Scolaris Content Display Scolaris Content Display

Corticosteroides prenatales para acelerar la maduración del pulmón fetal en mujeres con riesgo de parto prematuro

This is not the most recent version

Collapse all Expand all

Resumen

available in

Antecedentes

La morbilidad respiratoria, incluido el síndrome de dificultad respiratoria (SDR), es una complicación grave del parto prematuro y la causa principal de mortalidad neonatal temprana y discapacidad. Cuando investigaba los efectos del corticosteroide dexametasona sobre el parto prematuro en fetos de ovejas en 1969, Liggins encontró que se producía más distensión de los pulmones de las ovejas nacidas de gestaciones en que se esperaría una mala ventilación pulmonar. Liggins y Howie publicaron el primer ensayo controlado aleatorizado en seres humanos en 1972, al cual le siguieron muchos otros.

Objetivos

Evaluar los efectos de la administración de un ciclo de corticosteroides a la madre antes del parto prematuro previsto sobre la morbilidad y la mortalidad fetal y neonatal, la mortalidad y la morbilidad materna, y sobre el niño en su vida posterior.

Métodos de búsqueda

Se hicieron búsquedas en el registro de ensayos del Grupo Cochrane de Embarazo y Parto (Cochrane Pregnancy and Childbirth's Trials Register) (17 febrero 2016) y en las listas de referencias de los estudios obtenidos.

Criterios de selección

En esta revisión, se consideraron para la inclusión todas las comparaciones controladas aleatorias de administración de corticosteroides prenatales (betametasona, dexametasona o hidrocortisona) con placebo o ningún tratamiento, a mujeres con un embarazo único o múltiple, antes del parto prematuro previsto (electivo o después del trabajo de parto espontáneo), independientemente de otra comorbilidad. En esta revisión la mayoría de las mujeres recibieron un único ciclo de corticosteroides; sin embargo, nueve de los ensayos incluidos permitieron que se les repitiera a las mujeres a la semana.

Obtención y análisis de los datos

Dos autores de la revisión de forma independiente evaluaron los ensayos para la inclusión y el riesgo de sesgo, extrajeron los datos y verificaron su exactitud. La calidad de la evidencia se evaluó mediante los criterios GRADE.

Resultados principales

Esta actualización incluye 30 estudios (7774 mujeres y 8158 lactantes). La mayoría de los estudios tienen riesgo bajo o incierto en la mayoría de los dominios de sesgo. Una evaluación de alto riesgo generalmente significó que un ensayo tenía la posibilidad de sesgo de realización debido a la falta de cegamiento. Dos ensayos tuvieron riesgo bajo de sesgo en todos los dominios de riesgo de sesgo.

El tratamiento con corticosteroides prenatales (en comparación con placebo o ningún tratamiento) se asocia con una reducción de los desenlaces adversos más graves relacionados con la prematuridad, que incluyen: muerte perinatal (riesgo relativo (RR) promedio 0,72, intervalo de confianza (IC) del 95%: 0,58 a 0,89; participantes = 6729; estudios = 15; Tau² = 0,05, I² = 34%; calidad moderada); muerte neonatal (RR 0,69; IC del 95%: 0,59 a 0,81; participantes = 7188;estudios = 22); SDR (RR medio 0,66, IC del 95%: 0,56 a 0,77; participantes = 7764; estudios = 28; Tau² = 0,06, I² = 48%; calidad moderada); SDR moderado/grave (RR medio 0,59, IC del 95%: 0,38 a 0,91; participantes = 1686; estudios = 6; Tau² = 0,14, I² = 52%); hemorragia intraventricular (Hiv) (RR medio 0,55; IC del 95%: 0,40 a 0,76;participantes = 6093; estudios = 16; Tau² = 0,10, I² = 33%; calidad moderada); enterocolitis necrosante (RR 0,50; IC del 95%: 0,32 a 0,78; participantes = 4702; estudios = 10); necesidad de ventilación mecánica (RR 0,68; IC del 95%: 0,56 a 0,84; participantes = 1368; estudios = 9); e infecciones sistémicas en las primeras 48 horas de vida (RR 0,60; IC del 95%: 0,41 a 0,88; participantes = 1753; estudios = 8).

No hubo beneficios obvios para: enfermedad pulmonar crónica (RR medio 0,86; IC del 95%: 0,42 a 1,79; participantes = 818; estudios = 6; Tau² = 0,38 I² = 65%); peso medio al nacer (g) (DM ‐18,47; IC del 95%: ‐40,83 a 3,90; participantes = 6182; estudios = 16; calidad moderada); muerte en la infancia (RR 0,68, IC del 95%: 0,36 a 1,27; participantes = 1010; estudios = 4); retraso en el desarrollo neurológico en la infancia (RR 0,64, IC del 95%: 0,14 a 2,98; participantes = 82; estudios = 1); o muerte en la edad adulta (RR 1,00, IC del 95%: 0,56 a 1,81; participantes = 988; estudios = 1).

El tratamiento con corticosteroides prenatales no aumenta el riesgo de corioamnionitis (RR 0,83; IC del 95%: 0,66 a 1,06; participantes = 5546; estudios = 15; evidencia de calidad moderada) ni de endometritis (RR 1,20; IC del 95%: 0,87 a 1,63; participantes = 4030; estudios = 10; Tau² = 0,11, I² = 28%; calidad moderada). No se observó un aumento en el riesgo de la mortalidad materna. Sin embargo, los datos sobre la muerte materna se basan en los datos de un ensayo único con dos muertes; los otros cuatro ensayos que informan la muerte materna tuvieron cero eventos (participantes = 3392; estudios = 5; calidad moderada).

No existe evidencia definitiva para indicar que los corticosteroides prenatales funcionan de manera diferente en ningún subgrupo predeterminado (embarazo único versus múltiple; estado de las membranas; presencia de hipertensión) ni en protocolos de estudio diferentes (tipo de corticosteroide; ciclo único o repeticiones semanales).

Los desenlaces GRADE se disminuyeron a calidad moderada. Las decisiones para la disminución (para la muerte perinatal, el SDR, la Hiv y el peso promedio al nacer) se debieron a las limitaciones en el diseño de los estudios o a inquietudes con respecto a la precisión (corioamnionitis, endometritis). La muerte materna se disminuyó por imprecisión debido a la poca cantidad de eventos.

Conclusiones de los autores

La evidencia de esta nueva revisión apoya el uso continuado de un ciclo único de corticosteroides prenatales para acelerar la maduración del pulmón fetal en mujeres con riesgo de parto prematuro. Un ciclo único de corticosteroides prenatales se debe considerar la práctica habitual para el parto prematuro. Es importante señalar que la mayor parte de la evidencia proviene de países de ingresos altos y de contextos hospitalarios; por lo tanto, los resultados no pueden ser aplicables a los ámbitos de bajos recursos con altas tasas de infecciones.

Hay poca necesidad de ensayos adicionales de un ciclo único de corticosteroides prenatales versus placebo en embarazos únicos en países de ingresos más altos y en contextos hospitalarios. Sin embargo, los datos en ámbitos de menores ingresos son escasos. También hay pocos datos con respecto a los riesgos y los efectos beneficiosos de los corticosteroides prenatales en los embarazos múltiples y otros grupos obstétricos de alto riesgo. También se necesita más información con respecto al intervalo óptimo de dosis hasta el parto y el corticosteroide óptimo a utilizar.

Se estimula a los autores de los estudios anteriores a que proporcionen mayor información que pueda responder otras interrogantes acerca de la administración de corticosteroides prenatales en estos embarazos sin la necesidad de ensayos controlados aleatorizados adicionales. Es probable que el metanálisis de los datos de pacientes individuales de los ensayos publicados responda algunas de las brechas en la evidencia. Se necesitan estudios de seguimiento en la niñez y la edad adulta, en especial en los grupos de embarazos prematuros tardíos y ciclos repetidos. En esta revisión no se han examinado los posibles efectos perjudiciales de los corticosteroides prenatales en los ámbitos de bajos recursos. Sería particularmente relevante explorar este resultado en ensayos prospectivos con poder estadístico suficiente.

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Resumen en términos sencillos

Corticosteroides prenatales para acelerar la maduración del pulmón fetal en mujeres con riesgo de parto prematuro

¿Cuál es el problema?

Los neonatos que nacen muy temprano, o muy prematuros, tienen riesgo de presentar dificultades para respirar y otros problemas de salud graves al nacer, durante la niñez y en las etapas posteriores de la vida. Algunos neonatos que nacen muy temprano no sobreviven a estas dificultades. Algunos neonatos tienen problemas de salud que impiden que se desarrollen como deberían, lo que puede dar lugar a problemas con el movimiento o el aprendizaje. Los corticosteroides administrados a las mujeres en trabajo de parto temprano aceleran la maduración pulmonar de los bebés y reducen el número de neonatos que mueren o sufren problemas respiratorios al nacer.

¿Por qué es esto importante?

Las dificultades respiratorias son la causa principal de los problemas de muerte y de salud graves de los neonatos que nacen muy temprano. Las embarazadas que presentan rotura de las membranas o trabajo de parto prematuro espontáneo pueden recibir corticosteroides para ayudar a madurar los pulmones del bebé. En esta revisión se compararon las mujeres y los bebés que recibieron estos fármacos con las mujeres y los bebés que no los recibieron.

¿Qué evidencia se encontró?

Se hicieron búsquedas en el registro de ensayos del Grupo Cochrane de Embarazo y Parto (Cochrane Pregnancy and Childbirth's Trials Register ) (17 de febrero de 2016).

