamethasone in 6 ml total injections), with a range from $0.44 to $1.38. The average buyer
price was $1.08 per course, with a range from $0.12 to $2.65 per course. The average price across
more than 10 Indian suppliers is $0.51 per course of treatment (Drugs Update 2011). The same
course would wholesale for about $5 in the USA (March 2012, San Francisco, CA).
Table 7a. Supplier prices for dexamethasone injection (source: MSH 2010)
Supplier
MISSION (Denmark)
MEDEOR/TZ
(Tanzania)
IMRES (Netherlands)
MEDS
(Kenya)
DURBIN (UK)
MEG (Netherlands)
UNFPA
(Denmark)
Mean price per
treatment
0.77

Package

Package price
(USD)

Price/ml (USD)

100 AMP (1 mL)

100 AMP (2 mL)

7.25
15.62

0.0725
0.0781

Price per treatment (4 x

6mg = 24 mg or 6 ml)
USD
0.44
0.47

100 AMP (1 mL)

1 AMP (1 mL)

8.20
0.12

0.0820
0.1170

0.49
0.70

100 AMP (1 mL)

100 AMP (1 mL)
100 AMP (1 mL)

14.40
17.00
23.00

0.1440
0.1700
0.2300

0.86
1.02
1.38

Median price per treatment

Lowest price per

treatment
0.44

Highest price per

treatment
1.38

High/low ratio

0.70

3.17

Table 7b. Buyer prices for dexamethasone injection (source: MSH 2010)
Buyer
CAMERWA (Rwanda)
DOMREPUB
(Dominican Republic)
GUATEMALA
LESOTHO
CRSS
(Costa Rica)
OECS/PPS
(Eastern Caribbean States)
NAMIBIA
SAFRICA
Mean price per treatment
1.08

Package

Package price
(USD)

Price/mL (USD)

100 AMP (1 mL)

1 AMP (2 mL)

2.01
0.04

0.0201
0.0206

Price per treatment (4 x

6mg = 24 mg or 6 mL)
USD
0.12
0.12

1 AMP (1 mL)
100 AMP (1 mL)
1 AMP (1 mL)

0.09
10.55
0.15

0.0854
0.1055
0.1500

0.51
0.63
0.90

100 VIAL (1 mL)

23.00

0.2300

1.38

10 AMP (2 mL)
1 AMP (1 mL)

7.69
0.44

0.3845
0.4424

2.31
2.65

Median price per treatment

Lowest price per

treatment
0.12

Highest price per

treatment
2.65

High/low ratio

0.77

22.01

In practice, due the available package size for dexamethasone injection, each dose of 6 mg
requires 1 ampoules (1 mL at 4 mg/mL), with mL wastage from the non-resealable ampoule.

23

Given a total of four doses, the real quantity of dexamethasone used therefore totals 8 mL instead
of 6 mL. Table 8 shows the real drug cost per treatment accounting for this necessary wastage.
Table 8. Price per treatment: hypothetical 6 mL (Tables 5a,b) vs actual 8 mL, accounting for 4
doses x mL wastage per dose
Supplier price per 6 mL
Supplier price per real
treatment (8 mL)
Buyer price per 6 mL
Buyer price per real treatment
(8 mL)

Mean
0.77
1.02

Median
0.70
0.94

Lowest
0.44
0.58

Highest
1.38
1.84

1.08
1.44

0.77
1.02

0.12
0.16

2.65
3.54

12.2 Comparative cost

The only other antenatal corticosteroid with proven efficacy is betamethasone. A course of
betamethasone costs an average of $37.44 (Pattinson et al. 2011b), or 26 times the average buyer
price for dexamethasone even accounting for wastage. The cost of dexamethasone per treatment
is thus less than 4% of the cost of betamethasone.
Injectable dexamethasone is widely available and low cost from many producers of generic drugs
as described above. Injectable betamethasone is less commonly available and more costly. For
this indication, most caregivers in developed countries prefer brand known as Celestone
Soluspan. The wholesale price is around US $40 for a full course in developed countries, and it
retails closer to US $70. Without ACS, newborns with respiratory distress syndrome require
additional NICU support to survive, often including pulmonary surfactants which cost hundreds
of dollars per treatment (Vidyasagar et al. 2011) and extended periods of time with more
sophisticated NICU treatments, which incur substantial additional costs.
12.3. Cost-effectiveness of ACS using betamethasone
Limited cost-effectiveness data for ACS is available, and estimates vary substantially. However,
the published data, which address ACS using betamethasone, indicate that ACS is a highly costeffective treatment overall, even with the more expensive drug. This section reviews published
data for betamethasone; see section 12.4 for estimates of cost-effectiveness for dexamethasone
based on these publications and comparative drug cost.
Cost per life saved global
A 2011 analysis by Pattinson et al. in The Lancet Stillbirth Series considered MNCH
interventions including ACS, and estimated costs and impact in 2015 for 99% coverage in the 68
countries included in the 2010 Countdown Decade Report. These 68 countries were prioritized
due to their high child mortality burden and together account for over 94% of child deaths
globally (Bhutta et al. 2010, Bryce et al. 2006).
The study authors provided detailed data used to estimate additional cost compared to baseline,
including an adjustment for increased delivery cost at coverage above 80%. The additional cost of
ACS at 99% coverage was 847 million USD. The total of 374,000 neonatal lives saved at 99%
coverage does not correspond exactly to the differential cost, but provides a useful rough
approximation given the low baseline coverage. This approach produces an estimate of 2,260
USD per life saved.
The total estimated cost of ACS before the high-coverage adjustment was 655 million USD,
based on average cost per case. The lower number is more relevant to cost-effectiveness, since

