0

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 Clínica y Sanitaria (IECS)

Ravignani 2024

Buenos Aires 1414

Argentina

Tel: +5411 47778767 ext. 17

falthabe@gmail.com

falthabe@iecs.org.ar

1

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

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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 low-

income 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 meta-

analysis 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).

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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

child’s 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 Gülmezoglu

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 Women’s and Children’s 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 ½ ml (2 mg) per

dose, or 2 ml (8 mg) per 4-dose treatment (see 9.1. Dosage regimen and duration).

4

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 sub-

Saharan 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).

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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).

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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).

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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 two-

thirds 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 first 48 hours of life (RR 0.56, 95% CI 0.38 to 0.85, five studies, 1319

infants).

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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).

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 upper-

middle-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-

Risk ratio.1 1 10

Study % Weight

Risk ratio

(95% CI)

0.87 (0.63,1.19) Liggins 1972 24.3

0.19 (0.02,1.54) Block 1977 1.8

1.02 (0.43,2.41) Taeusch 1979 3.0

0.27 (0.09,0.81) Doran 1980 4.3

0.23 (0.07,0.79) Schutte 1980 4.2

1.06 (0.67,1.68) Collaborative 1981 10.9

1.00 (0.07,15.00) Nelson 1985 0.3

0.32 (0.01,7.45) Parsons 1988 0.5

0.84 (0.43,1.63) Gamsu 1989 5.8

0.78 (0.30,2.06) Morales 1989 2.9

0.99 (0.47,2.10) Garite 1992 3.4

0.64 (0.19,2.21) Kari 1994 2.1

1.03 (0.07,15.82) Lewis 1996 0.3

0.68 (0.27,1.73) Silver 1995 3.1

0.50 (0.28,0.89) Amorim 1999 9.6

0.48 (0.15,1.55) Dexiprom 1999 2.8

0.45 (0.29,0.70) Qublan 2001 13.8

0.46 (0.23,0.93) Fekih 2002 6.9

0.69 (0.58,0.81) Overall (95% CI)

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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.

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

Risk ratio.1 1 10

Study % Weight

Risk ratio

(95% CI)

0.50 (0.28,0.89) Amorium 1999 28.9

0.48 (0.15,1.55) Dexiprom 1999 8.4

0.45 (0.29,0.70) Qublan 2001 41.8

0.46 (0.23,0.93) Fekih 2002 20.9

0.47 (0.35,0.64) Overall (95% CI)

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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.

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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).

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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

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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

14

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 All cases (except contraindication) Special cases

WHO < 37 weeks

NIH/ACOG 24-34 weeks

RCOG 24-34+6

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

WPAM 24-34 weeks > 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

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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.

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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.

17

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 (Heljić 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 Heljić 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

Study Dosage regimen Neonates in

treatment arm

OUTCOME compared to placebo or no treatment

RDS Neonatal death

RR 95% CI RR 95% CI

Taeusch 1979 6 x 4mg

8 hrs apart 54 0.64 [0.28, 1.47] 1.02 [0.43, 2.41]

Collaborative 1981 4 x 5mg

12 hrs apart 378 0.70 [0.50, 1.00] 1.06 [0.67, 1.68]

Kari 1994 4 x 6mg

12 hrs apart 95 0.73 [0.52, 1.02] 0.64 [0.19, 2.21]

Silver 1996 4 x 5mg

12 hrs apart (weekly until delivery)

54 0.98 [0.81, 1.20] 0.68 [0.27, 1.73]

Dexiprom 1999 2 x 12mg

24 hrs apart 105 1.16 [0.75, 1.79] 0.48 [0.15, 1.55]

Qublan 2001

4 x 6mg 12 hrs apart

(+ 2nd course after 1

week)

72 0.54 [0.31, 0.95] 0.45 [0.29, 0.70]

POOLED 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 I² =39.7%

Test for overall effect z=2.43 p=0.02

Source: Roberts and Dalziel 2006

18

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 Neonates in treatment

arm

Cerebroventricular hemorrhage 0.63 [0.43, 0.91] 5 360

Necrotizing enterocolitis 0.46 [0.27, 0.80] 4 574

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.

19

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 Importance

No of studies

Design Risk of

bias Inconsistency Indirectness Imprecision

Other considerations

Antenatal dexamethasone

Control Relative (95% CI)

Absolute

Neonatal death

6 Randomised trials

no serious risk of bias

1

no serious inconsistency

no serious indirectness

serious2 none 76/739

(10.3%) 103/729 (14.1%)

RR 0.72 (0.55 to 0.94)

40 fewer per 1000 (from 8 fewer to 64

fewer)

MODERATE

CRITICAL

Respiratory distress syndrome

6 Randomised trials

no serious risk of bias

1

no serious inconsistency

no serious indirectness

no serious imprecision

none 176/732 (24%)

210/725 (29%)

RR 0.80 (0.68 to 0.93)