Se consideraron 30 ensayos en los que se administraron corticosteroides a las mujeres con riesgo de parto prematuro (7774 mujeres y 8158 lactantes). Todos los ensayos se realizaron en hospitales de países de altos ingresos. La revisión actual muestra que un único ciclo de corticosteroides, administrado a la madre durante el trabajo de parto prematuro y antes de que el bebé nazca, ayuda a desarrollar los pulmones del bebé y reduce complicaciones como los problemas respiratorios. Además, este tratamiento da lugar a que menos bebés mueran al nacer y a que menos presenten otros problemas de salud graves que habitualmente afectan a los neonatos que nacen muy temprano (como la hemorragia en el cerebro o el daño a los intestinos del neonato).

En la madre, recibir un ciclo único de corticosteroides no pareció repercutir sobre el número de mujeres que tuvieron infecciones de la matriz (corioamnionitis o endometritis). Hubo muy pocos datos disponibles para evaluar completamente el desenlace de muerte materna.

La calidad de la evidencia de los ensayos fue moderada, lo que significa que hay una confiabilidad razonable acerca de que estudios futuros similares de corticosteroides en ámbitos hospitalarios establecerán las mismas conclusiones acerca de los efectos beneficiosos y la seguridad del tratamiento en las mujeres y sus hijos.

¿Qué significa esto?

La mayoría de las mujeres embarazadas con riesgo de tener un parto muy temprano o muy prematuro se beneficiarán de recibir corticosteroides. Este fármaco parece ser seguro para las embarazadas y los bebés cuando se administra en ámbitos hospitalarios en países de ingresos altos, y mejora la oportunidad de que el neonato prematuro sobreviva y se eviten problemas de salud inmediatos. Hay menos información acerca de la repercusión de los corticosteroides en las mujeres con embarazos múltiples y en las mujeres con otros problemas durante el embarazo como la hipertensión o las membranas rotas. No existe seguridad acerca de qué corticosteroide específico o qué dosis son mejores para las mujeres y los bebés.

La evidencia de esta revisión proviene de países de ingresos altos y de contextos hospitalarios; por lo tanto, los resultados no pueden ser aplicables a los ámbitos de bajos recursos con altas tasas de infecciones.

Authors' conclusions

Implications for practice

The evidence from this review update supports the continued use of a single course of antenatal corticosteroids in women at risk of preterm birth. Treatment with antenatal corticosteroids reduces the risk of perinatal death, neonatal death, RDS, IVH, necrotising enterocolitis, need for respiratory support and NICU admission, even in the current era of advanced neonatal care.

Antenatal corticosteroids can continue to be used in women at high risk of preterm birth. Further information is required regarding the optimal dose‐to‐delivery interval, the optimal steroid, the effects in multiple pregnancy and long‐term effects into adulthood. We advise that birth should not be delayed to administer antenatal corticosteroids when there are serious concerns about maternal condition that will be alleviated by expedited delivery.

It is important to note that most of the evidence in this review comes from high‐income countries and hospital settings; therefore, the results may not be applicable to low‐resource settings with high rates of infections.

Implications for research

There is little need for further trials of a single course of antenatal corticosteroids versus placebo in singleton pregnancies in high‐income countries and hospital settings. However, data are sparse in lower‐income settings. There are also few data regarding risks and benefits of antenatal corticosteroids in multiple pregnancies and other high‐risk obstetric groups. We encourage authors of previous studies to provide further information, which may answer any remaining questions about the use of antenatal corticosteroids in such pregnancies without the need for further randomised controlled trials. Individual patient data meta‐analysis from published trials is likely to answer some of the evidence gaps. Follow‐up studies into childhood and adulthood, particularly in the late‐preterm‐gestation and repeat‐courses groups are needed. The possible harmful effects of antenatal corticosteroids in low‐resource settings were not examined in this review. It would be particularly relevant to explore this finding in adequately powered prospective trials.

Summary of findings

Open in table viewer
Summary of findings 1. Corticosteroids versus placebo or no treatment

Corticosteroids versus placebo or no treatment

Patient or population: pregnant women at high risk of preterm birth receiving a corticosteroid or placebo/no treatment; women with singleton and multiple pregnancy and intact and ruptured membranes
Setting: hospital settings in high‐income countries. For example, data for RDS come from 28 trials in 15 different countries, but only one of these countries is of lower income (Tunisia)
Intervention: corticosteroids (dexamethasone or betamethasone) according to various doses and regimens; some trials with weekly repeats
Comparison: placebo (usually normal saline) or no treatment

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with placebo or no treatment

Risk with corticosteroids

Maternal death

Study population

RR 0.98
(0.06 to 15.50)

3392
(5 RCTs)

⊕⊕⊕⊝
Moderate1

RR based on 2 deaths in a single trial (1 death in each group). Four trials reported zero events

1 per 1000

1 per 1000
(0 to 9)

Chorioamnionitis

Study population

RR 0.83
(0.66 to 1.06)

5546
(15 RCTs)

⊕⊕⊕⊝
Moderate2

48 per 1000

40 per 1000
(32 to 51)

Endometritis (infections)

Study population

RR 1.20
(0.87 to 1.63)

4030
(10 RCTs)

⊕⊕⊕⊝
Moderate2,3

7 of 10 trials reported endometritis; the remaining trials report 'infections'

33 per 1000

39 per 1000
(27 to 59)

Perinatal deaths

Study population

average RR 0.72
(0.58 to 0.89)

6729
(15 RCTs)

⊕⊕⊕
Moderate4

102 per 1000

73 per 1000
(59 to 91)

Respiratory distress syndrome

Study population

average RR 0.66
(0.56 to 0.77)

7764
(28 RCTs)

⊕⊕⊕
Moderate5

176 per 1000

116 per 1000
(98 to 135)

Intraventricular haemorrhage

Study population

average RR 0.55
(0.40 to 0.76)

6093
(16 RCTs)

⊕⊕⊕
Moderate6

51 per 1000

28 per 1000
(20 to 39)

Mean birthweight (grams)

(less is worse)

Absolute risks not calculated

The mean birthweight was 18.47g less (40.83g less to 3.90g more)

6182
(16 RCTs)

⊕⊕⊕
Moderate7

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: we are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect
Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect

1Few events and wide confidence interval led to a downgrade for imprecision (‐1). Because maternal death is a rare event and the total population is over 3000 women, we have opted for (‐1) rather than (‐2).
2Wide confidence interval crossing the line of no effect (‐1).
3Value of I2 = 34% with random‐effects model. We have not downgraded evidence for heterogeneity.
4Value of I2 = 37% with random‐effects model. We have not downgraded for heterogeneity. Result downgraded once for risks of bias in included trials (‐1).
5Value of I2 = 47% with random‐effects model. We have not downgraded for heterogeneity. Result downgraded once for risks of bias in included trials (‐1).
6Value of I2 = 33% with random‐effects model. We have not downgraded for heterogeneity. Result downgraded once for risks of bias in included trials (‐1).
7The confidence interval showed a difference at most on average of 40 g in weight; because this is less than 10% of the lightest average for babies in any trial, we have not downgraded evidence for imprecision. We have downgraded the result for risks of bias concerns in included trials (‐1).

Background

Description of the condition

Respiratory distress syndrome (RDS) is a serious complication of preterm birth and the primary cause of early neonatal death and disability (Rodriguez 2002). It affects up to half of babies born before 28 weeks and a third of babies born before 32 weeks. Approximately 42% of extremely low birthweight babies have RDS (less than 1500 g) (Hintz 2007).

Respiratory failure in these infants occurs as a result of surfactant deficiency, poor lung anatomical development and immaturity in other organs. Neonatal survival after preterm birth improves with gestation (Doyle 2001a), reflecting improved maturity of organ systems. However, those who survive early neonatal care are at increased risk of long‐term neurological disability (Doyle 2001b).

Some understanding of fetal lung development may be useful in understanding why RDS occurs and why corticosteroids work. Fetal lung development can be divided into five stages: embryonic, pseudoglandular, canalicular, terminal sac and alveolar. The lung first appears as an outgrowth of the primitive foregut at 22 to 26 days after conception. By 34 days, the outgrowth has divided into left and right sides and further to form the major units of the lung. Mature lungs contain more than 40 different cell types derived from this early tissue. From eight to 16 weeks' gestation, the major bronchial airways and associated respiratory units of the lung are progressively formed. At this time the lung blood vessels also begin to grow in parallel. From 17 to 25 weeks' gestation, the airways grow, widen and lengthen (canalisation). Terminal bronchioles with enlargements that subsequently give rise to terminal sacs (the primitive alveoli) are formed. These are the functional units of the lung (respiratory lobules). It is at this stage that the increasing proximity of blood capillaries begins the air‐blood interface, required for effective air exchange. This can only take place at the terminal bronchioles. At the end of the canalicular stage, type I and II pneumocytes can be seen in the alveoli. From 28 to 35 weeks' gestation, the alveoli can be counted and with increasing age they become more mature. Lung volume increases four‐fold between 29 weeks and term. Alveolar number shows a curvilinear increase with age but a linear relationship with bodyweight. At birth there are an average of 150 million alveoli (half the expected adult number). The alveoli produce surfactant. The alveolar stage continues for one to two years after birth. In the preterm infant, low alveolar numbers probably contribute to respiratory dysfunction.

The fetal lung also matures biochemically with increasing gestation. Lamellar bodies, which store surfactant, appear at 22 to 24 weeks. Surfactant is a complex mixture of lipids and apoproteins, the main constituents of which are dipalmitoylphosphatidyl choline, phosphatidylglycerol and apoproteins A, B, C and D. Surfactant is needed to maintain stability when breathing out, to prevent collapse of the alveoli. Premature infants have a qualitative and quantitative deficiency of surfactant, which predisposes to RDS. At the low lung volume associated with expiration, surface tension becomes very high, leading to atelectasis with subsequent intrapulmonary shunting, ventilation perfusion inequalities, and ultimately respiratory failure. Capillary leakage allows inhibitors from plasma to reach alveoli and inactivate any surfactant that may be present. Hypoxia, acidosis and hypothermia (common problems in the very preterm infant) can reduce surfactant synthesis required to replenish surfactant lost from the system. The pulmonary antioxidant system develops in parallel to the surfactant system and deficiency in this also puts the preterm infant at risk of chronic lung disease.

