Invest Clin 66(3): 332 - 346, 2025 https://doi.org/10.54817/IC.v66n3a09

Corresponding author: Carlos Briceño-Pérez. Departamento de Obstetricia y Ginecología. Universidad del Zulia.

Maracaibo, Venezuela. E-mail: cabripe@hotmail.com

Long-term effects of antenatal

administration of corticosteroids.

Where are we?

Carlos Briceño-Pérez1, Liliana Briceño-Sanabria2, Eduardo Reyna-Villasmil3

and Paulino Vigil-De Gracia4

1Departamento de Obstetricia y Ginecología. Universidad del Zulia. Maracaibo,

Venezuela.

2Bayview Surgery Center. Sarasota, Florida, United States of America.

3Departamento de Obstetricia y Ginecología. Hospital Central “Dr. Urquinaona,

Maracaibo, Venezuela.

4Complejo Hospitalario “Dr. Arnulfo Arias Madrid” de la Caja de Seguro Social.

Sistema Nacional de Investigación SENACYT Panamá.

Key words: corticosteroids, pregnancy; betamethasone; dexamethasone; delayed effects

of medical treatment; neurologic manifestations; premature birth.

Abstract. There is increasing concern about the long-term effects of an-

tenatal administration of corticosteroids, as some complications have been

reported in neonates, adolescents and adults, which could be transmitted to

subsequent generations, as it has been shown in animal and observational stud-

ies in humans. In this review, we summarize the current understanding of the

long-term effects of antenatal corticosteroid administration and provide data

to inform the preparation of guidelines. A literature search was performed in

the PubMed database. A mechanism has been proposed as to how antenatal

administration of corticosteroids could produce morbidity in neonatal neuro-

development and lead to future diseases in adulthood. However, this hypothesis

has not been proven in large randomized controlled trials. We summarize here

the current data supporting and opposing the long-term effects of antenatal

corticosteroid administration. Follow-up studies from randomized controlled

trials have found no increased risk of neurologic impairment in children af-

ter exposure to a single course of antenatal corticosteroids. Observational and

clinical trials of maternally administered antenatal corticosteroids show no evi-

dence of increased disability on follow-up and describe associations rather than

a proximate cause. Before 34 weeks of gestation, antenatal administration of

corticosteroids in women at high risk for preterm birth appears to improve

most neurodevelopmental outcomes. It is still recommended to administer a

single course of corticosteroid treatment before preterm delivery.

Long-term effects of antenatal administration of corticosteroids. Where are we? 333

Vol. 66(3): 332 - 346, 2025

Efectos a largo plazo de la administración antenatal

de corticosteroides. ¿Dónde estamos?

Invest Clin 2025; 66 (3): 332 – 346

Palabras clave: corticosteroides; embarazo; betametasona; dexametasona; efectos

a largo plazo del tratamiento; manifestaciones neurológicas; parto

pretérmino.

Resumen. Basándose en estudios en animales y observacionales en huma-

nos, recientemente se han planteado una serie de dudas sobre los efectos a lar-

go plazo de la administración antenatal de corticosteroides y se han notificado

algunas complicaciones en neonatos, adolescentes y adultos; que incluso, po-

drían transmitirse a generaciones posteriores. Extenderla al periodo prematuro

tardío, podría conducir a un aumento drástico del número de recién nacidos

expuestos in útero. En esta revisión se resume el conocimiento actual de los

efectos a largo plazo de la administración antenatal de corticosteroides y se

aportan datos para la elaboración de guías para su uso. Para la metodología se

realizó una búsqueda bibliográfica en la base de datos PubMed. Se ha propuesto

un mecanismo para explicar cómo la administración antenatal de corticoste-

roides puede causar morbilidad en el neurodesarrollo neonatal y enfermedades

programadas del adulto. Sin embargo, esta teoría no se ha demostrado en gran-

des pruebas controladas aleatorizadas. Aquí resumimos los efectos, a favor y

en contra, a largo plazo de la administración antenatal de corticosteroides. La

evidencia actual es inconsistente, los estudios de seguimiento de los ensayos

controlados aleatorizados no han encontrado un mayor riesgo de deterioro neu-

rológico en los niños, después de un solo curso antenatal de corticosteroides.

Los ensayos observacionales y clínicos no muestran pruebas de aumento de

discapacidad y describen asociaciones más que causas. Antes de las 34 semanas

de embarazo, la administración antenatal de corticosteroides en mujeres con

alto riesgo de parto pretérmino, parece mejorar la mayoría de resultados del

neurodesarrollo. Antes del parto pretérmino, se recomienda un curso simple de

tratamiento con corticosteroides.

Received: 10-03-2025 Accepted: 29-06-2025

INTRODUCTION

Preterm birth (PB) is a significant pub-

lic health problem in the United States, with

1 in 10 infants being born before term 1.

Antenatal administration of corticosteroids

(ACS) is a worldwide standard of care for

preventing and reducing perinatal morbid-

ity and mortality (PM) 2-4. To establish the

standards for ACS, after more than five de-

cades, two NIH Consensus Conferences were

held in 1994 and 2000, and numerous pro-

nouncements from important institutions

and scientific societies worldwide have been

made 5,6.

