The n e w e ng l a n d j o u r na l of m e dic i n e

bilateral stimulation of the subthalamic nucleus in advanced 8. Merello M, Tenca E, Pérez Lloret S, et al. Prospective ran-
Parkinson’s disease. N Engl J Med 2003;​349:​1925-34.
5. Tabbal SD, Revilla FJ, Mink JW, et al. Safety and efficacy of
subthalamic nucleus deep brain stimulation performed with
limited intraoperative mapping for treatment of Parkinson’s dis-
ease. Neurosurgery 2007;​61:​3 Suppl:​119-27.
6. Rizzone MG, Fasano A, Daniele A, et al. Long-term outcome
of subthalamic nucleus DBS in Parkinson’s disease: from the
advanced phase towards the late stage of the disease? Parkin-
sonism Relat Disord 2014;​20:​376-81.
7. Alvarez L, Macias R, Pavón N, et al. Therapeutic efficacy of
unilateral subthalamotomy in Parkinson’s disease: results in 89
patients followed for up to 36 months. J Neurol Neurosurg Psy-
chiatry 2009;​80:​979-85.
domized 1-year follow-up comparison of bilateral subthalamot-
omy versus bilateral subthalamic stimulation and the combina-
tion of both in Parkinson’s disease patients: a pilot study. Br J
Neurosurg 2008;​22:​415-22.
9. Elias WJ, Lipsman N, Ondo WG, et al. A randomized trial of
focused ultrasound thalamotomy for essential tremor. N Engl J
Med 2016;​375:​730-9.
10. Martínez-Fernández R, Máñez-Miró JU, Rodríguez-Rojas R,
et al. Randomized trial of focused ultrasound subthalamotomy
for Parkinson’s disease. N Engl J Med 2020;​383:​2501-13.
DOI: 10.1056/NEJMe2031151
Copyright © 2020 Massachusetts Medical Society.

Antenatal Glucocorticoids in Low-Resource Settings

— Who, When, and Where?
Dwight J. Rouse, M.D., and Jeffrey S.A. Stringer, M.D.

It has been known for decades that women who
receive betamethasone or dexamethasone before
preterm delivery have neonates who fare better
than those of women who do not receive these
agents. The earliest established effect of this
glucocorticoid therapy was an acceleration in
fetal lung maturation, with a marked decrease in
the incidence of neonatal respiratory distress
syndrome. Over time, additional benefits be-
came evident, including decreased risks of intra-
ventricular hemorrhage, necrotizing enterocoli-
tis, early neonatal infection, and death.1 Most
evidence supporting the use of antenatal gluco-
corticoids comes from high-resource countries,
where the neonatal benefits are accompanied by
minimal risks to the mother or child. Antenatal
glucocorticoids have thus become the standard
of care for preterm births in high-resource set-
tings.2,3
Antenatal glucocorticoids are inexpensive and
easily administered by intramuscular injection.
As such, they would appear to be an ideal re-
dress for the staggering toll of prematurity in
low- and middle-income countries, where each
year more than 1 million preterm infants die in
the first year of life and countless more face
lifelong disability.4 However, major questions
were raised about the more global use of this
therapy after the results of the Antenatal Corti-
costeroids Trial (ACT) were published in 2015.5
The investigators of ACT, which was conducted
in sub-Saharan Africa, South Asia, and Latin
America, used a pragmatic, cluster-randomized
design to assess whether antenatal dexametha-
sone could be safely and effectively administered
in community and primary care settings where
access to obstetricians and neonatal intensive
care was limited. The results were troubling: not
only did the intervention fail to reduce mortality
among neonates with a birth weight below a
site-specific fifth percentile (the trial proxy for
prematurity), but it was also associated with a
higher overall neonatal mortality than placebo
(27.4, vs. 23.9 deaths per 1000 live births) and a
higher incidence of suspected maternal infection
(3%, vs. 2%). These findings prompted policy-
makers to urge caution in the use of antenatal
glucocorticoids in low-resource settings and to
call for further research.6
The results of the World Health Organiza-
tion (WHO) Antenatal Corticosteroids for Im-
proving Outcomes in Preterm Newborns (WHO
ACTION-I) trial, now reported in the Journal,7 are
an answer to that call. In this trial, which was
conducted in hospitals in five low-resource coun-
tries, almost 3000 women between 26 weeks 0 days
and 33 weeks 6 days of gestation who were at
imminent risk for delivery were randomly as-
signed to receive dexamethasone (up to four in-
tramuscular injections of 6 mg, administered 12
hours apart) or matching placebo. Neonatal death
occurred less frequently in the dexamethasone
group than in the placebo group (in 19.6% vs.
23.5%; relative risk, 0.84; 95% confidence inter-
val [CI], 0.72 to 0.97), as did the combined out-
come of stillbirth or neonatal death (in 25.7%