58 fewer per 1000 (from 20

fewer to 93 fewer)

HIGH

CRITICAL

Fetal death

5 Randomised trials

no serious risk of bias

3

no serious inconsistency

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 1000 (from 19

fewer to 22 more)

MODERATE

CRITICAL

Maternal death

1 Randomised trials

serious5 no serious

inconsistency no serious indirectness

serious6 none 0/28

(0%) 0/18 (0%)

- - LOW

CRITICAL

20

Chorioamnionitis

4 Randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious7 none 43/290

(14.8%) 31/285 (10.9%)

RR 1.35 (0.89 to 2.05)

38 more per 1000 (from 12 fewer to 114

more)

MODERATE

IMPORTANT

Puerperal sepsis

4 Randomised trials

no serious risk of bias

no serious inconsistency

no serious indirectness

serious2 none 35/265

(13.2%) 21/271 (7.7%)

RR 1.74 (1.04 to 2.89)

57 more per 1000 (from 3 more to 146

more)

MODERATE

IMPORTANT

1 One study with inadequate and 3 with unclear allocation concealment as assessed by Roberts and Dalziel, but overall low risk of bias

2 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

21

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 Dalziel’s 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 Dalziel’s 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).

22

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).

23

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 Package Package price

(USD) Price/ml (USD) Price per treatment (4 x

6mg = 24 mg or 6 ml)

USD

MISSION (Denmark) 100 AMP (1 mL) 7.25 0.0725 0.44 MEDEOR/TZ

(Tanzania)

100 AMP (2 mL) 15.62 0.0781 0.47

IMRES (Netherlands) 100 AMP (1 mL) 8.20 0.0820 0.49 MEDS

(Kenya)

1 AMP (1 mL) 0.12 0.1170 0.70

DURBIN (UK) 100 AMP (1 mL) 14.40 0.1440 0.86 MEG (Netherlands) 100 AMP (1 mL) 17.00 0.1700 1.02

UNFPA

(Denmark)

100 AMP (1 mL) 23.00 0.2300 1.38

Mean price per treatment

Median price per treatment Lowest price per treatment

Highest price per treatment

High/low ratio

0.77 0.70 0.44 1.38 3.17

Table 7b. Buyer prices for dexamethasone injection (source: MSH 2010) Buyer Package Package price

(USD) Price/mL (USD) Price per treatment (4 x

6mg = 24 mg or 6 mL)

USD

CAMERWA (Rwanda) 100 AMP (1 mL) 2.01 0.0201 0.12 DOMREPUB

(Dominican Republic)

1 AMP (2 mL) 0.04 0.0206 0.12

GUATEMALA 1 AMP (1 mL) 0.09 0.0854 0.51 LESOTHO 100 AMP (1 mL) 10.55 0.1055 0.63

CRSS

(Costa Rica)

1 AMP (1 mL) 0.15 0.1500 0.90

OECS/PPS

(Eastern Caribbean States)

100 VIAL (1 mL) 23.00 0.2300 1.38

NAMIBIA 10 AMP (2 mL) 7.69 0.3845 2.31 SAFRICA 1 AMP (1 mL) 0.44 0.4424 2.65

Mean price per treatment Median price per treatment Lowest price per treatment

Highest price per treatment

High/low ratio

1.08 0.77 0.12 2.65 22.01

In practice, due the available package size for dexamethasone injection, each dose of 6 mg

requires 1½ ampoules (1 mL at 4 mg/mL), with ½ mL wastage from the non-resealable ampoule.

24

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 ½ mL wastage per dose Mean Median Lowest Highest

Supplier price per 6 mL 0.77 0.70 0.44 1.38

Supplier price per real

treatment (8 mL)

1.02 0.94 0.58 1.84

Buyer price per 6 mL 1.08 0.77 0.12 2.65

Buyer price per real treatment

(8 mL)

1.44 1.02 0.16 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 cost-

effective 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

25

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 middle-

income 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

26

(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

27

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

28

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 (varicella-

zoster 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.

1 The proposed text is adapted from the current WHO Model Formulary 2008, based on the 15th 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).

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.