Recently, some complications have

been reported in neonates, adolescents and

adults, which could even be transmitted to

subsequent generations, and concern has

been raised about the long-term effects of

334 Briceño-Pérez et al.

Investigación Clínica 66(3): 2025

ACS 7. Recent literature suggests that the

benefits of ACS may extend to late-preterm

and early-term infants as well. These expand-

ed uses may expose populations to ACS at

gestational ages that have been minimally

evaluated for their efficacy or risks. Re-

searchers continue to investigate the possi-

ble associations between ACS and long-term

neurodevelopmental outcomes in exposed

children, given the potential implications of

the overuse of ACS 8.

The objective of this review is to de-

scribe the current status of the long-term

effects of ACS, based on existing evidence.

Methods/design

We conducted a narrative review of the

targeted literature focusing on the long-

term effects of ACS. The PubMed database

was searched for literature published up

from January, 01 2015 to May 26, 2024, us-

ing the following keywords: “corticosteroid”,

“betamethasone”, “dexamethasone”, “an-

tenatal betamethasone”, “antenatal dexa-

methasone”, “antenatal corticosteroids”,

“late preterm antenatal corticosteroids”,

“at term antenatal corticosteroids”, “neu-

rodevelopmental outcomes”, “neonatal out-

comes”, and “long-term effects”. We also

included studies from other sources that

we considered historical or relevant to the

topic. We excluded studies that were not

focused on the long-term effects of ACS or

that focused on the description, guidelines,

and other aspects of ACS.

Antenatal administration

of corticosteroids

ACS has led to its demonstration of

efficacy and safety, making it a worldwide

standard of care for the prevention and re-

duction of fetal morbidity and PM (Tables 1

and 2) 1,2-4,5,6,9,10.

Additionally, there is evidence sup-

porting the recommendation of a “rescue”

course of corticosteroids if seven days have

passed after the initial course 2,11-13.

ACS in late preterm pregnancy

Recently, ACS has been extended be-

yond 34 weeks of gestation (34.0 to 36.6

weeks of gestation) because studies dem-

onstrate modest benefits from ACS for late

preterm and term elective cesarean deliver-

ies 3. In 2016, a great multicenter, random-

ized trial 14 involved women with a singleton

pregnancy at late preterm pregnancy who

were at high risk for delivery. Participants

received two injections of betamethasone

phosphate/acetate or a matching placebo

24 hours apart. The primary outcome was a

neonatal composite of treatment in the first

72 hours or stillbirth or neonatal death with-

in 72 hours after delivery. Primary outcome

occurred in 165 of 1427 infants (11.6%) in

the betamethasone group and 202 of 1400

(14.4%) in the placebo group (relative risk

in the betamethasone group, 0.80; 95%

confidence interval [CI], 0.66 to 0.97; p=

0.02). In the betamethasone group, neona-

tal hypoglycemia was more common (24.0%

vs. 15.0%; relative risk, 1.60; 95% CI, 1.37

to 1.87; p<0.001). ACS (betamethasone)

significantly reduced the rate of neonatal re-

spiratory complications in women at risk for

late preterm delivery 14.

The Society for Maternal-Fetal Medi-

cine (SMFM), in march 2016 15, in the “Im-

plementation of the use of ACS in the late

PB period in women at risk for preterm de-

livery”, recommended the treatment with

a betamethasone phosphate/acetate single

course, in women with late preterm gesta-

tion, with a singleton pregnancy, who are at

high risk for PB within the next seven days,

15. In October 2016, the American College

of Obstetricians and Gynecologists (ACOG)

11, recommended the administration of be-

tamethasone phosphate/acetate in late pre-

term gestations, in pregnant women who

have not received a previous course of ACS

and are at risk of PB within seven days 11.

Two trials of antenatal dexamethasone

in preventing mortality and severe morbidity

among late preterm newborns, in low-income

Long-term effects of antenatal administration of corticosteroids. Where are we? 335

Vol. 66(3): 332 - 346, 2025

Table 1. Recommendations of scientific institutions on ACS in early preterm, late preterm and term gestation.

Gestation SMFM 16 ACOG 11,12 RCOG 13,20 FIGO 21 WHO 17,22 WAPM-PMF 10 EGPC 19

Early

preterm

ACS prior to

34 weeks is

standard

practice for

women at

high risk for

delivery in the

next 7 days.

For pregnant

women between

24 0/7 and 33

6/7 weeks at

risk of PB within

7 days. Also for

pregnant women

starting at 23

0/7 at risk of PB

within 7 days.

Should be offered to women

between 24+0 and 34+6

weeks’ gestation in whom

imminent PB is anticipated

For whom PB is

anticipated between

24 and 34 weeks,

one course of ACS

should ideally be

offered, 18 to 72 be-

fore PB is expected.

ACS is recommen-

ded for women

with a high

likelihood of

PB from 24

weeks to 34

weeks.