24

current coverage is as low as 10% in LICs and MICs and Pattinson et al. concede that reaching
even 60% coverage by 2015 may be unrealistic. The same simplification as before produces a low
approximation of 1,750 USD per life saved.
The study estimates were based on cost of betamethasone, WHO-CHOICE data for unit costs,
and statistical modelling using the Lives Saved Tool (LiST). Efficacy data was taken from the
Mwansa et al. meta-analysis (2010) of both betamethasone and dexamethasone studies in middleincome countries.
Cost per life saved global and regional
A 2008 cost-effectiveness analysis by Darmstadt et al. (a) reviewed several neonatal intervention
packages, including emergency obstetric care bundled with ACS and emergency obstetric care
alone. Comparing these two packages, and taking the midpoint for the range of costs and range of
outcomes (expressed as percentage of deaths averted), we can estimate the cost per life saved at
around $1200 globally and in Sub-Saharan Africa, and at $800 per life saved in South Asia.
Estimates were based on WHO-CHOICE data for unit costs and use of betamethasone (Darmstadt
et al. 2008b). Efficacy was based on an earlier Cochrane meta-analysis (Crowley 1996) of both
betamethasone and dexamethasone studies. Global estimates were for 60 countries, including 54
in Sub-Saharan Africa, North Africa, South Asia, and East Asia & Pacific.
Cost per DALY regional
A 2005 cost-effectiveness analysis by Darmstadt et al. (a) estimated average cost per DALY in
the WHO Afro-D region at 79.57 USD for 50% coverage and 86.70 USD for 95% coverage. This
study identified the threshold for cost-effectiveness at 4,143 USD/DALY for cost-effective
interventions and 1,381 USD/DALY for very cost-effective interventions (Darmstadt et al.
2005c).
A separate 2005 analysis by Adam et al. (a) of several neonatal intervention packages estimated
incremental cost-effectiveness of ACS at 117 USD per DALY averted in the Afro-E region, and
16,930 USD per DALY averted in the Sear-D region, assuming 95% coverage in both cases.
Both analyses used WHO-CHOICE estimates of facility costs and assumed administration of
betamethasone (Darmstadt et al. 2005b, Adam et al. 2005b).
Cost per case treated
Additional data provided by Pattinson et al. (2011) showed cost per case at 44.88 USD including
a course of betamethasone. Unit costs were estimated from the WHO-CHOICE database.
Cost per person to reach full coverage
Pattinson et al. (2011) estimated additional costs to scale up ACS along with 11 other MNCH
interventions at 10.9 billion USD total or 2.32 USD per person, already well below WHO and
World Bank criteria for cost-effectiveness. The 847 million USD cost of ACS provided by the
authors represents under 8% of the total package costs, or an additional 0.18 USD per person to
reach universal coverage for ACS alone.
12.4. Comparative cost-effectiveness of dexamethasone
The cost-effectiveness data above considers betamethasone rather than dexamethasone. However,
since the two interventions differ only in the drug injected and produce comparable outcomes