Description of the intervention

While researching the effects of the steroid dexamethasone on premature parturition in fetal sheep in 1969, Liggins found that there was some inflation of the lungs of lambs born at gestations at which the lungs would be expected to be airless (Liggins 1969). Liggins and Howie performed the first randomised controlled trial in humans of betamethasone for the prevention of RDS in 1972 (Liggins 1972a).

Several clinical trials have been performed on the effects of corticosteroids before preterm birth since the original Liggins study. The first structured review on corticosteroids in preterm birth was published in 1990 (Crowley 1990). This review showed that corticosteroids given prior to preterm birth (as a result of either preterm labour or planned preterm delivery) are effective in preventing RDS and neonatal mortality. Corticosteroid treatment was also associated with a significant reduction in the risk of intraventricular haemorrhage (IVH). Corticosteroids appear to exert major vasoconstrictive effects on fetal cerebral blood flow, protecting the fetus against IVH at rest and when challenged by conditions causing vasodilatation such as hypercapnia (Schwab 2000). Crowley found no effect on necrotising enterocolitis or chronic lung disease from antenatal corticosteroid administration. The influence of the results of the original trial and Crowley's review was the subject of a Wellcome Witness Seminar (Wellcome 2005) held in 2004.

Corticosteroids have become the mainstay of prophylactic treatment in preterm birth, as a result of these findings and subsequent work. However, there have remained a number of outstanding issues regarding the use of antenatal corticosteroids. The original trial by Liggins suggested an increased rate of stillbirth in women with hypertension syndromes (Liggins 1976). There is concern about using corticosteroids in women with premature rupture of membranes due to the possible increased risk of neonatal and maternal infection (Imseis 1996; NIH 1994). The efficacy of this treatment in multiple births has only been addressed retrospectively (Turrentine 1996). From the time of the original Liggins paper, debate has continued around whether the treatment is effective at lower gestations and at differing treatment‐to‐delivery intervals. Recently, debate has also centred around whether treatment is effective at latter gestations, up to and including term delivery (Sotiriadis 2009). These issues will be addressed in this review in subgroup analyses. The effectiveness and safety of repeat doses of corticosteroids for women who remain undelivered, but at increased risk of preterm birth after an initial course of treatment, is addressed in a separate Cochrane Review (Crowther 2015).

Recent epidemiological evidence and animal work suggests that there may be adverse long‐term consequences of antenatal exposure to corticosteroids (Seckl 2000). Exposure to excess corticosteroids before birth is hypothesised to be a key mechanism underlying the fetal origins of adult disease hypothesis (Barker 1998; Benediktsson 1993). This hypothesis postulates a link between impaired fetal growth, and cardiovascular disease and type 2 diabetes in later life along with their risk factors of impaired glucose tolerance, dyslipidaemia, and hypertension (Barker 1998). A large body of animal experimental work has documented impaired glucose tolerance and increased blood pressure in adult animals after antenatal exposure to corticosteroids (Clark 1998; Dodic 1999; Edwards 2001). Thus, this review has considered blood pressure, glucose intolerance, dyslipidaemia, and hypothalamo‐pituitary‐adrenal axis function in childhood and adulthood.

Experimental animal studies have also shown decreased brain growth in preterm and term infants exposed to single courses of corticosteroid (Huang 1999; Jobe 1998). This review has therefore also addressed long‐term neurodevelopment and other childhood and adult outcomes after antenatal corticosteroid exposure.

How the intervention might work

Liggins 1972a theorised that dexamethasone might have accelerated the appearance of pulmonary surfactant. The hypothesis is that corticosteroids act to trigger the synthesis of ribonucleic acid that codes for particular proteins involved in the biosynthesis of phospholipids or in the breakdown of glycogen. Subsequent work has suggested that, in animal models, corticosteroids mature a number of organ systems (Padbury 1996; Vyas 1997).

Why it is important to do this review

There was a need for an updated systematic review of the effects of prophylactic corticosteroids for preterm birth, as a result of current interest and due to further published trials. In the previous review we were able to re‐analyse the Auckland Steroid Study by intention‐to‐treat. This study contributes 15% of the participants to the review so this was an important development for the review. This update is needed because it has been some time since the previous version was published, review methodology for Cochrane Reviews has changed, and we attempted to standardise the review with the Cochrane Review on 'Repeat doses of prenatal corticosteroids for women at risk of preterm birth for improving neonatal health outcomes' (Crowther 2015).

Objectives

To assess the effects of administering a course of corticosteroids to the mother prior to anticipated preterm birth on fetal and neonatal morbidity and mortality, maternal mortality and morbidity, and on the child in later life.

Methods

Criteria for considering studies for this review

Types of studies

We considered all randomised controlled comparisons of antenatal corticosteroid administration (betamethasone, dexamethasone, or hydrocortisone) with placebo, or with no treatment, given to women prior to anticipated preterm delivery (elective, or following spontaneous labour), regardless of other co‐morbidity, for inclusion in this review. Quasi‐randomised (e.g. allocation by date of birth or record number), cross‐over and cluster‐randomised trials were not eligible for inclusion. We included trials where the method of randomisation was not specified in detail in the expectation that their inclusion in this review would encourage the study authors to make available further information on the method of randomisation. We excluded trials where non‐randomised cohorts were amalgamated with randomised participants if the results of the randomised participants could not be separated out. We also excluded trials that tested the effect of corticosteroids along with other co‐interventions. We included trials in which placebo was not used in the control group. We also included published, unpublished and ongoing randomised trials with reported data.

Types of participants

Women, with a singleton or multiple pregnancy, expected to deliver preterm as a result of either spontaneous preterm labour, preterm prelabour rupture of the membranes or planned preterm delivery.

Types of interventions

Trials tested a corticosteroid capable of crossing the placenta (betamethasone, dexamethasone, hydrocortisone) compared with placebo or with no treatment. Most trials tested a single course of steroid, though some included trials allowed for weekly repeats. We discarded data from trials involving the use of methyl‐prednisolone (Block 1977; Schmidt 1984), as this corticosteroid has not been shown to induce maturation in animal models and is known to have altered placental transfer (Block 1977). We planned predefined subgroups to separately examine primary outcomes in women and infants depending on the specific drug used. Single versus multiple doses of corticosteroids is the subject of another Cochrane Review (Crowther 2015).

Types of outcome measures

Primary outcomes chosen were those which were thought to be the most clinically valuable in assessing effectiveness and safety of the treatment for the woman and her offspring. Secondary outcomes included possible complications and other measures of effectiveness.

Primary outcomes

For the woman:

  1. death;

  2. chorioamnionitis (however defined by study authors);

  3. endometritis (however defined by study authors and including infections).

For the fetus/neonate:

  1. perinatal death;

  2. neonatal deaths;

  3. fetal deaths;

  4. RDS;

  5. moderate/severe RDS;

  6. chronic lung disease (need for continuous supplemental oxygen at 28 days postnatal age or 36 weeks' postmenstrual age, whichever was later);

  7. intraventricular haemorrhage (IVH) (diagnosed by ultrasound, diagnosed by autopsy);

  8. mean birthweight (g).

For the child:

  1. death;

  2. neurodevelopmental disability at follow‐up (blindness, deafness, moderate/severe cerebral palsy (however defined by study authors), or development delay/intellectual impairment (defined as developmental quotient or intelligence quotient less than ‐2 standard deviation below population mean)).

For the child as adult:

  1. death;

  2. neurodevelopmental disability at follow‐up (blindness, deafness, moderate/severe cerebral palsy (however defined by study authors), or development delay/intellectual impairment (defined as developmental quotient or intelligence quotient less than ‐2 standard deviation below population mean)).

Secondary outcomes

For the woman:

  1. fever after trial entry requiring the use of antibiotics;

  2. intrapartum fever requiring the use of antibiotics;

  3. postnatal fever;

  4. admission to intensive care unit;

  5. side effects of therapy;

  6. glucose intolerance (however defined by study authors);

  7. hypertension (however defined by study authors).

For the fetus/neonate:

  1. Apgar score less than seven at five minutes;

  2. interval between trial entry and birth;

  3. mean length at birth (height);

  4. mean head circumference at birth;

  5. mean skin fold thickness at birth;

  6. small‐for‐gestational age (however defined by study authors);

  7. mean placental weight;

  8. neonatal blood pressure;

  9. admission to neonatal intensive care unit (NICU);

  10. need for inotropic support;

  11. mean duration of inotropic support (days);

  12. need for mechanical ventilation/continuous positive airways pressure;

  13. mean duration of mechanical ventilation/continuous positive airways pressure (days);

  14. air leak syndrome;

  15. duration of oxygen supplementation (days);

  16. surfactant use;

  17. systemic infection in first 48 hours of life;

  18. proven infection while in the NICU)

  19. necrotising enterocolitis;

  20. hypothalamo‐pituitary‐adrenal (HPA) axis function (however defined by study authors).

For the child:

  1. mean weight;

  2. mean head circumference;

  3. mean height;

  4. mean skin fold thickness;

  5. abnormal lung function (however defined by study authors);

  6. mean blood pressure;

  7. glucose intolerance (however defined by study authors);

  8. HPA axis function (however defined by study authors);

  9. dyslipidaemia (however defined by study authors);

  10. visual impairment (however defined by study authors);

  11. hearing impairment (however defined by study authors);

  12. developmental delay (defined as developmental quotient less than ‐2 standard deviation below population mean);

  13. intellectual impairment (defined as intelligence quotient less than ‐2 standard deviation below population mean);

  14. cerebral palsy (however defined by study authors);

  15. behavioural/learning difficulties (however defined by study authors).