A single course of ACS

should be administe-

red bet-ween 24+0

and 33+6 weeks of

gestation in women

at high-risk of PB

within the next 7

days.

ACS should be

administered to

women between

24 and 33weeks,

when PB is

anticipated in

the next seven

days.

Late

preterm

To patients who

meet the

inclusion criteria

of the Antenatal

Late Preterm

Steroids trial.

ACS may be

considered in

pregnant women

between 34 0/7

and 36 6/7 weeks

who are at risk of

PB Within 7 days

and who have not

received a

previous course

of ACS.

In very late preterm women,

ACS should be considered

in light of the balance of

risks and benefits.

ACS should not be

offered routinely

to women in whom

late preterm birth

between 34 and 36

weeks is anticipated.

ACS is not recom-

mended for wo-

men undergoing

planned caesarean

section at 34

weeks 0 days to 36

weeks 6 days.

ACS is not routinely

recommendded

between 34+0 and

36+6 weeks in wo-

men at high-risk of

PB within the next 7

days because of the

current uncertainty

regarding the benefit

to risk ratio.

ACS between 34,0

and 34,6 weeks

should only be

offered to a few

selected cases

(Expert opinion).

ACS between 35

and 36 weeks

should be restric-

ted to prospective

randomized trials.

Term – – For women undergoing planned

caesarean birth between 37+0

and 38+6 weeks an informed

discussion about the

potential risks and benefits

of ACS. Although ACS may

reduce admission to the NICU

for respiratory morbidity, it is

uncertain if there is any

reduction in RDS, transient

tachypnoea or NICU admission,

and may result in

hypoglycaemia and potential

developmental delay morbidity.

ACS should not

be given routinely

before cesarean

delivery at term.

– ACS is not routi-

nely recommended

before scheduled

cesarean section at

term because of the

current uncertain-

ty regarding the

benefit to risk ratio.

In the absence of

other indications, a

scheduled cesarean

section should not

be performed before

39+0 weeks.

ACS in preg-

nancies beyond

37weeks is not

indicated, even

for scheduled ce-

sarean delivery.

SMFM: society of maternal fetal medicine ACOG: American college of obstetricians and gynecologists RCOG: royal college of obstetricians and gynecologists

FIGO: federation international of obstetrics and gynecology WHO: world health organization WAPM-PMF: world association of perinatal medicine-perinatal

medicine foundation EGPC: European guide of perinatal care ACS: antenatal administration of corticosteroids PB: preterm birth.

336 Briceño-Pérez et al.

Investigación Clínica 66(3): 2025

countries, did not show adverse childhood

neurodevelopmental outcomes and proved

safe and efficacious 16,17. In the ALPS follow-

up study of a Randomized Controlled Trial

(RCT) 16, ACS initially showed improvement

in short-term neonatal respiratory outcomes

at age six years or older, without adverse

childhood neurodevelopmental outcomes,

but with an increased rate of hypoglycemia

16. In a multicenter, two-arm, parallel, double-

blind, placebo-controlled, randomized trial17;

antenatal dexamethasone for late preterm

birth did not result in a reduction in neonatal

death, stillbirth, or severe neonatal respira-

tory distress 17.

Currently, there is no agreement on the

use of ACS in the late preterm period, as the

SMFM 18 and ACOG 12 recommend its use

in the United States, whereas many institu-

tions and scientific societies worldwide do

not 10,13,19-22.

The expanded use of ACS in late preterm

pregnancy

Literature suggests that the benefits of

ACS may extend to late-preterm and early-

term infants as well 2,11,12,14,18. This expanded

use exposes populations to ACS at gesta-

tional ages that have been minimally evalu-

ated for efficacy or risk. Extending the use

of ACS to the late preterm period may lead

to a dramatic increase in the number of in-

fants exposed in utero to ACS (nearly 10%

of fetuses) and an even greater increase in

the proportion of fetuses exposed to ACS,

which will eventually be born at term. As

treatments expand, benefits decrease and

risks increase3,23-27.

ACS in a term pregnancy

In 2005, the multicenter RCT study AS-

TECS (Antenatal Steroids for Term Elective

Cesarean Section) included 998 women with

term pregnancies, of whom 503 received a

single course of betamethasone phosphate/

acetate in the 48 hours preceding a cesarean

section. The primary outcome was admission

to the special care baby unit with respiratory

distress. Of the 35 children admitted to the

special baby units with respiratory distress,

24 babies were in the control group and 11

in the intervention group, a statistically sig-

nificant difference (p = 0.02). The incidence

of admission with respiratory distress in the

control group was 0.051, and in the treat-

ment group, was 0.024 (relative risk 0.46,

95% confidence interval 0.23 to 0.93). In

this study, both ACS and delaying delivery

until 39 weeks reduce admissions to special

care baby units with respiratory distress af-

ter elective cesarean section at term28. In

2009, a Cochrane systematic review 29, con-

cluded that results from the single trial are

promising, but more studies with larger sam-

ples were needed.