25

(33% vs 28% reduction in neonatal mortality, section 10.3), the fractional cost of dexamethasone
(less than 4%, section 12.2) clearly makes it more cost-effective than betamethasone.
Cost per case treated
The Pattinson et al. study (2011b) and additional detail from the authors provide a full breakdown
of costs for the course of betamethasone (37.44 USD); syringe, needle, and swab (0.13);
personnel (0.43 USD); training (0.07 USD); and clinic visit (6.81 USD).
To estimate cost per case for dexamethasone, we substitute the average buyer price per real
treatment (8 mL, 1.44 USD) for the estimated cost of betamethasone treatment, and add back the
other costs. To account for the regimen of 4 doses of dexamethasone, versus 2 doses for
betamethasone, we double costs for syringe, needle, and swab; personnel; and clinic visit.
This calculation results in a total cost per case of 16.25 USD, or just over one-third the cost per
case of antenatal betamethasone treatment.
Cost per life saved
In additional data provided by Pattinson et al. and used in their 2011 Lancet publication, the
estimated total cost of ACS using betamethasone at 99% coverage was 655 million USD based on
average cost per case multiplied by number of cases. Accounting for increased delivery cost
above 80% coverage resulted in the final cost estimate of 847 million USD, or an adjustment of
191 million USD. This delivery-related cost is independent of the drug.
The cost of dexamethasone treatment, calculated from comparative cost per case, yields an
estimate of 237 million USD before considering additional delivery costs at high coverage.
Applying the adjustment yields a final estimate of 428 million USD, or half the cost using
betamethasone.
Assuming the same efficacy as used by the study authors (Mwansa et al. 2010), and again
approximating differential lives saved by total lives saved, cost per life saved at 99% coverage
would be around 1,150 USD, or half the cost using betamethasone. At coverage levels below
80%, the estimated cost per life drops to only 634 USD, again just over one-third the cost using
betamethasone.
Cost per person to reach full coverage
Based on the 50% relative cost to scale up using dexamethasone, we estimate additional cost to
reach 99% antenatal dexamethasone coverage at 0.09 USD per person. This figure is based on the
published estimate of cost to scale up using betamethasone (Pattinson et al. 2011) and does not
involve the previous simplifying assumption.
12.5. Comparative cost and cost-effectiveness of prevention of RDS
ACS is a highly cost-effective intervention which prophylactically targets RDS. Standard
treatment of RDS requires both high costs and high skills. Treatment includes use of mechanical
ventilation (MV), continuous positive airway pressure (CPAP), and surfactant replacement
therapy (SRT) using artificial surfactants, which were recently added to the EML for this use
(Vidyasagar et al. 2011).
Artificial surfactants are costly, with four available products in India ranging from 1.5 to 8 mL
selling between 77 and 485 USD. In South Africa, two available products between 1.5 and 8 mL
ranged in price from 192 to 547 USD in public hospitals and from 467 to 1,470 USD in private

26

hospitals (Vidyasagar et al. 2011). Recommended surfactant dose varies by infant birthweight,
and most infants require more than one dose. For a very low birthweight infant at 1500 g, the
average price of the recommended single dose (Bassler and Poets 2008) was 296 USD in India,
461 USD in South African public hospitals, and 1,152 USD in South African private hospitals.
Management of RDS may require both mechanical ventilation and CPAP technologies, as well as
a method and skilled providers to deliver the surfactant (Vidyasagar et al. 2011). Surfactant
delivery is achieved either through invasive intubation or through one of several newer methods
requiring still greater skill for short intubation (Dani et al. 2010) or yet another device (nebulizer,
laryngeal mask, fine catheter, or gastric tube). RDS also increases the likelihood of long-term
disability, further adding to health care costs.

13. Summary of regulatory status of the medicine

13.1 Regulatory status
Dexamethasone is widely approved for numerous indications. For use in preterm labor,
dexamethasone is only known to be approved in very few countries including: Australia, and
New Zealand. In nearly all other countries, its specific antenatal use is off-label.
13.2 Rationale for off-label use
Despite the lack of approval for antenatal indications, the use of dexamethasone to prevent RDS
in preterm births is strongly supported by the following:
1. Proven efficacy (section 10) in addressing an important disease burden (section 8.1)
2. Proven safety (section 11)
3. Guidelines and recommendations from public health organizations including the WHO (section
9.2)
4. Common practice and high coverage in high-income countries (section 8.3)

14. Availability of pharmacopoeial standards

Dexamethasone sodium phosphate standards are available in
British Pharmacopoeia
International Pharmacopoeia
United States Pharmacopoeia
European Pharmacopoeia

27

15. Proposed adapted1 text for the WHO Model Formulary

Section: 29. Specific medicines for neonatal care
Dexamethasone Injection: 4 mg/ml dexamethasone phosphate (as disodium salt) in 1-ml or 2-ml
ampoule, or in 5-ml, 10-ml, 20-ml, 25-ml, or 30-ml multi-dose vial.
Uses: indicated for anticipated preterm birth within 7 days (either spontaneous or planned,
including preterm elective caesarean section), to improve fetal lung maturity, reduce respiratory
distress and other neonatal morbidity, and increase chances of neonatal survival.
Contraindications: presence of frank or systemic infection including tuberculosis or sepsis
(WHO 2000, RCOG 2010), systemic fungal infections (NIH Daily Med), cerebral malaria (FDA
MedWatch, July 2006), administration of live virus vaccines (WHO 2008)
Precautions: increased susceptibility to, and severity of, infection including chorioamnionitis and
puerperal sepsis (Roberts and Dalziel 2006); activation or exacerbation of tuberculosis,
amoebiasis and strongyloidiasis; risk of severe chickenpox in non-immune patients (varicellazoster immunoglobulin required if exposed to chickenpox); avoid exposure to measles (normal
immunoglobulin possibly required if exposed); diabetes mellitus; peptic ulcer; hypertension;
corneal perforation; caution is advised in women with chorioamnionitis (Miracle et al. 2008).
Dose: by intramuscular injection, ADULT, a single course of 4 injections of 6 mg each
administered 12 hours apart (24 mg total)
Adverse effects: fever (Roberts and Dalziel 2006); nausea, dyspepsia, malaise, hiccups;
hypersensitivity reactions including anaphylaxis.
Interactions: a list of interactions is given in Appendix 1 of the WHO Model Formulary 2008.
Rationale for inclusion: dexamethasone is a widely available, low-cost, and safe means of
reducing respiratory distress syndrome and consequent neonatal mortality following preterm
birth, the leading cause of neonatal mortality worldwide.
Note: treatment with antenatal dexamethasone should be followed by standard care for preterm
newborns.