For the child as adult:

  1. mean weight;

  2. mean head circumference;

  3. mean height;

  4. mean skin fold thickness;

  5. abnormal lung function (however defined by study authors);

  6. mean blood pressure;

  7. glucose intolerance (however defined by study authors);

  8. HPA axis function (however defined by study authors);

  9. dyslipidaemia (however defined by study authors);

  10. mean age at puberty;

  11. bone density (however defined by study authors);

  12. educational achievement (completion of high school, or however defined by study authors);

  13. visual impairment (however defined by study authors);

  14. hearing impairment (however defined by study authors);

  15. intellectual impairment (defined as intelligence quotient less than ‐2 standard deviation below population mean).

For health services:

  1. mean length of antenatal hospitalisation for women (days);

  2. mean length of postnatal hospitalisation for women (days);

  3. mean length of neonatal hospitalisation (days);

  4. cost of maternal care (in 10s of 1000s of USD);

  5. cost of neonatal care (in 10s of 1000s of USD).

Search methods for identification of studies

The following methods section of this review is based on a standard template used by Cochrane Pregnancy and Childbirth.

Electronic searches

We searched Cochrane Pregnancy and Childbirth’s Trials Register by contacting their Information Specialist (17 February 2016).

The Register is a database containing over 22,000 reports of controlled trials in the field of pregnancy and childbirth. For full search methods used to populate Pregnancy and Childbirth’s Trials Register including the detailed search strategies for CENTRAL, MEDLINE, Embase and CINAHL; the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service, please follow this link to the editorial information about Cochrane Pregnancy and Childbirth in the Cochrane Library and select the ‘Specialized Register ’ section from the options on the left side of the screen.

Briefly, Cochrane Pregnancy and Childbirth’s Trials Register is maintained by their Information Specialist and contains trials identified from:

  1. monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);

  2. weekly searches of MEDLINE (Ovid);

  3. weekly searches of Embase (Ovid);

  4. monthly searches of CINAHL (EBSCO);

  5. handsearches of 30 journals and the proceedings of major conferences;

  6. weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Search results are screened by two people and the full text of all relevant trial reports identified through the searching activities described above is reviewed. Based on the intervention described, each trial report is assigned a number that corresponds to a specific Pregnancy and Childbirth review topic (or topics), and is then added to the Register. The Information Specialist searches the Register for each review using this topic number rather than keywords. This results in a more specific search set which has been fully accounted for in the relevant review sections (Included studies; Excluded studies).

Searching other resources

We searched the reference lists of retrieved studies.

We did not apply any language or date restrictions.

Data collection and analysis

For methods used in the previous version of this review, see Roberts 2006.

For this update, we used the following methods to assess the new reports that were identified as a result of the updated search.

The following methods section of this review is based on a standard template used by Cochrane Pregnancy and Childbirth.

Selection of studies

Two review authors assessed the trials for eligibility and methodological quality without consideration of the results. Reasons for excluding any trial are detailed in the Characteristics of excluded studies table. Trials were not assessed blind, as we knew the author's name, institution and the source of publication. We resolved any disagreement by discussion until we reached consensus.

Data extraction and management

Two review authors extracted the data, checked them for discrepancies and processed them as described in Higgins 2011a. We contacted authors of each included trial for further information, if we thought this to be necessary.

Assessment of risk of bias in included studies

Two review authors independently assessed the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). We resolved any disagreement by discussion.

(1) Random sequence generation (checking for possible selection bias)

We described for each included study the methods used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We assessed the methods as:

  • low risk of bias (any truly random process, e.g. random number table; computer random‐number generator; tossing a coin, minimisation);

  • high risk of bias (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number; quasi‐randomised studies were excluded from the review);

  • unclear risk of bias (unclear description or no description of randomisation sequence generation). 

(2) Allocation concealment (checking for possible selection bias)

We described for each included study the method used to conceal the allocation sequence in sufficient detail and determine whether intervention allocation could have been foreseen in advance of, or during, recruitment.

We assessed the methods as:

  • low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

  • high risk of bias (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);

  • unclear risk of bias.

(3.1) Blinding of participants and personnel (checking for possible performance bias)

We described for each included study all the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We also provided any information relating to whether the intended blinding was effective. Where blinding was not possible, we assessed whether the lack of blinding was likely to have introduced bias.

We assessed the methods as:

  • low, high or unclear risk of bias for participants;

  • low, high or unclear risk of bias for personnel;

  • low, high or unclear risk of bias for outcome assessors

where low risk of bias was when there was blinding or where we assessed that the outcome or the outcome measurement was not likely to have been influenced by lack of blinding.

(3.2) Blinding of outcome assessment (checking for possible detection bias)

We described for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We assessed blinding separately for different outcomes or classes of outcomes.

We have assessed methods used to blind outcome assessment as:

  • low, high or unclear risk of bias.

(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

We described for each included study the completeness of outcome data for each main outcome, including attrition and exclusions from the analysis. We stated whether attrition and exclusions were reported, the numbers included in the analyses at each stage (compared with the total randomised participants), reasons for attrition/exclusion where reported, and any re‐inclusions in analyses undertaken.

We assessed the methods as:

  • low risk of bias (e.g. where there were no missing data or where reasons for missing data were balanced across groups);

  • high risk of bias (e.g. where missing data were likely to be related to outcomes or were not balanced across groups);

  • unclear risk of bias (e.g. where there was insufficient reporting of attrition or exclusions to permit a judgement to be made).

(5) Selective reporting bias

We described for each included study how we examined the possibility of selective outcome reporting bias and what we found.

We assessed the methods as:

  • low risk of bias (where it was clear that all of the study's pre‐specified outcomes and all expected outcomes of interest to the review were reported);

  • high risk of bias (where not all the study's pre‐specified outcomes were reported; one or more reported primary outcomes were not pre‐specified; outcomes of interest were reported incompletely and so could not be used; study failed to include results of a key outcome that would have been expected to have been reported);

  • unclear risk of bias.

(6) Other sources of bias

We described for each included study any important concerns we had about other possible sources of bias. For example, was there a potential source of bias related to the specific study design? Was the trial stopped early due to some data‐dependent process? Was there extreme baseline imbalance? Had the study been claimed to be fraudulent?

We assessed whether each study was free of other problems that could put it at risk of bias:

  • low risk of bias;

  • high risk of bias;

  • unclear.

(7) Overall risk of bias

We made explicit judgements about risk of bias for important outcomes both within and across studies. With reference to (1) to (6) above we assessed the likely magnitude and direction of the bias and whether we considered it likely to impact on the findings.

Assessment of the quality of the evidence using GRADE

For this update the quality of the evidence was assessed using the GRADE approach as outlined in the GRADE Handbook in order to assess the quality of the body of evidence relating to the following outcomes for the main comparison, corticosteroids versus placebo or no treatment.

  1. Maternal death

  2. Chorioamnionitis (however defined by study authors)

  3. Endometritis (however defined by study authors and including infections)

  4. Perinatal death

  5. Respiratory distress syndrome

  6. Intraventricular haemorrhage (IVH) (diagnosed by ultrasound, diagnosed by autopsy)

  7. Mean birthweight (g)

We used the GRADEpro Guideline Development Tool to import data from Review Manager 5 (RevMan 5) (RevMan 2014) in order to create 'Summary of findings' tables. A summary of the intervention effect and a measure of quality for each of the above outcomes was produced using the GRADE approach. The GRADE approach uses five considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence for each outcome. The evidence can be downgraded from 'high quality' by one level for serious (or by two levels for very serious) limitations, depending on assessments for risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect estimates or potential publication bias.

Measures of treatment effect

Dichotomous data

In the original review, a weighted estimate of the typical treatment effect across studies was performed using the 'Peto method' (i.e. 'the typical odds ratio': the odds of an unfavourable outcome among treatment‐allocated participants to the corresponding odds among controls). For this update, we have calculated risk ratios (RR) and 95% confidence intervals (CI) for dichotomous data. Although odds ratios have been commonly used in meta‐analysis, there is potential for them to be interpreted incorrectly, and current advice is that risk ratios should be used wherever possible (Deeks 2011). We analysed outcomes on an intention‐to‐treat basis.

Continuous data

For continuous data, we used the mean difference (MD) with 95% CI where outcomes were measured using the same instrument. Where different instruments were used we planned to use the standardised mean difference with 95% CI.

Unit of analysis issues

Cluster‐randomised trials

Cluster‐randomised trials were not considered eligible for inclusion in this review.

Cross‐over trials

Cross‐over trials were not considered eligible for inclusion in this review.

Other unit of analysis issues

Where possible for multiple pregnancies, the number of babies was used as the denominator for fetal and neonatal outcomes.

Dealing with missing data

In cases where trial data were missing, we first sought information from the original trial investigators. Details of trial authors contacted and the questions asked of them are contained in Characteristics of included studies. In addition, and where possible, we performed analyses on all outcomes on an intention‐to‐treat basis. It was our intention to include in the analyses all women randomly assigned to each group and to analyse all women in the group to which they were allocated, regardless of whether or not they received the allocated intervention.

Assessment of heterogeneity

We assessed statistical heterogeneity in each meta‐analysis using the Tau², I² (Higgins 2003) and Chi² statistics. We regarded heterogeneity as substantial if an I² was greater than 30% and either the Tau² was greater than zero, or there was a low P value (less than 0.10) in the Chi² test for heterogeneity. Where we found substantial heterogeneity we used a random‐effects model to conduct the analysis and attempted to explain possible sources of heterogeneity (Deeks 2011).

Assessment of reporting biases

If there were 10 or more studies in the meta‐analysis we investigated reporting biases (such as publication bias) using funnel plots (Sterne 2011). We assessed funnel plot asymmetry visually. If asymmetry was suggested by a visual assessment, we performed exploratory analyses to investigate it.

Data synthesis

We carried out statistical analysis using the RevMan 5 software (RevMan 2014). We used fixed‐effect meta‐analysis for combining data where it was reasonable to assume that studies were estimating the same underlying treatment effect: that is, where trials were examining the same intervention, and the trials’ populations and methods were judged sufficiently similar.