Additionally, more data and a longer fol-

low-up would be needed to assess potential

harms and complications. In October 2010,

the Royal College of Obstetricians and Gy-

necologists of the United Kingdom 13 estab-

lished that there is a lack of evidence avail-

able regarding the safety of ACS in babies

born after 36+0 weeks of gestation. Elective

lower-segment cesarean section should not

typically be performed until 39+0 weeks of

gestation, rather than the ACS 13.

Table 2. Benefits and risk of ACS.

– ACS before 34 weeks presents an undeniable benefit for the unborn child if born prematurely.

– Identifying patients who will actually deliver within 7 days following the treatment is difficult

and further studies need to be conducted.

– After 34 weeks of gestation the benefit/risk balance is against ACS.

– Studies should be conducted on reducing ACS.

ACS: antenatal administration of corticosteroids.

Long-term effects of antenatal administration of corticosteroids. Where are we? 337

Vol. 66(3): 332 - 346, 2025

ACS and long-term effects

The increased use of ACS during the

late prenatal period and prior to cesarean

sections at term, due to their proven efficacy

and safety, has resulted in a significant rise

in the number of infants exposed to ACS in

utero. Approximately three-fourths of all PB

occur in the late preterm period 16. Current-

ly, almost 10% of fetuses are exposed in utero

to ACS, and >50% of women given ACS for

presumed PB will not deliver within the op-

timal exposure window of seven days 3,7,24,30.

The net effect is that a substantial fraction

of the delivery population will be exposed to

ACS, and more fetuses exposed to ACS are

delivered at term (most recipients deliver

after 35 weeks’ gestation and 44% to 50%

deliver at term) 3,7,24.

The New Zealand Group followed chil-

dren who received betamethasone in utero

during the study of Liggins study 4 for many

years, 2005-2007, establishing that 2: 1. ACS

with a single course of betamethasone do not

alter psychological, pulmonary and cardiovas-

cular functions at 30-31 years of follow-up.

2. Adults who were born moderately preterm

have increased blood pressure and insulin

resistance at 30 years of age; 3. PB, and not

poor fetal growth, is the primary determinant

of this association; 4. Obstetricians should

continue to use a single course of ACS for the

prevention of neonatal respiratory distress

syndrome (RDS).

Based on animal and observational

studies in humans, several concerns have

recently been raised about the long-term ef-

fects of ACS, and some complications have

been reported in neonates, adolescents, and

adults, which could even be transmitted to

subsequent generations 7,18. Although the

long-term risks associated with ACS use

(such as neonatal neurodevelopmental is-

sues and adult program diseases) remain

uncertain, several observations have been

reported on the likely long-term effects of

ACS. Late effects of ACS suggest caution

for the expanded use of ACS beyond at-risk

pregnancies at 24-34 weeks ²,²4.

ACS and the hypothalamic-pituitary-

adrenal axis

In animal studies, exposure to exoge-

nous ACS has been associated with a delay in

brain growth and development, as well as in-

creased activity and persistent changes in the

hypothalamic-pituitary-adrenal (HPA) axis

and endogenous corticosteroid production.

At the molecular level, transcriptional chang-

es occur in metabolic and growth pathways.

Epigenetic mechanisms participate in trans-

generational inheritance, not genomic7,25. Ex-

posures that alter the methylation status of

the 11β-hydroxysteroid dehydrogenase type

2 enzyme in the placenta can lead to tran-

scriptional repression of the gene, resulting

in the fetus being exposed to higher levels

of cortisol. Such an adaptation to an intra-

uterine insult is thought to be beneficial in

the short term and is linked to an increased

chance of offspring survival to reproductive

age. In adults, activation of the HPA axis has

been linked to increased likelihood of cardio-

vascular risk factors comprising the meta-

bolic syndrome, including higher glucose,

blood pressure, and triglycerides, as well as

ischemic heart disease, cognitive decline, and

depression in later life25. It remains to be de-

termined whether the HPA axis hyperactivity

contributes to such effects 7,25,26.

Evidence on the long-term effects of ACS

Let us now review some recent animal

and human evidence on the long-term ef-

fects of ACS (Table 3).

Animal studies

In utero exposure to single doses of

exogenous corticosteroids may affect fetal

brain development and neurological out-

comes, as suggested by some animal studies.

The hypothesis proposed by Seckl in 2004

31 was recognized in an editorial by Reyn-

olds and Seckl 25, indicating that rats and

lambs exposed to an adverse in utero envi-

ronment during development can experi-

ence long-term effects on physiology and an

increased risk of adult disease. Overall, the

338 Briceño-Pérez et al.

Investigación Clínica 66(3): 2025

Authors Year Type of evidence Results/Conclusions/Comments

Evidence in animals

Reynolds,

Seckl 25

2012 Editorial Recognize the hypothesis of Seckl 31, in 2004.

Seckl 31 2004 Review Hypothesized that prenatal exposure to excess glucocorticoids or stress might re-

present a mechanism linking fetal growth with adult pathophysiology. The data

suggest that both pharmacological and physiological exposure prenatally to ex-

cess glucocorticoids, programmes cardiovascular, metabolic and neuroendocrine

disorders in adult life. It was published in 2004, i.e. 19 years ago. It was based on

a majority of animal studies. Most of the cited animal studies, in which weight

reduction was obtained, were conducted between 1978-2001, and used multiple

courses of ACS, characterized because they do not enhance the beneficial effects

of single courses and because produce fetal injury. Multiple courses of ACS are not

recommended since 2000 6.