The proposed text is adapted from the current WHO Model Formulary 2008, based on the 15 th Model List of Essential Medicines
2007, which included injectable dexamethasone phosphate (as disodium salt) for indications in section 3 Antiallergics and medicines
used in anaphylaxis, subsection 8.3 Hormones and antihormones (complementary list), and subsection 18.1 Adrenal hormones and
synthetic substitutes (dexamethasone has since been removed from this subsection of the EML).
1

Note that precautions and adverse effects (see 18.1 Adrenal hormones and synthetic substitutes) and risks in pregnancy (see Appendix
2 Pregnancy) related to long-term corticosteroid use are not included in this adaptation since only a single course of dexamethasone
should be used.

28

References
Adam T, Lim SS, Mehta S, Bhutta ZA, Fogstad H, Mathai M, Zupan J, Darmstadt GL. Cost effectiveness
analysis of strategies for maternal and neonatal health in developing countries. BMJ 2005; 331:1107.
Adam T, Lim SS, Mehta S, Bhutta ZA, Fogstad H, Mathai M, Zupan J, Darmstadt GL. Cost effectiveness
analysis of strategies for maternal and neonatal health in developing countries. Data supplement: Table 5
(E). BMJ 2005; 331:1107. Retrieved from
http://www.bmj.com/content/suppl/2005/11/10/331.7525.1107.DC1.
ACOG Committee on Obstetric Practice. Antenatal Corticosteroid Therapy for Fetal Maturation. ACOG
Committee Opinion No. 475. Obstetrics and Gynecology 2011; 117:422-4.
Bassler D and Poets C. Proposal for the inclusion of surfactant in the WHO model list of essential
medicines. Prepared for the Second Meeting of the Subcommittee of the Expert Committee on the
Selection and Use of Essential Medicines 2008 (approved). Retrieved from
http://www.who.int/selection_medicines/committees/subcommittee/2/surfactant.pdf.
Behrooz A, Shahbazian N, Behrooz B. Effect of dexamethasone on frequency of respiratory distres
syndrom among preterm newborns in Ahvaz Imam Khomeini Hospital. Jundishapur Scientific Medical
Journal 2010; 9(4)
Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller AB, Narwal R, Adler A, Garcia CV, Rohde S,
Say L, Lawn JE. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with
time trends since 1990 for selected countries: a systematic analysis and implications. Lancet 2012; 379:
2162-72.
Bhutta ZA, Chopra M, Axelson H, Berman P, Boerma T, Bryce J, et al. Countdown to 2015 decade report
(2000-10): taking stock of maternal, newborn, and child survival. Lancet 2010; 375: 2032-2044.
Brownfoot FC, Crowther CA, Middleton P. Different corticosteroids and regimens for accelerating fetal
lung maturation for women at risk of preterm birth (Review). Cochrane Database of Systematic Reviews
2008, Issue 4. Art. No.: CD00006764. DOI: 10.1002/14651858.CD006764.pub2.
Bryce J, Terreri N, Victora CG, Mason E, Daelmans B, Bhutta ZA, et al. Countdown to 2015: tracking
intervention coverage for child survival. Lancet 2006; 368: 1067-1076.
Crowley P. Prophylactic corticosteroids for preterm birth. Cochrane Database of Systematic Reviews, 1,
1996. (Withdrawn on publication of Roberts and Dalziel 2006.)
Crowther CA, Harding JE. Repeat doses of prenatal corticosteroids for women at risk of preterm birth for
preventing neonatal respiratory disease. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.:
CD003935. DOI: 10.1002/14651858.CD003935.pub2.
Dani C, Corsini I, Bertini G, Fontanelli G, Pratesi S, Rubaltelli FF. The INSURE method in preterm infants
of less than 30 weeks gestation. The Journal of Maternal-Fetal and Neonatal Medicine 2010; 23(0): 10241029.
Darmstadt GL, Bhutta ZA, Cousens S, Adam T, Walker N, de Bernis L, for the Lancet Neonatal Survival
Steering Team. Evidence-based, cost-effective interventions: how many newborn babies can we save?
Lancet 2005; 365(9463): 977-988.
Darmstadt GL, Bhutta ZA, Cousens S, Adam T, Walker N, de Bernis L, for the Lancet Neonatal Survival
Steering Team. Evidence-based, cost-effective interventions: how many newborn babies can we save? Web
Table 2. Lancet 2005; 365(9463). Retrieved from
http://image.thelancet.com/extras/05art1217webtable2.pdf.