If there was clinical heterogeneity sufficient to expect that the underlying treatment effects differed between trials, or if substantial statistical heterogeneity was detected, we used random‐effects meta‐analysis to produce an overall summary if an average treatment effect across trials was considered clinically meaningful. The random‐effects summary was treated as the average of the range of possible treatment effects and we have discussed the clinical implications of treatment effects differing between trials. If the average treatment effect was not clinically meaningful, we planned not to combine trials. If we used random‐effects analyses, we presented the results as the average treatment effect with 95% CIs, and the estimates of Tau² and I².

Subgroup analysis and investigation of heterogeneity

We performed analysis of clinical groups for primary outcomes only (where data were available).

We analysed the following clinical groups:

  1. singleton versus multiple pregnancy;

  2. intact membranes versus ruptured membranes at first dose;

  3. pregnancy‐induced hypertension syndromes;

  4. type of glucocorticoid (betamethasone, dexamethasone, hydrocortisone);

  5. decade of trial (post‐hoc, i.e.not pre‐specified in the protocol);

  6. protocol with weekly repeats (post hoc, i.e. not pre‐specified in the protocol);

  7. gestational age at trial entry (post hoc, i.e. not pre‐specified in the protocol).

All covariates were proposed after deliberation with clinical experts. We planned to explore potential differences in the effect of corticosteroids in distinct clinical populations, such as pregnant women with ruptured membranes or multiple pregnancy, and in different types of trials.

For the main analysis we did not adjust data for multiple pregnancies to take account of non‐independence of outcomes for babies from the same pregnancy. For some outcomes there will be a higher correlation between babies from the same pregnancy than between babies from different pregnancies. The degree of non‐independence of outcomes for babies from multiple pregnancies will vary considerably depending on the outcome and the type of multiple pregnancy. For some outcomes the risk of an adverse event will be highly correlated in babies from the same pregnancy (e.g. preterm birth); while for others the degree of correlation will be lower (e.g. fetal death) but still higher than for babies from different pregnancies. In view of this non‐independence, subgroup analysis examining fetal and neonatal outcomes in singleton versus multiple pregnancies must be interpreted with particular caution.

We found that some trials included in this review had a protocol of weekly repeat doses of corticosteroid if the mother remained undelivered. None of the trials that allowed weekly repeat doses reported outcomes separately for those exposed to repeat doses. We performed a post hoc analysis for primary outcomes of trials where a single course was used versus those where weekly repeat doses were allowed in the protocol to determine if the inclusion of such trials biased our results. Single versus multiple doses of corticosteroids is the subject of another Cochrane Review (Crowther 2015). The analysis in this update will differ from that of the single versus multiple doses review, because the latter review includes only those studies where the women were randomised to either single or multiple doses.

Because the case‐fatality rate for RDS has decreased with improvements in neonatal care, we postulated that the effect of corticosteroids may not be as apparent in more recent trials. This hypothesis was tested in a post‐hoc subgroup analysis with trials grouped by the main decade of recruitment or publication of results.

Many trials did not report outcome data split according to the listed clinical characteristics (covariates). Due to this missing information, the total number of events/participants in subgroup analysis for some outcomes does not match the overall analysis. We have indicated in footnotes on the forest plots where the data are discrepant between the main analysis and the clinical subgroups.

All analyses by the covariates listed above should be considered hypothesis‐generating.

Finally, it should be noted that we did not conduct subgroup analysis where there were too few trials reporting data to conduct meaningful analyses.

Sensitivity analysis

We have not conducted any formal sensitivity analysis based on risks of bias in included trials. We conducted sensitivity analysis to determine whether conclusions were robust to decisions made during the review process ‐ for example, regarding missing data, the definitions of subgroups or the impact of single trials.

We conducted sensitivity analyses for the following specific cases: where we found heterogeneity greater than 50% for primary outcomes (see Comparison 1); where we found small amounts of missing data reported for subgroups compared with the numbers reported in the main analyses (see Comparison 3); where specific trials fitted into multiple potential subgroups for our analysis of gestational age at trial entry (see Comparison 8); and for analysis of results according to the decade of the trial (see Analysis 6.6).

Summary of findings and assessment of the certainty of the evidence

For this update the quality of the evidence was assessed using the GRADE approach as outlined in the GRADE Handbook in order to assess the quality of the body of evidence relating to the following outcomes for the main comparison, corticosteroids versus placebo or no treatment.

  1. Maternal death <<FS: specify time point

  2. Chorioamnionitis (however defined by study authors) <<FS: specify time point

  3. Endometritis (however defined by study authors and including infections) <<FS: specify time point

  4. Perinatal death <<FS: what's the definition of perinatal death?

  5. Respiratory distress syndrome <<FS: any RDS, or just moderate/severe?

  6. Intraventricular haemorrhage (IVH) (diagnosed by ultrasound, diagnosed by autopsy) <<FS: any IVH, or just grades 3 and 4?

  7. Mean birthweight (g)

We used the GRADEpro Guideline Development Tool to import data from Review Manager 5 (RevMan 5) (RevMan 2014) in order to create 'Summary of findings' tables. A summary of the intervention effect and a measure of quality for each of the above outcomes was produced using the GRADE approach. The GRADE approach uses five considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence for each outcome. The evidence can be downgraded from 'high quality' by one level for serious (or by two levels for very serious) limitations, depending on assessments for risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect estimates or potential publication bias.

Results

Description of studies

Results of the search

A total of 48 studies were identified and 30 met the inclusion criteria. Twenty‐eight were excluded. One study report previously in ongoing studies was included at this update with the full trial report (Gyamfi‐Bannerman 2016).

Included studies

Thirty studies met our inclusion criteria, with data available for 7774 women and 8158 infants. The included studies were conducted over a wide range of gestational ages, including those of extreme prematurity and late prematurity. Obstetric indications for recruitment to trials were premature rupture of membranes, spontaneous preterm labour and planned preterm delivery. Please also refer to the Characteristics of included studies tables.

The included studies came from a range of healthcare systems and treatment eras. Thirteen of the studies were conducted in the USA (Block 1977; Carlan 1991; Collaborative 1981; Garite 1992; Goodner 1979; Gyamfi‐Bannerman 2016; Lewis 1996; Morales 1989; Nelson 1985; Parsons 1988; Shanks 2010; Silver 1996; Taeusch 1979), two studies each were conducted in Finland (Kari 1994; Teramo 1980), Iran (Khazardoust 2012; Mansouri 2010), and Brazil (Amorim 1999; Porto 2011), and one study from each of the following countries, Colombia (Lopez 1989), Spain (Cararach 1991), South Africa (Dexiprom 1999), Turkey (Balci 2010), Canada (Doran 1980),Tunisia (Fekih 2002), United Kingdom (Gamsu 1989), New Zealand (Liggins 1972b), Jordan (Qublan 2001), Thailand (Attawattanakul 2015) and the Netherlands (Schutte 1980). In this update, nine recent trials since 2000 contribute approximately 51% of the data available for analysis (Attawattanakul 2015; Balci 2010; Fekih 2002; Gyamfi‐Bannerman 2016; Khazardoust 2012; Mansouri 2010; Porto 2011; Qublan 2001; Shanks 2010).

It should be noted that Khazardoust 2012 contributes no outcome data to the review.

Multiple pregnancy

The majority of trials recruited only women with singleton pregnancy. Twelve trials Collaborative 1981, Dexiprom 1999, Doran 1980, Fekih 2002, Gamsu 1989, Garite 1992, Kari 1994, Liggins 1972b, Schutte 1980, Silver 1996, Taeusch 1979 and Teramo 1980 recruited women with singleton or multiple pregnancy. Of these, only Collaborative 1981, Gamsu 1989, Liggins 1972b and Silver 1996 reported outcome data separately for included women with multiple pregnancy. For two trials recruitment was unclear, and we analysed available data with the mixed population clinical group (Goodner 1979 and Lopez 1989).

Membrane status

Several trials specifically excluded women with premature rupture of membranes: Amorim 1999, Attawattanakul 2015, Balci 2010, Garite 1992, Kari 1994 and Shanks 2010. Twelve trials reported outcome data for women with premature rupture of membranes (Cararach 1991; Carlan 1991; Dexiprom 1999; Fekih 2002; Lewis 1996; Liggins 1972b; Lopez 1989; Morales 1989; Nelson 1985; Parsons 1988; Qublan 2001; Schutte 1980). The remaining included trials reported data for a mixed population or the membrane status of included women was unclear. Only Liggins 1972b reported outcome data separately for women with intact or ruptured membranes.

Type of Steroid

Seven of the included studies used dexamethasone as the corticosteroid in the treatment arm (1585 women and 1708 infants), while 21 studies used betamethasone (6133 women and 6314 infants). One study did not specify the corticosteroid used (Cararach 1991; 18 women and infants), and one study used either betamethasone or dexamethasone (Shanks 2010; 32 women and infants).

Decade of trial

Four included trials were published during the 1970s; nine during the 1980s; eight during the 1990s; five during the 2000s, and four during the 2010s. The largest trial contributing the most data to the review is the recent ALPS study (n = 2831; Gyamfi‐Bannerman 2016). Please see the Included studies tables for details.

Gestational age at trial entry

We have attached a table stating the gestational parameters for trials included in the review (Table 1). For the analysis of clinical subgroups for this update, we have compared trials recruiting women at gestational age of less than and including 35 weeks + 0 days with trials recruiting women 34 weeks + 0 days' gestation or greater for the review's primary outcomes. Most trials fall on either side of this division, with the exception of four studies; Block 1977, Collaborative 1981, Liggins 1972b, and Teramo 1980. Data from Liggins 1972b was available for women receiving their first dose at less than 35 weeks + 0 days and from between 35 weeks + 0 days and 37 weeks + 0 days, footnotes detailing this have been added to the appropriate forest plots. The majority of women in the remaining three studies (Block 1977; Collaborative 1981; Teramo 1980) received their first dose prior to 34 weeks + 0 days, therefore we included these studies in the younger gestational age grouping for the analysis (women less than, and including, 35 weeks and 0 days), but undertook a sensitivity analysis with the studies' data removed.