Jobe, Gol-

denberg 3

2018 Clinical

opinion

Noted that cardiovascular and metabolic abnormalities have been identified in

large animal models and cohorts of children exposed to ACS, that are consis-

tent with fetal programming for adult diseases.

Evidence in humans

A single course of ACS

Smolder

et al. 33

1990 RCT ACS does not alter lung function or the prevalence of wheeze and asthma at age 30.

Found no difference in neurologic and ophthalmologic examination results.

Dalziel et al.,

cited by 2

2006 Longitudinal

by 30 years

ACS of a single course of betamethasone, found no increased risk of impair-

ment in cognitive functioning, working memory, attention, psychiatric morbi-

dity, or health-related quality of life.

Stutchfield

et al. 34

2013 Multicenter

RCT

(ASTECS trial),

No difference in behavioral, cognitive, or developmental outcomes among chil-

dren aged 8-15 years whose mothers received a single course of ACS before

elective cesarean delivery at 37-38 weeks of gestation.

Sotiriadis

et al. 35

2015 Systematic

review

A single course of ACS in women at high risk for PB appears to improve most

neurodevelopmental outcomes in offspring born before 34 weeks of gestation.

Alexander

et al. 36

2016 Cross-sectional

study

A single course of ACS does not aggravate long-term cognitive deficits. Our

data indicated that conditions related to a threatening PB rather than ACS

per se, were associated with long-term decreases in the child’s intelligence.

Melamed

et al. 27

2019 Retrospective

cohort study

Children exposed to ACS were more likely to have suspected neurocognitive

disorders.

Raikkönen

et al. 8

2020 Retrospective

cohort study

Siblings exposed to ACS were more likely to exhibit any childhood mental or

behavioral disorder.

Ninan

et al. 37

2022 Systematic

review

A single course of ACS, was associated with a significant decrease in the adjusted

odds of neurodevelopmental impairment in children with extremely preterm birth..

Hutcheon

et al. 38

2022 Regression

discontinuity

design

Found little evidence that children with higher probability of exposure to ACS

have higher rates of ADHD prescriptions in childhood, supporting the safety of

ACS for this neurodevelopmental outcome.

Multiple course of ACS

Asztalos

et al. 42

2014 Secondary analysis

of the RCT MACS

(MACS-5 trial)

Children born ≥ 37 weeks and exposed to multiple ACS therapy may have an in-

creased risk of neurodevelopmental/neurosensory impairment by 5 years of age.

Table 3. Evidences on the long-term effects.

ACS: Antenatal administration of corticosteroids RCT: Randomized controlled trials ASTECS: Antenatal betametha-

sone for term caesarean section PB: Preterm birth ADHD: Attention deficit/hyperactivity disorder MACS: Mul-

tiple antenatal courses of steroids.

Long-term effects of antenatal administration of corticosteroids. Where are we? 339

Vol. 66(3): 332 - 346, 2025

data suggest that both pharmacological and

physiological exposure prenatally to excess

glucocorticoids can lead to cardiovascular,

metabolic and neuroendocrine disorders in

adult life 31.

Concerning the Seckl’s study 31, it

should be noted that: 1. It was published in

2004, i.e. 20 years ago. 2. It was based on a

majority of animal studies. 3. Most of the cit-

ed animal studies, in which weight reduction

was obtained used multiple courses of ACS

(defined as the use of ACS multiple courses:

three, four, five, six or more courses), char-

acterized because they do not enhance the

beneficial effects of single courses and be-

cause produce fetal injuries and were con-

ducted between 1978 and 2001 2. For these

reasons, they have not been recommended

since 2000. The four extensive studies world-

wide, using multiple ACS courses, reported

fetal injuries (TEAMS, NIH, ACTORDS, and

MACS) 2,6. On multiple courses, in the sec-

tion “Human Clinical Observations,” Seckl31

notes that a single course of ACS is associ-

ated with a significant reduction in the in-

cidence of intraventricular hemorrhage and

a trend toward fewer neurodevelopmental

disabilities. However, a survey by the Brit-

ish Obstetric Departments showed that 98%

of participants were prescribing multiple

courses of ACS. There is little evidence of

the safety and efficacy of such a regime. Re-

cent overviews suggest that there is no evi-

dence of additional benefits from multiple

courses of glucocorticoid therapy during

pregnancy, but that clear conclusions are

prevented by the lack of prospective RCTs

and by variations in the protocols employed.

ACS has also been linked with higher blood

pressure in adolescence and subtle effects

on neurological function, including reduced

visual closure and visual memory. In 2018,

Jobe and Goldenberg 3 noted in a clinical

opinion article that cardiovascular and met-

abolic abnormalities have been identified in

large animal models and cohorts of children

exposed to ACS, which are consistent with

fetal programming for adult diseases 3. Af-

ter 34 weeks of gestation, when rapid brain

growth occurs, theoretically, these effects

could be more pronounced 32.

