Antenatal Corticosteroids

PRODUCT PROFILE

Potential Lives Saved/Year: 400,000 newborns from preterm birth complications¹

>>>Read the full case study (PDF)

Problem and Proposed Intervention

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Lydia Atinbusa practices Kangaroo Mother Care to help stabilize the heart rate and temperature of her pre-term baby, in Ghana in 2012. ©UNICEF/Logan

Preterm birth is one of the highest burden single conditions highlighted in the Global Burden of Disease. An estimated 1 in 10 babies are born preterm each year2, and over one million die from preterm birth complications 3 most commonly due to lung immaturity called Respiratory Distress Syndrome (RDS). Of those that survive without proper intervention, millions have long-term disabilities and a higher risk of adult chronic disease that put a major strain on families and economic potential globally. There is an important preterm birth survival gap between high-income and low-income countries, due to differences in access to proven interventions, leaving an unethically large majority of the deaths in low-income countries. Although neonatal intensive care is widely available in high income settings, major reductions in deaths due to preterm birth complications are possible without this – for example both the UK and the US reduced their newborn death rates from 40 to 15 per 1000 without intensive care.4

Around 400,000 lives could be saved each year, with effective, high coverage Antenatal Corticosteroid (ANCS) injection interventions implemented in the highest burden countries.1 ANCS injection for women at risk of preterm delivery is the most effective intervention to reduce the risk of RDS for preterm babies5 and is the standard-of-care in most high-income countries. According to a meta-analysis of 18 randomized controlled trials (RCTs) in a Cochrane Review, ANCS injection for women with preterm labor has been found to reduce neonatal mortality by 31% and moderate/severe RDS by 45%5. Currently, there is an estimated 90% coverage of indicated cases of women in preterm labor in high-income countries with ANCS injections, compared to an estimated 10% coverage in middle/low income, high burden countries.4 Immediate action is needed to close this coverage gap and save lives.

See also the work that the Antenatal Corticosteroids Working Group is doing.

ANCS Injection characteristics:

Drug/Active Ingredient: Betamethasone (Beta) – combination of betamethasone phosphate and betamethasone acetate Dexamethasone (Dexa)
Proposed Indication: Triggers production of surfactant in fetal lung, reducing or negating need for ventilation.  Administration effect is greatest 31-36 weeks gestation, which is when over 80% of preterm births occur.
Formulation6: injection 5.7 mg/ml as betamethasone sodium phosphate 3.9 mg (in solution) or betamethasone acetate 3 mg (in suspension) in an aqueous vehicle injection 4 mg dexamethasonephosphate (as disodium salt) in 1-ml ampoule
Dose: 2 Intramuscular injections spaced 24 hours apart totaling 24mg of active ingredient 4 Intramuscular injections spaced 12 hours apart totaling 24mg of active ingredient
Avg. Cost: ~$40 for a full course (brand name Celestone Soluspan)[1] ~$0.51 per course of treatment 7

[1] The ~$40/full course estimate comes from an American company, while the ~$0.51/treatment comes from an Indian website (as cited).

Initial Findings from Product Case Study Working Paper

* Note: The strengths and challenges outlined below are initial findings from a longer working paper developed to analyze the current global situation of each product. The findings are presented below to catalyze further thinking and discussion in order to finalize a list of issues and recommendations. The full working paper texts are forthcoming.

Strengths Challenges
Policy and Regulation
Global * Dexa is listed on the WHO Essential Medicines List (WHO EML)6
* Dexa and Beta are both listed on the WHO Priority Medicines for Mothers and Children for preterm indications8
* Dexa is on the WHO EML[1], but not for preterm indications6.*Beta is not on the WHO EML.
National * Antenatal Corticosteroids are widely recommended by obstetric societies. In most high income countries, irrespective of registration, antenatal corticosteroids are widely used and failure by a physician to provide them when indicated would run a high risk of litigation. * In many countries, product use for fetal lung maturation is often off-label and only Argentina, Australia and New Zealand have registered ANCS for the indication of fetal lung maturation.
Product specification & characteristics * Minimal side effects (both products)
* Beta requires fewer injections than Dexa (2 versus 4)
* One Cochrane Review found that Beta resulted in a greater reduction in RDS than Dexa
* One Cochrane Review found that Dexa was associated with a lower incidence of intraventricular hemorrhage
* ANCS has maximal effect if administered at least 24 hours before birth, and some effect within a few hours before birth, which can be difficult in low-income settings where obstetric care is limited and home births are common.
* Beta is less stable than Dexa at high temperatures, which may be an important consideration for low/middle-income countries.
* Cochrane Review found that Dexa may be associated with puerperal sepsis, although small numbers in the trial.
Financing, Procurement & Supply * Dexa: Widely available and low cost (average $0.51 per course of treatment 7). * Beta:  High price ~$40/course and supply shortages hamper widespread use.
* ANCS injections in general: 90% coverage of indicated cases of women in preterm labor in high-income countries, compared to an estimated 10% coverage in middle/low income, high burden countries.9
Service Provision (Rational Use) * Even a few hours between the administration of an antenatal corticosteroid and birth has some effect on reducing RDS.  Given minimal side effects, administration should be encouraged among providers. * Limited provider awareness, especially in low income/high burden settings, is a key issue.  Uncertainty of gestational age, for example, makes it hard for providers to know if labor is occurring preterm.  Studies show these challenges can be overcome.
  • Estimate from new List Analysis which will be in the upcoming report Born too Soon: Global Action Report on Preterm Birth. March of Dimes, PMNCH, Save the Children, WHO. The report will be launched on May 2nd by the UN Secretary General.
  • Systematic national estimates of preterm birth rates and time trends will be released May 2nd 2012 and then the global number for 2010 can be provided.
  • Black R, Cousens S, Johnson HL, et al. Global, regional, and national causes of child mortality in 2008: a systematic analysis. Lancet. June 2010;375(9730):1969–1987. Updated 2010 numbers will be available when paper is published
  • 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:i122–i133
  • Roberts D, Dalziel S. ANCS for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2008 Jul 19;3:CD004454.
  • WHO. WHO Model List of Essential Medicines (March 2011), 17th edition. Available at: http://whqlibdoc.who.int/hq/2011/a95053_eng.pdf. Accessed March 26, 2011.
  • DrugsUpdate.com. (2011). Dexamethasone>>Dexamethasone INJ. http://www.drugsupdate.com/brand/generic/Dexamethasone/24374 (Accessed January 2012).
  • WHO. Priority Medicines for Mothers and Children 2011, 3rd edition. http://www.who.int/medicines/publications/A4prioritymedicines.pdf (Accessed March 2012).
  • Darmstadt GL, Bhutta ZA, Cousens S, Adam T, Walker N, de Bernis L: Evidence-based, cost-effective interventions: how many newborn babies can we save? Lancet 2005, 365(9463):977-988. Details in the webtables.
  • Darmstadt GL, Bhutta ZA, Cousens S, Adam T, Walker N, de Bernis L: Evidence-based, cost-effective interventions: how many newborn babies can we save? Lancet 2005, 365(9463):977-988. Details in the webtables.