Open in table viewer
Table 1. Gestational age parameters for included trials

Trial

Year

Minimum

(weeks+days)

Maximum

(weeks+days)

Amorim 1999

1999

28+0

34+6

Attawattanakul 2015

2015

34+0

36+6

Balci 2010

2010

34+0

36+6

Block 1977

1976

Not reported

36+6

Carlan 1991

1991

24+0

34+6

Cararach 1991

1994

28+0

30+6

Collaborative 1981

1981

26+0

37+0

Dexiprom 1999

1999

28+0

34+6

Doran 1980

1980

24+0

34+6

Fekih 2002

2002

26+0

34+6

Gamsu 1989

1989

Not reported

34+6

Garite 1992

1992

24+0

27+6

Goodner 1979

1979

Not reported

33+6

Gyamfi‐Bannerman 2016

2016

34+0

36+6

Kari 1994

1994

24+0

31+6

Khazardoust 2012

(no outcome data)

2012

34+0

37+0

Lewis 1996

1996

24+0

34+6

Liggins 1972b

1972

24+0

36+6

Lopez 1989

1989

27+0

35+0

Mansouri 2010

2010

35+0

36+6

Morales 1989

1989

26+0

34+6

Nelson 1985

1985

28+0

34+6

Parsons 1988

1988

25+0

32+6

Porto 2011

2011

34+0

36+6

Qublan 2001

2001

27+0

34+6

Schutte 1980

1980

26+0

32+6

Shanks 2010

2010

34+0

36+6

Silver 1996

1996

24+0

29+6

Taeusch 1979

1979

Not reported

33+6

Teramo 1980

1980

28+0

35+6

Weekly repeats

Most trials included in this review tested a single course of corticosteroid. Nine of the included studies allowed weekly repeat courses of study medication in their study protocols (Amorim 1999; Carlan 1991; Fekih 2002; Garite 1992; Lewis 1996; Morales 1989; Parsons 1988; Qublan 2001; Silver 1996) (932 women and 946 infants). We conducted post hoc analysis of primary outcomes comparing studies testing a single course of study medication with studies allowing weekly repeat courses.

Excluded studies

We excluded 28 studies. Reasons for exclusion included the following.

  1. The study did not compare a corticosteroid with placebo or no treatment (Abuhamad 1999; Althabe 2015; Dola 1997; Egerman 1998; Garite 1981; Iams 1985; Koivisto 2007; Magee 1997; Minoui 1998; Mulder 1997; Rotmensch 1999; Whitt 1976).

  2. The study was not a randomised controlled trial (Grgic 2003; Halac 1990; Maksic 2008).

  3. The study was a quasi‐randomised trial (Asnafei 2004; Liu 2006; Morales 1986; Morrison 1978; Simpson 1985).

  4. Study participants were combined with a non‐randomised cohort and results were not presented separately (Butterfill 1979; Kuhn 1982).

  5. Two studies were excluded from this update because of greater than 20% post‐randomisation exclusions (Papageorgiou 1979; Schmidt 1984).

  6. Several studies compared repeat‐dose corticosteroids and are eligible for inclusion in the Crowther 2015 review (Khandelwal 2012; Koivisto 2007; Kurtzman 2008; McEvoy 2010).

Refer to Characteristics of excluded studies table.

Risk of bias in included studies

Three studies that were included in the previous review have been excluded. Two (Papageorgiou 1979; Schmidt 1984) were excluded because of greater than 20% post‐randomisation exclusions. The third (Morales 1986) was excluded as it was quasi‐randomised.

Figure 1 and Figure 2 illustrate the risks of bias which are explained in more detail below.


'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies


'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study

Allocation

Sequence generation

We have summarised the methods of randomisation used in the included studies in the Characteristics of included studies table. Thirteen studies used computer‐generated or random number‐generated randomisation sequences (Amorim 1999; Balci 2010; Block 1977; Dexiprom 1999; Garite 1992; Gyamfi‐Bannerman 2016; Khazardoust 2012; Lewis 1996; Liggins 1972b; Nelson 1985; Porto 2011; Qublan 2001; Silver 1996). We considered these studies at low risk of bias from sequence generation. The 17 remaining studies did not describe the method of sequence generation in sufficient detail to enable a judgement of low risk.

Allocation concealment

Thirteen studies used coded drug boxes/vials in order to conceal the randomisation sequence or study treatment. We assessed one of these studies as having a high risk of bias due to a sealed envelope containing the identity of the contents being attached to each vial "to be opened in emergency only in case of an emergency"; the manuscripts do not state how often these were opened (Collaborative 1981). We assessed a further two studies as unclear risk due to insufficient information provided to confirm the boxes were sequentially numbered (Taeusch 1979; Teramo 1980).

Six studies used sealed envelopes (Garite 1992; Khazardoust 2012; Lewis 1996; Morales 1989; Nelson 1985; Shanks 2010), only one of which was described as opaque (Lewis 1996). The remaining studies did not specify if the envelopes were opaque and we therefore assessed them as having an unclear risk of bias.

Eleven studies did not include any description of the method of allocation concealment and we also assessed them as having an unclear risk of bias (Attawattanakul 2015; Cararach 1991; Carlan 1991; Fekih 2002; Gamsu 1989; Goodner 1979; Kari 1994; Lopez 1989; Mansouri 2010; Parsons 1988; Qublan 2001).

Blinding

Eighteen of the included trials were placebo controlled with the majority of these studies using normal saline, or the vehicle of the corticosteroid preparation, as the placebo (Amorim 1999; Block 1977; Collaborative 1981; Dexiprom 1999; Doran 1980; Gamsu 1989; Garite 1992; Goodner 1979; Gyamfi‐Bannerman 2016; Kari 1994; Khazardoust 2012; Liggins 1972b; Mansouri 2010; Porto 2011; Schutte 1980; Silver 1996; Taeusch 1979; Teramo 1980). The remainder of the included trials were not blinded as they used expectant management in the control arm (Attawattanakul 2015; Balci 2010; Cararach 1991; Carlan 1991; Fekih 2002; Lewis 1996; Lopez 1989; Morales 1989; Nelson 1985; Parsons 1988; Qublan 2001; Shanks 2010).

Blinding of outcome assessors was reported in nine of the 30 trials (Amorim 1999; Doran 1980; Gyamfi‐Bannerman 2016; Liggins 1972b; Mansouri 2010; Porto 2011; Schutte 1980; Silver 1996; Taeusch 1979).

Incomplete outcome data

Nine of the 30 studies reported no losses to follow‐up at birth, which was their only time point for measuring outcome (Attawattanakul 2015; Cararach 1991; Doran 1980; Gamsu 1989; Mansouri 2010; Nelson 1985; Parsons 1988; Qublan 2001; Teramo 1980). In the remaining studies, losses to follow‐up were generally small and less than 5%. There was no evidence to suggest that these exclusions occurred preferentially in one arm or the other of the studies, and we assessed all of them as low risk of bias. We assessed 11 trials as unclear risk of bias due to lack of information or unknown impact of stated exclusions. We assessed two trials as high risk of bias due to loss of over 20% (Shanks 2010) or unclear exclusion (Khazardoust 2012); neither of these trials conducted intention‐to‐treat analysis.

The four studies (Collaborative 1981; Kari 1994; Liggins 1972b; Schutte 1980) that reported long‐term follow‐up after the neonatal period had their follow‐up data included regardless of the follow‐up rate unless there was evidence of bias in follow‐up rates between the treatment and control groups; this was not found to be the case. The Collaborative 1981 trial reported 37% loss to follow‐up at three years of age and we judged it to be at unclear risk of bias. Kari 1994 reported 11% loss to follow‐up at two years of age and we judged it as low risk of bias. Liggins 1972b reported 18% loss to follow‐up at four to six years and 44% losses at the 30‐year follow‐up, we judged risk of bias as unclear. Schutte 1980 reported 12% loss to follow‐up at age 10 to 14 years and 21% at the 20‐year follow‐up, we judged risk of bias as unclear.

Selective reporting

Pre‐specified outcomes appear to have been reported on in 24 of the trials; we assessed these trials as low risk of bias (Amorim 1999; Attawattanakul 2015; Block 1977; Collaborative 1981; Dexiprom 1999; Doran 1980; Fekih 2002; Gamsu 1989; Garite 1992; Gyamfi‐Bannerman 2016; Kari 1994; Khazardoust 2012; Lewis 1996; Liggins 1972b; Lopez 1989; Mansouri 2010; Morales 1989; Nelson 1985; Parsons 1988; Porto 2011; Schutte 1980; Silver 1996; Taeusch 1979; Teramo 1980). Three studies were only available in abstract form and were not published as full‐text articles (Cararach 1991; Carlan 1991; Goodner 1979); we assessed these trials as unclear risk of bias. One trial reported on maternal outcomes that were not pre‐specified (Balci 2010) and one trial pre‐specified RDS as an outcome but did not report the data (Shanks 2010). Shanks 2010 also only reported on maternal outcomes. A third trial (Goodner 1979) only reported on RDS and no other maternal or neonatal outcomes; we assessed these three trials as high risk of bias.

Other potential sources of bias

We assessed Shanks 2010 as high risk of other bias because the trial was stopped early due to problems with recruitment.

In only ten studies was evidence available to suggest that sample‐size calculations had been performed prospectively (Attawattanakul 2015; Amorim 1999; Collaborative 1981; Dexiprom 1999; Gyamfi‐Bannerman 2016; Kari 1994; Porto 2011; Shanks 2010; Silver 1996; Taeusch 1979).