Human studies:

A single course of ACS

In children born after exposure to a

single course of ACS, follow-up studies from

RCTs of ACS have found no increased risk

of neurologic impairment. Their precise as-

sessment of neurodevelopmental outcomes

was a strength of these studies 16. However,

findings are mixed, in observational studies.

No differences between the corticoid

and the placebo groups were found in 1990,

in one RCT of betamethasone, when Smol-

der et al. 33 studied potential side effects

of ACS to prevent neonatal RDS, in 10- to

12-year-old children (N: 84). The lung func-

tion as assessed by the presence of wheeze

and asthma at age 30, was not altered by

ACS. This study found no difference in neu-

rologic and ophthalmologic examination re-

sults 33. These findings were similar to those

of a longitudinal study conducted in 2006,

which followed 534 30-year-old adults33.

ACS by a single course of betamethasone

did not increase the risk of impairment in

lung function, cognitive functioning, work-

ing memory, attention, psychiatric morbid-

ity, or health-related quality of life between

the betamethasone and placebo groups 2.

In a questionnaire-based follow-up of a mul-

ticenter RCT (ASTECS Trial), Stutchfield

et al. 34 demonstrated no difference in be-

havioral, cognitive, or developmental out-

comes among children aged 8 to 15 years

whose mothers received a single course of

ACS before elective cesarean at 37 to 38

weeks of gestation 34. In 2015, Sotiriadis et

al. 35, concluded that a single course of ACS

in women at high risk for PB appears to im-

prove most neurodevelopmental outcomes

in offspring born before 34 weeks of gesta-

tion as showed by reduced risk for cerebral

palsy (seven studies; treated: 390 of 5,199,

untreated: 146 of 1,379; RR 0.678, 95% con-

fidence interval [CI] 0.564-0.815), psycho-

340 Briceño-Pérez et al.

Investigación Clínica 66(3): 2025

motor development index less than 70 (two

studies; treated: 783 of 3,049, untreated:

258 of 969; RR 0.829, 95% CI 0.737-0.933),

and severe disability (five studies; treated:

1,567 of 4,840, untreated: 475 of 1,211; RR

0.787, 95% CI 0.729-0.850); in a systematic

review, included RCT and non RCT, report-

ing on the neurodevelopmental outcomes of

children whose mothers were administered a

single course of ACS for threatened PB 35. In

a cross-sectional study of a mixed-sex cohort

of 222 term-born children (aged 6-11 years),

Alexander et al. 36 concluded that their data

indicated that ACS does not aggravate long-

term cognitive deficits 36.

In 2019, a retrospective cohort study

(2006-2011), by Melamed et al. 27, examined

outcomes at five years of age in 5432 chil-

dren exposed to ACS compared with 523,782

children not exposed. Children exposed

to ACS were more likely to have suspected

neurocognitive disorders (exposure to ACS

vs no exposure: 25.8% vs 21.6%; p<0.001;

adjusted hazard ratio [aHR] 1.16, 95% CI

1.10 to 1.21) 27. In 2020, Raikkönen et al. 8

conducted a population-based retrospective

cohort study using nationwide registries of

all singleton live births in Finland that sur-

vived until one year, along with a within-sib-

pair comparison among term siblings. They

found that siblings exposed to ACS were

more likely to exhibit any childhood mental

or behavioral disorder and concluded that

ACS was significantly associated with mental

and behavioral disorders in term-born chil-

dren (12.01% among those exposed to ACS

vs 6.45% among those not exposed; absolute

difference, 5.56% [95% CI, 5.04%-6.19%];

p<.001) 8. In 2022, in another systematic

review and meta-analysis of 30 studies in-

volving more than 1.25 million children,

Ninan et al. 37 noted that exposure to a single

course of ACS was associated with a signifi-

cant decrease in the adjusted odds of neuro-

developmental impairment in children with

extremely high PB. ACS exposure was associ-

ated with increased adjusted risks of neuro-

cognitive and/or psychological impairment

in children with late-preterm and full-term

birth 37. Furthermore, in 2022, Hutcheon et

al. 38, found little evidence that children with

a higher probability of exposure to ACS have

higher rates of attention-deficit/hyperactiv-

ity disorder (ADHD) prescriptions in child-

hood, supporting the safety of ACS for this

neurodevelopmental outcome. They used a

regression discontinuity design, over a medi-

an follow-up period of nine years, 892 (5.5%)