2584 n engl j med 383;26  nejm.org  December 24, 2020

The New England Journal of Medicine

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Copyright © 2020 Massachusetts Medical Society. All rights reserved.
 Editorials
vs. 29.2%; relative risk, 0.88; 95% CI, 0.78 to
0.99). In a reassuring contrast to ACT, there was
no significant between-group difference in the
incidence of adverse outcomes and no increase
in the occurrence of possible maternal bacterial
infection (4.8% in the dexamethasone group and
6.3% in the placebo group; relative risk, 0.76;
95% CI, 0.56 to 1.03).
To make sense of the conflicting results of
these two trials, it is important to consider the
different ways in which they were conducted.
ACT was a strategy trial that was intended to
democratize the benefits of antenatal glucocor-
ticoids by placing them in the hands of providers
(including nurses, midwives, and traditional birth
attendants) who care for most pregnant women
in low- and middle-income countries. Gesta-
tional age was estimated with methods that are
recognized to be less accurate than ultrasonog-
raphy,8 and some providers lacked the clinical
expertise to assess the risk of imminent delivery.
Thus, in the intervention clusters, only 16% of
the women receiving glucocorticoids went on to
deliver preterm, and only 45% of those who de-
livered preterm received these agents. Further-
more, only a minority of infants in ACT who
received glucocorticoids were delivered at a facil-
ity with adequate neonatal care capacity, which
in a secondary analysis was associated with the
effectiveness of the intervention.9
In contrast, the WHO ACTION-I trial was
conducted in hospital settings that ensured a
higher level of care, including dating of gesta-
tional age by ultrasonography, infection man-
agement, newborn thermal and feeding support,
and the availability of continuous positive airway
pressure devices. The risk of imminent preterm
delivery was assessed by trained obstetrical pro-
viders, and this assessment resulted in improved
targeting of the intervention. Among women
who were assigned to dexamethasone, 70% de-
livered within 1 week after receiving the first
dose and 90% delivered before 37 weeks of ges-
tation.
The WHO ACTION-I trial makes clear that
there are many areas in low- and middle-income
countries where antenatal glucocorticoids can be
prescribed safely and effectively. Facilities that
meet the clinical standards of the trial sites (or
to which resources could be provided to meet
n engl j med 383;26  nejm.org  December 24, 2020
The New England Journal of Medicine
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Copyright © 2020 Massachusetts Medical Society. All rights reserved.
these standards) should use them. With a num-
ber needed to treat of 25 to prevent 1 neonatal
death, the WHO ACTION-I trial confirms the
tremendous benefit of antenatal glucocorticoids
for the right patient, at the right time, and in the
right setting. The minimum level of obstetrical
and neonatal care necessary for glucocorticoids
to achieve their promise remains uncertain. Since
a plurality of births in low- and middle-income
countries occur in the nebulous space between
good and demonstrably inadequate perinatal care,
this is a question of urgency.
Disclosure forms provided by the authors are available with
the full text of this editorial at NEJM.org.
From the Division of Maternal–Fetal Medicine, Department of
Obstetrics and Gynecology, Warren Alpert Medical School
of Brown University, Providence, RI (D.J.R.); and the Division of
Global Women’s Health, Department of Obstetrics and Gyne-
cology, University of North Carolina School of Medicine, Cha-
pel Hill (J.S.A.S.).
1. Roberts D, Brown J, Medley N, Dalziel SR. Antenatal corti-
costeroids for accelerating fetal lung maturation for women at
risk of preterm birth. Cochrane Database Syst Rev 2017;​ 3:​
CD004454.
2. American College of Obstetricians and Gynecologists. Ante-
natal corticosteroids for fetal maturation: committee opinion
#713. August 2017 (https://www​.­acog​.­org/​­clinical/​­clinical​-­guidance/​
­committee​-­opinion/​­a rticles/​­2017/​­08/​­a ntenatal​-­corticosteroid​
-­t herapy​-­for​-­fetal​-­maturation).
3. Travers CP, Clark RH, Spitzer AR, Das A, Garite TJ, Carlo
WA. Exposure to any antenatal corticosteroids and outcomes in
preterm infants by gestational age: prospective cohort study.
BMJ 2017;​356:​j1039.
4. Survive and thrive: transforming care for every small and
sick newborn. Geneva: World Health Organization, 2019 (https://
www​.­who​.­int/​­maternal_child_adolescent/​­documents/​­care​-­small​
-­sick​-­newborns​-­survive​-­t hrive/​­en/​­).
5. Althabe F, Belizán JM, McClure EM, et al. A population-
based, multifaceted strategy to implement antenatal corticoste-
roid treatment versus standard care for the reduction of neonatal
mortality due to preterm birth in low-income and middle-­
income countries: the ACT cluster-randomised trial. Lancet
2015;​385:​629-39.
6. WHO recommendations on interventions to improve pre-
term birth outcomes. Geneva:​World Health Organization, 2015
(https://apps​.­who​.­int/​­iris/​­bitstream/​­handle/​­10665/​­183037/​
­9789241508988_eng​.­pdf).
7. The WHO ACTION Trials Collaborators. Antenatal dexameth-
asone for early preterm birth in low-resource countries. N Engl
J Med 2020;​383:​2514-25.
8. Vwalika B, Price JT, Rosenbaum A, Stringer JSA. Reducing
the global burden of preterm births. Lancet Glob Health 2019;​
7(4):​e415.
9. Garces A, McClure EM, Figueroa L, et al. A multi-faceted
intervention including antenatal corticosteroids to reduce neo-
natal mortality associated with preterm birth: a case study from
the Guatemalan Western Highlands. Reprod Health 2016;​13:​63.
DOI: 10.1056/NEJMe2032499
Copyright © 2020 Massachusetts Medical Society.
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