29

Darmstadt GL, Bhutta ZA, Cousens S, Adam T, Walker N, de Bernis L, for the Lancet Neonatal Survival
Steering Team. Evidence-based, cost-effective interventions: how many newborn babies can we save? Web
Table 3. Lancet 2005; 365(9463). Retrieved from
http://image.thelancet.com/extras/05art1217webtable3.pdf
Darmstadt GL, Walker N, Lawn JE, Bhutta ZA, Haws RA, Cousens S. Saving newborn lives in Asia and
Africa: cost and impact of phased scale-up of interventions within the continuum of care. Health Policy and
Planning 2008; 23: 101-117.
Darmstadt GL, Walker N, Lawn JE, Bhutta ZA, Haws RA, Cousens S. Saving newborn lives in Asia and
Africa: cost and impact of phased scale-up of interventions within the continuum of care. Supplementary
Data 1: Web Table 2. Health Policy and Planning 2008; 23. Retrieved from
http://heapol.oxfordjournals.org/content/23/2/101/suppl/DC1.
Drugs Update. Dexamethasone brands in India. Retrieved December 8, 2011, from
http://www.drugsupdate.com/brand/showavailablebrands/794
FIGO and IPA. Joint FIGO and IPA statement on Prevention and Treatment of Preterm Births. August 3 rd,
2012. Retrieved from http://www.figo.org/news/new-download-joint-figo-and-ipa-statement-preventionand-treatment-preterm-births-0010282.
Gulmezoglu AM, Langer A, Piaggio G, Lumbiganon P, Villar J, Grimshaw J. Cluster randomised trial of
an active, multifaceted educational intervention based on the WHO Reproductive Health Library to
improve obstetric practices. BJOG. 2007; 114:16-23.
Harding JE, Pang J, Knight DB, Liggins GC. Do antenatal corticosteroids help in the setting of preterm
rupture of membranes? Am J Obstet Gynecol 2001.
Helji S, Maksi H, Misanovi V, Dizdarevi J. Antenatal corticosteroids in respiratory distress syndrome
prevention: efficacy in relation to treatment-delivery interval [article in Bosnian]. Med Arh 2009; 63(4):
200-2.
Howson CP, Kinney MV, Lawn JE (Eds). Born Too Soon: The Global Action Report on Preterm Birth.
March of Dimes, PMNCH, Save the Children, WHO. Geneva: World Health Organization, 2012.
Lawn JE, Segre J, Buekens P, Althabe F, Belizn JM, Jobe A, et al. Antenatal Corticosteroids for the
Reduction of Deaths in Preterm Babies. United Nations Commission for Life-Saving Commodities for
Women and Children. March 2012.
Lawn JE, Kinney MV, Black RE, Pitt C, Cousens S, Kerber K, Corbett E, Moran AC, Morrissey CS,
Oestergaard MZ. Newborn survival: a multi-country analysis of a decade of change. Health Policy Plan.
2012 Jul;27 Suppl 3:iii6-iii28.
Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of RDS in
premature infants. Pediatrics 1972; 50: 515-25.
Liu J, Feng ZC, Li J, Wang Q. Antenatal dexamethasone has no adverse effects on child physical and
cognitive development: a long-term cohort follow-up investigation. Journal of Maternal-Fetal and Neonatal
Medicine 2012; 25(11): 2369-71.
Liu L, Johnson HL, Cousens S, Perin J, Scott S, Lawn JE, Rudan I, Campbell H, Cibulskis R, Li M,
Mathers C, Black RE, for the Child Health Epidemiology Reference Group of WHO and UNICEF. Global,
regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends
since 2000. Lancet 2012; 379: 2151-61.