children had one or more dispensations of

ADHD 38. In 2022, Sarid et al. 39, synthesized

the association between ACS exposure and

the risk of preterm birth and brain devel-

opment in infants ultimately born at late

preterm and term. Their protocol included

27 observational studies (12 retrospective

cohort studies, 11 prospective cohort stud-

ies and four cross-sectional studies). In 14

studies, a single course of ACS was admin-

istered; in two studies, two or more courses

of ACS were administered. In seven studies,

the number of courses of ACS varied among

study participants and in four studies, the

regimen was not specified. The most com-

mon adverse outcomes were reduced neona-

tal head circumference, structural cortical

differences on magnetic resonance images,

increased prevalence of psychiatric prob-

lems, and increased risk of neurodevelop-

mental delays, in ACS-exposed late preterm

and term infants. Further research, such as

preterm labor, maternal stress, and the num-

ber of ACS courses, is needed to establish bet-

ter the long-term neurological effects of ACS

on late preterm and term infants, given that

the existing research was at serious risk for

bias 39. In 2023, Yao et al. 40, investigated the

associations between ACS and serious infec-

tions in children during the first 3, 6, and 12

months of life. This nationwide cohort study

found that children exposed to one course

of ACS were significantly more likely to have

an increased risk of serious infection during

the first 12 months of life. The study cohort

consisted of 1,960,545 singleton children:

45,232 children were exposed to one course

of ACS, and 1,915,313 children were not ex-

Long-term effects of antenatal administration of corticosteroids. Where are we? 341

Vol. 66(3): 332 - 346, 2025

posed. The adjusted hazard ratios for overall

serious infections, sepsis, pneumonia, and

acute gastroenteritis, among children ex-

posed to ACS, were significantly higher than

those not exposed. The adjusted hazard ra-

tios for overall serious infection (p<0.001),

sepsis (p = 0.02), pneumonia (p<0.001),

and acute gastroenteritis (p<0.001) were

significantly higher from birth to 12 months

of life 40. In 2023, Weiss et al. 41 determined if

ACS exposure was associated with infant cor-

tisol levels. One hundred eighty-one women

and their infants participated in the study.

Infants whose mothers received ACS had

significantly lower resting-state (B = -2.47,

CI: -3.691; to 0.0484) and post-stressor (B

= 0.51, CI: -4.283, to -0.4276) cortisol lev-

els across the first year of life than infants

whose mothers did not receive ACS. Results

indicate a state of dampened HPA activation

and cortisol hypo-arousal that persists across

the first year of life among infants who were

exposed to ACS in utero. They concluded

that further research is needed to examine

the mechanisms responsible for any altera-

tions that occur during the development of

the fetal HPA axis, including epigenetic and

biochemical factors 41.

Multiple, repeat or weekly courses of ACS:

In 2000, studies examining multiple

courses of ACS, were reserved for patients

enrolled in clinical trials 2,6. However, we

will point out that after multiple courses

of ACS, different outcomes have been ob-

served. In 2014, in the trial MACS-5, Asz-

talos et al. 42 concluded that children born

≥ 37 weeks and exposed to multiple ACS

therapy may have an increased risk of neu-

rodevelopmental/neurosensory impairment

by five years of age 42; they studied the as-

sociation between gestational age at birth,

multiple courses of ACS and outcomes at

five years, In the previously cited 2022,

Sarid et al.´s trial 39, two or more courses of

ACS were administered.

Limitations of previous studies

Some limitations have been identified

in previous studies (Table 4) 18,24,42,43. Data

from RCT on the long-term effects of ACS on

the fetal brain are limited 22.

Table 4. Limitations to evidences on the long-term effects of ACS 18,24,42,43.

• Many of these studies either were from small samples or used population-based registry

data, from which the severity of illness may be difficult to discern.

• Given the retrospective, observational study designs, the authors did not account

for the admission or delivery indication or other antenatal complications (such as fe-

tal growth restriction, oligohydramnios, infections during pregnancy, red blood cell allo-

immunization, hydrops, or congenital anomalies) that may substantially influence long-

term neurologic outcomes.

• Previous studies have suggested that it is not, in fact, the ACS* itself but rather the

condition leading to a threat of PB† that is associated with neurologic impairment in

exposed children.

• Information regarding steroid type, dosing, frequency, and timing of exposure in most

studies is unknown.

• There is a potential bias related to differential referral or diagnosis of subjects exposed

to ACS with abnormal development

• The lack of standardized evaluations by trained professionals blinded to exposure sta-

tus, along with the absence of defined diagnostic criteria, leaves room for bias and sub-

jectivity in diagnosis.

ACS: Antenatal administration of corticosteroids PB: Preterm birth.

342 Briceño-Pérez et al.

Investigación Clínica 66(3): 2025

To answer the question of where we

stand, we summarize the current data for

and against the long-term effects of ACS.

Evidence for and against the long-term

effects of ACS

In recent years, there has been much

evidence for and against the long-term ef-

fects of ACS (Table 5) 2,3,7-9,18,23-27,29,35-37,42,43.

Summary and conclusions

Animal studies have found that ACS af-

fect many organs. Observational and clini-

cal trials of maternal ACS show no evidence

of increased disability on follow-up and de-

scribe associations rather than a proximate

cause.

ACS in women at high risk for PB ap-

pears to improve most neurodevelopmental

Table 5. Evidence for and against long-term effects of ACS 2,3,7-9,18,23-27,29,35-37,42,43

FOR

– Several concerns have been raised on the potential long-term effects of ACS* on cerebral function and

neonatal growth.

– It is now well recognized that exposure to an adverse in utero environment during development has

long-term effects on physiology and later risk of adult disease.