In most trials there was insufficient information to asses if other sources of bias existed. There were no other potential sources of bias identified in one trial Amorim 1999. We assessed one other trial (Khazardoust 2012) as being at high risk of bias for the following reason: "data was analysed for 35 women in the intervention arm versus 40 in the control arm because two delivered before cytokine sampling after the second dose of betamethasone, one opted out of the study and two developed high blood pressure".

We were unclear if further translation of Mansouri 2010 would clarify trial methods and consequent risk of bias domains.

Effects of interventions

See: Summary of findings 1 Corticosteroids versus placebo or no treatment

1. Antenatal corticosteroids versus placebo or no treatment (all included studies)

Primary outcomes

Data were not available for all primary outcomes from all included studies.

For the mother

We found similar rates of maternal death in treatment arms, but the calculated risk ratio (RR) is based on just two events from a single trial (one death in each arm); four trials report zero events in both treatment arms limiting our confidence in this finding (RR 0.98, 95% CI 0.06 to 15.50; participants = 3392; studies = 5; moderate‐quality evidence) (Analysis 1.1). There were similar rates of maternal infection: chorioamnionitis (RR 0.83, 95% CI 0.66 to 1.06; participants = 5546; studies = 15; moderate‐quality evidence) (Analysis 1.2) and endometritis (RR 1.20, 95% CI 0.87 to 1.63; participants = 4030; studies = 10; I² = 28%; moderate quality evidence) (Analysis 1.3).

For the fetus or neonate

Treatment with antenatal corticosteroids was associated with an overall average reduction in perinatal death of 28% (average RR 0.72, 95% CI 0.58 to 0.89; participants = 6729; studies = 15; I² = 34%; Tau² = 0.05; moderate‐quality evidence) (Analysis 1.4). This reduction is mainly due to a reduction in neonatal death of 31% (RR 0.69, 95% CI 0.59 to 0.81; participants = 7188; studies = 22) (Analysis 1.5), rather than an impact on fetal death (RR 0.98, 95% CI 0.74 to 1.30; participants = 6729; studies = 15) (Analysis 1.6) where results are inconclusive.

Treatment with antenatal corticosteroids was associated with an overall average reduction in RDS of 34% (average RR 0.66, 95% CI 0.56 to 0.77; participants = 7764; studies = 28; I² = 48%; Tau² = 0.06; moderate‐quality evidence) (Analysis 1.7). Moderate to severe RDS was reduced by 41% compared with no exposure to antenatal corticosteroids (average RR 0.59, 95% CI 0.38 to 0.91; participants = 1686; studies = 6; I² = 52%; Tau² = 0.14) (Analysis 1.8). The impact of corticosteroids on chronic lung disease was inconclusive (average RR 0.86, 95% CI 0.42 to 1.79; participants = 818; studies = 6; I² = 65%; Tau² = 0.38) (Analysis 1.9).

Sensitivity analysis

Moderate/severe RDS and chronic lung disease both had heterogeneity greater than 50%. For moderate/severe RDS (I² = 52%) when we removed one trial (Fekih 2002) with dramatic results favouring steroid use the heterogeneity reduced to 28% for a partial explanation of heterogeneity. Fekih 2002 took place in Tunisia and tested two doses of IM betamethasone 24 hours apart against no treatment (with weekly treatment repeats); the trial was reported in French, and there was limited information to assess several risk of bias domains. The meta‐analysis for chronic lung disease also had heterogeneity over 50%. All included trials were relatively small; three tested betamethasone and three dexamethasone, but the drug used did not explain heterogeneity; neither did the fact that four trials had weekly repeats and two did not (analyses not shown). None of our covariates (membrane status, multiple pregnancy, or decade of trial) explained the heterogeneity found.

Treatment with antenatal corticosteroids was associated with an overall average reduction in IVH of 45% (average RR 0.55, 95% CI 0.40 to 0.76; participants = 6093; studies = 16; I² = 33%; Tau² = 0.10; moderate‐quality evidence) (Analysis 1.10). A reduction was also seen for infants with severe IVH (Grades 3 and 4) (RR 0.26, 95% CI 0.11 to 0.60; participants = 3438; studies = 6; analysis not shown).

Babies in both treatment groups had similar mean birthweight (mean difference (MD) ‐18.47, 95% CI ‐40.83 to 3.90; participants = 6182; studies = 16; I² = 5%; moderate‐quality evidence) (Analysis 1.11).

For the child

The impact of corticosteroid exposure on death in childhood was inconclusive (RR 0.68, 95% CI 0.36 to 1.27; participants = 1010; studies = 4) (Analysis 1.12), with a similar result for neurodevelopmental delay (RR 0.64, 95% CI 0.14 to 2.98; participants = 82; studies = 1) (Analysis 1.13).

For the child as adult

The impact of corticosteroid exposure on death into adulthood was also inconclusive (RR 1.00, 95% CI 0.56 to 1.81; participants = 988; studies = 1) (Analysis 1.14).

Secondary outcomes

Data were available for several of the secondary outcomes that related to the mother, fetus or neonate, child, adult and health services.

For the mother

Women in both treatment groups had similar rates of: fever after trial entry requiring the use of antibiotics (average RR 0.95, 95% CI 0.43 to 2.06; participants = 481; studies = 4; I² = 61%, Tau² = 0.35) (Analysis 1.15), intrapartum fever requiring the use of antibiotics (average RR 0.66, 95% CI 0.09 to 4.89; participants = 319; studies = 2; I² = 36%, Tau² = 0.74) (Analysis 1.16), postnatal fever (RR 0.92, 95% CI 0.64 to 1.33; participants = 1323; studies = 5) (Analysis 1.20), admission to adult intensive care unit (RR 0.74, 95% CI 0.26 to 2.05; participants = 319; studies = 2) (Analysis 1.18), and hypertension (RR 1.00, 95% CI 0.36 to 2.76; participants = 220; studies = 1) (Analysis 1.19).

Five trials reported no side effects for women in any arm. In a sixth trial more women receiving antenatal corticosteroids reported side effects of treatment (RR 0.69, 95% CI 0.59 to 0.82; participants = 3572; studies = 6; all events from a single trial; Analysis 1.17). Most side effects were pain or bruising at the injection site (close to 80% of reported side effects in both arms); other side effects were local reactions at the injection site, gastrointestinal upset, headache and other.

One small study (Amorim 1999), reported that women in the corticosteroid arm were more likely to have glucose intolerance than in the control arm (RR 2.71, 95% CI 1.14 to 6.46; participants = 123; studies = 1; Analysis 1.21). This study used a treatment regimen that included weekly repeat doses of corticosteroids if the infant remained undelivered.

For the fetus or neonate

Treatment with antenatal corticosteroids was associated with a reduction in the incidence of necrotising enterocolitis (RR 0.50, 95% CI 0.32 to 0.78; participants = 4702; studies = 10) (Analysis 1.22). Treatment with antenatal corticosteroids was also associated with fewer infants having systemic infection in the first 48 hours after birth (RR 0.60, 95% CI 0.41 to 0.88; participants = 1753; studies = 8) (Analysis 1.23); however, infants in both treatment arms had similar rates of proven infection while in the NICU (average RR 0.77, 95% CI 0.55 to 1.08; participants = 5707; studies = 13; I² = 34%; Tau² = 0.09) (Analysis 1.24).

Treatment with antenatal corticosteroids was associated with less need for neonatal respiratory support, with a reduction in the need for mechanical ventilation/CPAP (RR 0.68, 95% CI 0.56 to 0.84; participants = 1368; studies = 9) (Analysis 1.25). Infants receiving corticosteroids also required less oxygen supplementation (MD ‐2.86 days, 95% CI ‐5.51 to ‐0.21 days; one study, 73 infants) (Analysis 1.27), and fewer infants receiving corticosteroids needed surfactant (RR 0.68, 95% CI 0.51 to 0.90; participants = 3556; studies = 5) (Analysis 1.28).

Infants in treatment and control groups had similar results for several outcomes: time requiring mechanical ventilation/CPAP (MD ‐1.91 days, 95% CI ‐4.59 to 0.76 days; participants = 471; studies = 3; I² = 77%; Tau² = 3.28) (Analysis 1.26), air leak syndrome (RR 0.76, 95% CI 0.32 to 1.80; participants = 2965; studies = 2) (Analysis 1.29), interval between trial entry and delivery (MD 0.23 days, 95% CI ‐1.86 to 2.32 days; participants = 1513; studies = 3) (Analysis 1.31), incidence of small‐for‐gestational‐age infants (RR 1.11, 95% CI 0.96 to 1.28; participants = 3478; studies = 5) (Analysis 1.32), or HPA axis function (cortisol MD 3.94, 95% CI ‐3.12 to 11.00 log units; participants = 27; studies = 1) (Analysis 1.33).

Fewer infants exposed to antenatal corticosteroids had an Apgar score less than seven at five minutes of age (RR 0.81, 95% CI 0.67 to 0.98; participants = 2419; studies = 10) (Analysis 1.30), or required admission into a NICU (RR 0.90, 95% CI 0.84 to 0.97; participants = 3803; studies = 7) (Analysis 1.34).

For the child

Treatment with corticosteroids was associated with less developmental delay in childhood (RR 0.49, 95% CI 0.24 to 1.00; participants = 518; studies = 2; age at follow‐up three years in one study and unknown in one study) (Analysis 1.35), but results for cerebral palsy less conclusive (RR 0.60, 95% CI 0.34 to 1.03; P = 0.86; participants = 904; studies = 5, age at follow‐up was two to six years in four studies, and unknown in one study) (Analysis 1.36).