30

McClure EM, de Graft-Johnson J et al. A conference report on prenatal corticosteroid use in low- and
middle-income countries. Int J Gynaecol Obstet. 2011 Dec;115(3):215-9. Epub 2011 Sep 17.
Meneguel JF, Guinsburg R, Miyoshi MH et al. Antenatal treatment with corticosteroids for preterm
neonates: Impact on the incidence of respiratory distress syndrome and intra-hospital mortality. Sao Paulo
Med J, 2003;121:4552.
Miracle X, Di Renzo GC, Stark A, Fanaroff A, Carbonell-Estrany X, Salng E (Coordinators of WAPM
Prematurity working group). Guideline for the use of antenatal corticosteroids for fetal maturation.
Recommendations and guidelines for perinatal practice. Journal of Perinatal Medicine 2008; 36: 191-196.
MSH. International Drug Price Indicator Guide. Cambridge, MA: Management Sciences for Health, 2010.
Mwansa-Kambafwile J, Cousens S, Hansen T, Lawn JE. Antenatal steroids in preterm labour for the
prevention of neonatal deaths due to complications of preterm birth. International Journal of Epidemiology
2010; 39: 1122-1133.
Nayeri F, Movaghar-Nezhad K, Assar-Zadegan F. Effects of antenatal steroids on the incidence and
severity of respiratory distress syndrome in an Iranian hospital. Eastern Mediterranean Health Journal
2005; 11: 716-22.
NIH. The Effect of Corticosteroids for Fetal Maturation on Perinatal Outcomes. NIH Consensus Statement
1994; 12(2): 1-24.
NIH Consensus Development Panel. Antenatal Corticosteroids Revisited: Repeat Courses. NIH Consensus
Statement. Obstetrics and Gynecology 2001; 98: 144-150.
NIH Daily Med. Search results for dexamethasone. Retrieved July 27, 2012, from
http://dailymed.nlm.nih.gov/dailymed/search.cfm?startswith=dexamethasone&x=0&y=0
Oken E, Kleinman KP, Rich-Edwards J, Gillman MW. A nearly continuous measure of birth weight for
gestational age using a United States national reference. BMC Pediatrics 2003; 3:6.
Pattanittum P, Ewens MR, Laopaiboon M, Lumbiganon P, McDonald SJ, Crowther CA, et al. Use of
antenatal corticosteroids prior to preterm birth in four South East Asian countries within the SEA-ORCHID
project. BMC Pregnancy Childbirth 2008;8:47.
Pattinson R, Kerber K, Friberg IK, Belizan M, Lansky S, Weissman E, et al, for The Lancets Stillbirths
Series steering committee. Stillbirths: how can health systems deliver for mothers and babies? Lancet 2011;
377: 1610-23.
Pattinson R, Kerber K, Friberg IK, Belizan M, Lansky S, Weissman E, et al, for The Lancets Stillbirths
Series steering committee. Supplementary webappendix to Stillbirths: how can health systems deliver for
mothers and babies? Lancet 2011; 377: 1610-23. Retrieved from
http://download.thelancet.com/mmcs/journals/lancet/PIIS0140673610623069/mmc1.pdf?id=e16241398b8e
b460:684b93b8:139620daa77:-33c51345971960237.
PubMed abstract [no authors listed]. Risk of preterm delivery: a single course of antenatal corticosteroids.
Prescrire Int. 2010; 19(108): 168-9.
RCOG. Antenatal Corticosteroids to Reduce Neonatal Morbidity and Mortality. Green-top Guideline No. 7,
4th ed. London: RCOG; 2010.
Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of
preterm birth (Review). Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD00004454.
DOI: 10.1002/14651858.CD004454.pub2.

31

Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC, et al. Neonatal outcomes of extremely
preterm infants from the NICHD Neonatal Research Network. Pediatrics 2010;126(3):44356.
Tarunotai T. Cardiac Function of Preterm Infants Whose Mothers Received Dexamethasone. Vajira
Medical Journal 2008; 52(3): 201-208.
UN. The Millenium Development Goals Report. New York: United Nations, 2012.
Vidyasagar D, Velaphi S, Bhat VB. Surfactant Replacement Therapy in Developing Countries.
Neonatology 2011; 99:355-366.
Walker N, Fischer-Walker C, Bryce J, Bahl R, Cousens S, for the CHERG Review Groups on Intervention
Effects. Standards for CHERG reviews of intervention effects on child survival. International Journal of
Epidemiology 2010; 39 (suppl 1): i21-i31.
Whitsett JA, Ward RR, Warner BB, Wert SE, Pryhuber GS. Acute respiratory disorders. In: Averys
Neonatology: Pathophysiology and Management of the Newborn, 6th ed. Philadelphia: Lippincott Williams
& Wilkins, 2005, pp. 553-577.
World Bank. Country and Lending Groups. Retrieved July 26, 2012, from
http://data.worldbank.org/about/country-classifications/country-and-lending-groups
WHO. Essential medicines for children: Priority life-saving medicines for women and children. Retrieved
July 29, 2012, from http://www.who.int/childmedicines/prioritymedicines/en/index.html.
WHO. The global burden of disease: 2004 update. Geneva: World Health Organization, 2008.
WHO. Integrated Management of Pregnancy and Childbirth Managing Complications in Pregnancy and
Childbirth: A guide for midwives and doctors. Geneva: World Health Organization, 2000. Reprinted 2007.
WHO. Model Formulary 2008. Based on the 14 th Model List of Essential Medicines 2007. Geneva: World
Health Organization.
WHO. Priority medicines for mothers and children 2011. Geneva: World Health Organization.
WHO. Priority life-saving medicines for women and children 2012. Geneva: World Health Organization.
WPAM and Matres Mundi International. Recommendations and Guidelines for Perinatal Medicine.
Barcelona: Matres Mundi, 2007.