– Large observational studies have reported reduced neonatal weight and length in children exposed to ACS.

– Cardiovascular and metabolic abnormalities have been identified in large animal models and cohorts

of children exposed to ACS that are consistent with fetal programming for adult diseases.

– There are observational data linking exposure to multiple courses of ACS to increased rates of

aggressive, destructive, distractible and hyperkinetic behavior at both ages of 3 and 6 years.

– Siblings exposed to ACS were more likely to exhibit any childhood mental or behavioral disorder.

– The RCT data also do not strongly support the optimal interval from ACS to delivery of 1-7 days.

– Epidemiology-based studies using large cohorts with >85% of at-risk pregnancies treated with ACS,

probably overestimate the benefits of ACS.

– Although most of the prematurity-associated mortality is in low-resource environments, the efficacy

and safety of ACS in those environments remain to be evaluated.

AGAINST

– The long-term outcomes in human children are not well understood. Animal studies have found that ACS

affect many organs across multiple stages of life.

– Data from RCT on the long-term effects of ACS on the fetal brain are limited. Another important factor is

that many of the included infants were born prematurely and it is likely that the immediate benefits of ACS

compensate for the potential long-term adverse effects of ACS.

– Observational reports describe associations rather than proximate cause and are subject to bias from unde-

tected and undetectable confounders.

– These high evidence level randomized data will allow us to reframe the late preterm ACS discussion around

the uncertain risk of developmental delay.

– ACS-exposed children born extremely preterm had a markedly lower risk of neurodevelopmental impair-

ment and/or psychological outcomes when compared with unexposed children.

– ACS in women at high risk for PB appears to improve most neurodevelopmental outcomes in offspring born

before 34 weeks of gestation and is significantly associated with reduced mortality before 3 years of age in very

low birth weight infants with chorioamnionitis (do not alter neurodevelopmental outcomes).

– Other studies either found no difference in neurodevelopmental outcomes or attributed the increased observed

risk for adverse neurologic outcomes among term-born children to receiving multiple courses (rather than a single

course) of ACS or to the underlying condition threatening preterm delivery rather than the steroid exposure itself.

– The short-term benefits of ACS for high-risk pregnancies in high-resource environments certainly justify ACS. Sin-

gle course ACS treatment before preterm delivery must still be recommended as life-saving and cost effective inter-

vention. Late effects of ACS suggest caution for the expanded use of ACS beyond at-risk pregnancies at 24-34 weeks

– Multiple ACS courses are not recommended since 2000.

ACS: Antenatal administration of corticosteroids RCT: Randomized controlled trials PB: Preterm birth.

Long-term effects of antenatal administration of corticosteroids. Where are we? 343

Vol. 66(3): 332 - 346, 2025

outcomes before 34 weeks of gestation, and

reduces mortality before three years of age

in very low birth weight infants with chorio-

amnionitis.

Other studies either found no difference

in neurodevelopmental outcomes or attrib-

uted the increased observed risk for adverse

neurologic outcomes among term-born chil-

dren to receiving multiple courses of ACS or

to the underlying condition threatening PB

rather than the steroid exposure itself.

On the long-term effects of ACS on

the fetal brain, there are limited data from

RCTs. The interpretation of available RCT

data is further hampered by both the lack

of an unexposed control group and insuffi-

cient power to detect significant differences

in rare events. Additionally, many of the in-

cluded infants were born prematurely, which

is another important factor.

In high-resource environments, the

short-term benefits of ACS for high-risk

pregnancies certainly justify ACS. Single-

course ACS treatment before preterm de-

livery must still be recommended as a life-

saving and cost-effective intervention.

Cautioning against the expanded use

of ACS beyond at-risk pregnancies at 24-34

weeks suggests late effects of ACS.

Multiple ACS courses are not recom-

mended since 2000.

The long-term outcomes in human chil-

dren are not well understood. Therefore,

the possible association between ACS and

long-term neurodevelopmental outcomes in

exposed children should be further investi-

gated. Specifically, longitudinal studies and

large RCTs are needed to provide more in-

sight into this topic.

Statement of ethics

This study was approved by the Univer-

sity of Zulia Ethics Committee (number 21-

2024) on March 21, 2024. It adhered to the

laws and national ethical guidelines of Ven-

ezuela, as well as the COPE guidelines and

the Declaration of Helsinki.

Conflict of interest

The authors declare that they have no

conflicts of interest.

Funding Sources

The authors did not receive support

from any organization for the submitted

work.

ORCID number of authors

• Carlos Briceño-Perez (CBP):

0000-0002-3270-8236

• Liliana Briceño-Sanabria (LBS):

0000-0002-5045-0072

• Eduardo Reyna-Villasmil (ERV):

0000-0002-5433-7149

• Paulino Vigil-De Gracia (PVDG):

0000-0002-1494-3654

Author contributions

CBP contributed to the study concep-

tion. CBP, LBS, ERV and PVDG contributed

to the design, researched literature, anal-

ized it and design the protocol, manuscript

revision and approved final version.

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