29

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33

Appendix A. Dexamethasone Injection Manufacturers and Trade Names

Product name Composition Company Country

Deccan 4 mg/ml x 2 ml Wockhardt (Merind) India

Decrina 4 mg/ml x 2 ml Intra Labs India

Demisone Inj 4 mg/ml x 10 ml or 20 ml

multi-dose vials

Cadilla (Genvista) India

Dex-V 4 mg/ml x 2 ml Vensat India

Dexar 4 mg/ml x 2 ml Rass HC India

Dexona 4 mg/ml x 2 ml Zydus (Alidac) India

Intradex 4 mg/ml x 2 ml Intra Labs India

Stedex Inj 4 mg/ml x 2 ml Ind-Swift India

Wymesone 4 mg/ml x 2 ml Wyeth India

Trofinan 4 mg/ml x 2 ml BIOL Argentina

Decadron 4 mg/ml x 2 ml Merck US

Fortecortin Inject 4 mg/ml x 1 ml or 2 ml Merck US

Dexacort 4 mg/ml x 1 ml or 2 ml Teva US

Dexamethasone Sodium Phosphate 4 mg/ml (unknown size) Sandoz US

Dexamethasone Sodium Phosphate

for Injection, USP

4 mg/ml x 1 ml

OR 5 ml or 30 ml multi-dose vials

Pfizer US

Dexamethasone Sodium Phosphate

Injection, USP

4 mg/ml x 1 ml

OR 5 ml or 30 ml multi-dose vials

American Regent, Inc US

Dexamethasone Sodium Phosphate

Injection, USP

4 mg/ml x 1 ml

OR 5 ml or 30 ml multi-dose vials

APP Pharmaceuticals

(Fresenius Kabi)

US

Dexamethasone Sodium Phosphate

Injection

4 mg/ml x 30 ml multi-dose vial Cardinal Health US

Dexamethasone OMEGA 4 mg/ml x 1 ml

OR 5 ml or 25 ml multi-dose vials

Omega Laboratories Canada

Dexamethasone Sodium Phosphate

Injection

4 mg/ml x 5 ml multi-dose vial Cytex Pharmaceuticals Canada

34

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 obstetrician-

gynecologists

Abstract

USA National Institutes of Health (NIH) 1994 Consensus Statement: The Effect of Corticosteroids for Fetal

Maturation on Perinatal Outcomes

Abstract

2000 Consensus Statement: Antenatal Corticosteroids Revisited:

Repeat Courses

HTML

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 Collège National des Gynécologues et

Obstétriciens Français (CNGOF)

2002 Recommandations pour la Pratique Clinique : La menace

d'accouchement prématuré à membranes intactes (Clinical

Practice Recommendations: The threat of premature delivery

with intact membranes)

HTML

Canada BC Children’s and BC Women’s 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

35

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 diagnóstico y tratamiento de la

Hipertensión en el Embarazo (Guide to the diagnosis and

treatment of Hypertension in Pregnancy)

PDF

Argentina Federación Argentina de Sociedades de

Ginecología y Obstetricia (FASGO,

Argentinian Federation of Societies of

Gynecology and Obstetrics)

2006 Consenso : Manejo de la Preeclampsia

Grave - Eclampsia (Consensus: Management of Severe Pre-

eclampsia/Eclampsia)

PDF

Argentina Colegio de Médicos de la Provincia de

Buenos Aires Distrito III (Medical

Association of the Province of Buenos Aires

District III)

2004 Guía de Procedimientos en Obstetricia, Capítulo 9: Parto

prematuro (Obstetrical Procedures Guide, Chapter 9: Preterm

birth)

PDF

Colombia Secretaría Distrital de Salud de Bogotá, D. C.

(Department of Health of Bogota),

Asociación Bogotana de Obstetricia y

Ginecología (Asbog, Bogotan Association of

Obstetrics and Gynecology)

2002 or

later

Guía de manejo del síndrome hipertensivo del embarazo

(Management guide for hypertension in pregnancy)

PDF

Brazil Ministerio de Saude (Ministry of Health),

FEBRASGO

2004 Urgências e Emergências Maternas: Guia para diagnóstico e

conduta em situações de risco de morte materna (Guide to

diagnosis and management in situations of risk of maternal

death)

PDF

Brazil Federação Brasileira das Sociedades de

Ginecologia e Obstetrícia (FEBRASGO,

Brazilian Federation of Societies of

Gynecology and Obstetrics)

2004 Diabete e Hipertensão na Gravidez: Manual de Orientação, Uso

dos Corticosteróides (Diabetes and Hypertension in Pregnancy:

Guidance Manual, Section: Use of Corticosteroids)

PDF

Peru Sociedad Peruana de Obstetricia y

Ginecología (Peruvian Society of Obstetrics

and Gynecology)

2012 Manejo del RPM Pretermino (Management of Preterm PROM) HTML

36

Chile Ministerio de Salud (Ministry of Health) 2011 Guia Clinica AUGE: Síndrome de Dificultad Respiratoria en el

recién nacido (Clinical Guide: Respiratory Distress Syndrome in

the newborn)

PDF

Uruguay Ministerio de Salud Publica (Ministry of

Public Health)

2007 Guías en Salud Sexual y Reproductiva, Normas de atención de la

Mujer embarazada (Guidelines on Sexual and Reproductive

Health, Chapter: Standards of Care for Pregnant Women)

PDF

Dominican

Republic

Secretaría de Estado de Salud Pública y

Asistencia Social (Ministry of Public Health

and Welfare)

2004 Protocolo de Atención en Hospitales 2do y 3er Nivel.Obstetricia

y Ginecología (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

37

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