32

Appendix A. Dexamethasone Injection Manufacturers and Trade Names

Product name
Deccan
Decrina
Demisone Inj
Dex-V
Dexar
Dexona
Intradex
Stedex Inj
Wymesone
Trofinan
Decadron
Fortecortin Inject
Dexacort
Dexamethasone Sodium Phosphate
Dexamethasone Sodium Phosphate
for Injection, USP
Dexamethasone Sodium Phosphate
Injection, USP
Dexamethasone Sodium Phosphate
Injection, USP
Dexamethasone Sodium Phosphate
Injection
Dexamethasone OMEGA
Dexamethasone Sodium Phosphate
Injection

Composition
4 mg/ml x 2 ml
4 mg/ml x 2 ml
4 mg/ml x 10 ml or 20 ml
multi-dose vials
4 mg/ml x 2 ml
4 mg/ml x 2 ml
4 mg/ml x 2 ml
4 mg/ml x 2 ml
4 mg/ml x 2 ml
4 mg/ml x 2 ml
4 mg/ml x 2 ml
4 mg/ml x 2 ml
4 mg/ml x 1 ml or 2 ml
4 mg/ml x 1 ml or 2 ml
4 mg/ml (unknown size)
4 mg/ml x 1 ml
OR 5 ml or 30 ml multi-dose vials
4 mg/ml x 1 ml
OR 5 ml or 30 ml multi-dose vials
4 mg/ml x 1 ml
OR 5 ml or 30 ml multi-dose vials
4 mg/ml x 30 ml multi-dose vial

Company
Wockhardt (Merind)
Intra Labs
Cadilla (Genvista)

Country
India
India
India

Vensat
Rass HC
Zydus (Alidac)
Intra Labs
Ind-Swift
Wyeth
BIOL
Merck
Merck
Teva
Sandoz
Pfizer

India
India
India
India
India
India
Argentina
US
US
US
US
US

American Regent, Inc

US

APP Pharmaceuticals
(Fresenius Kabi)
Cardinal Health

US

4 mg/ml x 1 ml
OR 5 ml or 25 ml multi-dose vials
4 mg/ml x 5 ml multi-dose vial

Omega Laboratories

Canada

Cytex Pharmaceuticals

Canada

33

US

Appendix B. National and Regional Guidelines Recommending Antenatal Dexamethasone for Preterm Labor
Country or
Region

Organization

Year

Publication

Source

USA

Institute for Clinical Systems Improvement

(ICSI)

2011

Health Care Guideline: Management of Labor

PDF

USA

American Congress of of Obstetricians and

Gynecologists (ACOG)

2011

Committee Opinion No. 475: Antenatal Corticosteroid Therapy

for Fetal Maturation

HTML

2007

ACOG Practice Bulletin No. 80: Premature rupture of

membranes: Clinical management guidelines for obstetriciangynecologists

Abstract

1994

Consensus Statement: The Effect of Corticosteroids for Fetal

Maturation on Perinatal Outcomes

Abstract

2000

Consensus Statement: Antenatal Corticosteroids Revisited:

Repeat Courses

HTML

USA

National Institutes of Health (NIH)

Europe

European Association of Perinatal Medicine

2010

European Consensus Guidelines on the Management of Neonatal

Respiratory Distress Syndrome in Preterm Infants

PDF

UK

Royal College of Obstetricians and

Gynaecologists

2010

Green-top Guideline No. 7: Antenatal Corticosteroids to Reduce

Neonatal Morbidity and Mortality

PDF

France

Collge National des Gyncologues et

Obsttriciens Franais (CNGOF)

2002

Recommandations pour la Pratique Clinique : La menace

d'accouchement prmatur membranes intactes (Clinical
Practice Recommendations: The threat of premature delivery
with intact membranes)

HTML

Canada

BC Childrens and BC Womens Hospital &

Health Centre

2008

Management of the newborn delivered at the threshold of

viability

HTML

Canada

The Society of Obstetricians and

2002

Preterm Birth: Clinical Practice Guidelines

PDF

34

Gynaecologists of Canada (SOGC)

2003

Committee Opinion: Antenatal Corticosteroid Therapy for Fetal

Maturation

PDF

Argentina

Ministerio de Salud (Ministry of Health)

2010

Guia para el diagnstico y tratamiento de la

Hipertensin en el Embarazo (Guide to the diagnosis and
treatment of Hypertension in Pregnancy)

PDF

Argentina

Federacin Argentina de Sociedades de

Ginecologa y Obstetricia (FASGO,
Argentinian Federation of Societies of
Gynecology and Obstetrics)

2006

Consenso : Manejo de la Preeclampsia

Grave - Eclampsia (Consensus: Management of Severe Preeclampsia/Eclampsia)

PDF

Argentina

Colegio de Mdicos de la Provincia de

Buenos Aires Distrito III (Medical
Association of the Province of Buenos Aires
District III)

2004

Gua de Procedimientos en Obstetricia, Captulo 9: Parto

prematuro (Obstetrical Procedures Guide, Chapter 9: Preterm
birth)

PDF

Colombia

Secretara Distrital de Salud de Bogot, D. C.

(Department of Health of Bogota),
Asociacin Bogotana de Obstetricia y
Ginecologa (Asbog, Bogotan Association of
Obstetrics and Gynecology)

2002 or
later

Gua de manejo del sndrome hipertensivo del embarazo

(Management guide for hypertension in pregnancy)

PDF

Brazil

Ministerio de Saude (Ministry of Health),

FEBRASGO

2004

Urgncias e Emergncias Maternas: Guia para diagnstico e

conduta em situaes de risco de morte materna (Guide to
diagnosis and management in situations of risk of maternal
death)

PDF

Brazil

Federao Brasileira das Sociedades de

Ginecologia e Obstetrcia (FEBRASGO,
Brazilian Federation of Societies of
Gynecology and Obstetrics)

2004

Diabete e Hipertenso na Gravidez: Manual de Orientao, Uso

dos Corticosterides (Diabetes and Hypertension in Pregnancy:
Guidance Manual, Section: Use of Corticosteroids)

PDF

Peru

Sociedad Peruana de Obstetricia y

Ginecologa (Peruvian Society of Obstetrics
and Gynecology)

2012

Manejo del RPM Pretermino (Management of Preterm PROM)

HTML

35

Chile

Ministerio de Salud (Ministry of Health)

2011

Guia Clinica AUGE: Sndrome de Dificultad Respiratoria en el

recin nacido (Clinical Guide: Respiratory Distress Syndrome in
the newborn)

PDF

Uruguay

Ministerio de Salud Publica (Ministry of

Public Health)

2007

Guas en Salud Sexual y Reproductiva, Normas de atencin de la

Mujer embarazada (Guidelines on Sexual and Reproductive
Health, Chapter: Standards of Care for Pregnant Women)

PDF

Dominican
Republic

Secretara de Estado de Salud Pblica y

Asistencia Social (Ministry of Public Health
and Welfare)

2004

Protocolo de Atencin en Hospitales 2do y 3er Nivel.Obstetricia

y Ginecologa (2nd- and 3rd-level Care Protocols in Obstetrics and
Gynecology)

PDF

Malaysia

Perinatal Society of Malaysia, Malaysian

Paediatric Association, Obstetrical and
Gynaecological Society of Malaysia,
Academy of Medicine Chapter of Paediatrics,
Academy of Medicine Chapter of Obstetrics
and Gynaecology

2001

Guideline on the use of Antenatal Corticosteroids to Prevent

Respiratory Distress Syndrome

PDF

Singapore

Ministry of Health

2001

Clinical Practice Guidelines: Management of

Preterm Labour

PDF

36

National guidelines reported in a 2011 survey of health authorities by country

Country

Respondent
Organization

Respondent Position

Publication title and/or description

Afghanistan

Ministry of Health

RHM&E officer

IMPACT & pre-service midwifery curriculum

Ethiopia

Ministry of Health

Maternal Health Advisor

Management protocol on selected obstetric topics

Ghana

Ghana Health Services

Safe Motherhood Officer

National Safe Motherhood Service Protocol for providers of maternal and

newborn services

Kenya

Jhpiego

RH Advisor

National MNH guidelines management of preterm labor

Mozambique

Save the Children

Program Coordinator

Quality Assurance Standards for Health Facilities

Rwanda

Ministry of Health

Maternal Death Audit

Specialist

BEmONC documents and national protocols

Honduras

Secretary of Health

Chief Technical Advisor

Part of preterm and newborn care

El Salvador

Ministry of Health

SRH Coordinator

National guideline for antenatal, prenatal, delivery and newborn care

Panama

Ministry of Health

Child Division National

Chief

Part of guideline

Belize

Ministry of Health

Family and Community

Healh

Obstetric care protocol

Nicaragua

MINSA

Chief Ob-Gyn

separate guideline for ACS

Bolivia

Ministry of Health

Director of Maternal Health

not specified

37