Children with and without treatment had similar results for: childhood weight (MD 0.30 kg, 95% CI ‐0.39 to 1.00 kg; participants = 333; studies = 2) (Analysis 1.37), height (MD 1.02 cm, 95% CI ‐0.26 to 2.29 cm; participants = 334; studies = 2) (Analysis 1.38), head circumference (MD 0.27 cm, 95% CI ‐0.08 to 0.63 cm; participants = 328; studies = 2) (Analysis 1.39), lung function (vital capacity (VC) MD ‐1.68 % predicted, 95% CI ‐5.12 to 1.75 % predicted; participants = 150; studies = 2) (Analysis 1.40), forced expiratory volume in one second (FEV1) (MD ‐4.73 % predicted, 95% CI ‐10.13 to 0.67 % predicted; participants = 75; studies = 1) (Analysis 1.41); FEV1/VC (MD ‐0.94, 95% CI ‐3.63 to 1.76; participants = 150; studies = 2; I² = 31%; Tau² = 1.78) (Analysis 1.42), systolic blood pressure (MD ‐1.60 mmHg, 95% CI ‐4.06 to 0.86 mmHg; participants = 223; studies = 1) (Analysis 1.43), visual impairment (RR 0.55, 95% CI 0.24 to 1.23; participants = 166; studies = 2) (Analysis 1.44), hearing impairment (RR 0.64, 95% CI 0.04 to 9.87; participants = 166; studies = 2) (Analysis 1.45), behavioural/learning difficulties (RR 0.86, 95% CI 0.35 to 2.09; participants = 90; studies = 1) (Analysis 1.47) or intellectual impairment (RR 0.86, 95% CI 0.44 to 1.69; participants = 778; studies = 3) (Analysis 1.46).

For the child as adult

Long‐term follow‐up in one study (Liggins 1972b) showed increased insulin release 30 minutes following a fasting 75 g oral glucose tolerance test (MD 0.16 log insulin units, 95% CI 0.04 to 0.28 log insulin units; participants = 412; studies = 1) in 30‐year‐olds who had been exposed to antenatal corticosteroid. Results were inconclusive for fasting glucose concentrations (MD 0.01 mmol/L, 95% CI ‐0.09 to 0.11 mmol/L; participants = 432; studies = 1), or 30 minutes following a 75 g oral glucose tolerance test (MD 0.19 mmol/L, 95% CI ‐0.14 to 0.52 mmol/L; participants = 413; studies = 1). At 120 minutes following a 75 g oral glucose tolerance test, exposure to antenatal corticosteroids was associated with a reduction in glucose concentration (MD ‐0.27 mmol/L; 95% CI ‐0.52 to ‐0.02 mmol/L; P = 0.04; participants = 410; studies = 1) (Analysis 1.48; Analysis 1.49). However, the study reported no difference between those exposed to antenatal corticosteroids and those not exposed in the prevalence of diabetes (results not shown).

The impact of corticosteroids on the following was inconclusive: weight (MD ‐0.83 kg, 95% CI ‐6.41 to 4.76 kg; participants = 538; studies = 2; I² = 60%; Tau² = 14.50) (Analysis 1.50), height (MD 0.91 cm, 95% CI ‐0.28 to 2.10 cm; participants = 537; studies = 2) (Analysis 1.51), head circumference (MD 0.03 cm, 95% CI ‐0.33 to 0.38 cm; participants = 537; studies = 2) (Analysis 1.52), skin fold thickness (triceps MD ‐0.02 log units, 95% CI ‐0.11 to 0.07 log units; participants = 456; studies = 1) (Analysis 1.53), systolic blood pressure (MD ‐1.53 mmHg, 95% CI ‐4.50 to 1.44 mmHg; participants = 545; studies = 2; I² = 47%; Tau² = 3.29) (Analysis 1.54), HPA axis function (cortisol MD 0.06 log units, 95% CI ‐0.02 to 0.14 log units; participants = 444; studies = 1) (Analysis 1.55), cholesterol (MD ‐0.11 mmol/L, 95% CI ‐0.28 to 0.06 mmol/L; participants = 445; studies = 1) (Analysis 1.56), age at puberty (MD for girls 0 years, 95% CI ‐0.94 to 0.94 years; participants = 38; studies = 1) (Analysis 1.57), educational achievement (RR 0.94, 95% CI 0.80 to 1.10; participants = 534; studies = 1) (Analysis 1.58), visual impairment (RR 0.91, 95% CI 0.53 to 1.55; participants = 192; studies = 1) (Analysis 1.59), hearing impairment (RR 0.24, 95% CI 0.03 to 2.03; participants = 192; studies = 1) (Analysis 1.60) or intellectual impairment (RR 0.24, 95% CI 0.01 to 4.95; participants = 273; studies = 2) (Analysis 1.61). There was no difference between those exposed to antenatal corticosteroids and those not exposed for lung function or bone density at age 30 years in participants followed from one study (Liggins 1972b).

Results were similar for treatment groups for all of the other child‐as‐an‐adult outcomes examined (Analysis 1.62; Analysis 1.63; Analysis 1.64; Analysis 1.65; Analysis 1.66; Analysis 1.67; Analysis 1.68; Analysis 1.69; Analysis 1.70; Analysis 1.71; Analysis 1.72; Analysis 1.73; Analysis 1.74; Analysis 1.75; Analysis 1.76; Analysis 1.77; Analysis 1.78; Analysis 1.79; Analysis 1.80; Analysis 1.81; Analysis 1.82; Analysis 1.83).

For the health services

Use of corticosteroids did not appear to shorten antenatal hospitalisation in women in a single small trial (MD 0.50 days, 95% CI ‐1.40 to 2.40 days; participants = 218; studies = 1) (Analysis 1.84); results were also inconclusive for postnatal hospitalisation in women (MD 0.00 days, 95% CI ‐1.72 to 1.72 days; participants = 218; studies = 1) (Analysis 1.85).

Mansouri 2010 (Iran) reported equal numbers of women in each group requiring a hospital stay of more than three days (12/100 corticosteroid and 12/100 placebo); Attawattanakul 2015 (Thailand) reported a similar overall maternal length of stay for both treatment groups (corticosteroid mean 3.57 (SD 0.87), n = 96; control mean 3.58 (SD 0.75), n = 98); and Gyamfi‐Bannerman 2016 (USA; n = 2827) reported a median maternal length of hospital stay of three days (IQR 3 to 5 days) for both treatment groups.

Infants with and without corticosteroids required similar stays in hospital (MD 0.18 days, 95% CI ‐0.51 to 0.87 days; participants = 788; studies = 5) (Analysis 1.86). Gyamfi‐Bannerman 2016 (USA) reported a median neonatal hospitalisation of seven days (IQR 4 to 12 days) in the corticosteroid group (n = 1427) and a median of eight days (IQR 4 to 13 days) for the controls (n = 1400).

Investigation of publication bias

Where more than 10 studies contributed data to the analyses, we inspected funnel plots for evidence of asymmetry and possible publication bias (Figure 3; Figure 4; Figure 5; Figure 6; Figure 7; Figure 8; Figure 9). Funnel plots for two outcomes 1.4 Perinatal deaths (Figure 4) and 1.11 IVH (Figure 8) both showed asymmetry. For perinatal deaths, two studies with very low event rates were the funnel plot outliers; one small study (Parsons 1988) had no events in the corticosteroid arm and one death in the control group, and one large study (Gyamfi‐Bannerman 2016) had no events in the control arm and two deaths in the corticosteroid group. For IVH, the funnel plot mapped 13 of the 16 studies due to no events in both arms of three studies (Attawattanakul 2015; Dexiprom 1999; Mansouri 2010). Two small studies (Lewis 1996; Taeusch 1979) had considerably larger effect sizes than the rest (with no events in the corticosteroid arm), one large study (Gyamfi‐Bannerman 2016) had no events in the control arm, and these studies contributed to funnel plot asymmetry. Publication bias could not be excluded as some of the asymmetry for both of these outcomes appeared attributable to small studies with positive results.


Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.2 Chorioamnionitis

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.2 Chorioamnionitis


Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.4 Perinatal deaths

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.4 Perinatal deaths


Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.5 Neonatal deaths

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.5 Neonatal deaths


Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.6 Fetal deaths

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.6 Fetal deaths


Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.7 Respiratory distress syndrome

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.7 Respiratory distress syndrome


Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.10 Intraventricular haemorrhage

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.10 Intraventricular haemorrhage


Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.11 Mean birthweight (g)

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.11 Mean birthweight (g)

In addition, we inspected funnel plots for evidence of asymmetry and possible publication bias in further analyses where exactly 10 trials contributed data: necrotising enterocolitis, need for mechanical ventilation/CPAP and Apgar less than seven at five minutes. For 1.26 need for mechanical ventilation there was asymmetry (Figure 10); two studies (Attawattanakul 2015; Shanks 2010) with sparse events and wide confidence intervals were the outliers. For 1.31 Apgar less than seven at five minutes of age (Figure 11), all studies apart from one (Gyamfi‐Bannerman 2016) favoured corticosteroids, creating the asymmetry. Due to the limited number of studies contributing to the funnel plots, and the impact of small studies and sparse events, we could not confirm or exclude possible publication bias for these outcomes.


Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.25 Need for mechanical ventilation/CPAP

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.25 Need for mechanical ventilation/CPAP


Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.30 Apgar < 7 at 5 minutes

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.30 Apgar < 7 at 5 minutes

Clinical subgroups

We have analysed the results for prespecified clinical subgroups (covariates) in the comparisons 2, 3 and 4, and added further post hoc analyses to explore the possible impact of change in practice over time (comparison 6), protocols with weekly steroid administration (comparison 7), and gestational age at randomisation (comparison 8). Where there were a sufficient number of trials reporting data for meaningful analyses, we have explored the evidence for the review primary outcomes for women and neonates. These analyses are hypothesis‐generating only and should not be interpreted as conclusive.

2. Antenatal corticosteroids versus placebo or no treatment (singleton and women with multiple pregnancies)

Discrete outcome data for those women delivering multiple pregnancies were available from only four studies (Collaborative 1981; Gamsu 1989; Liggins 1972b; Silver 1996), with the remainder of the studies including only singleton pregnancies, or reporting data from combined singleton and multiple pregnancies. We have been unable to confirm whether the Mansouri 2010 trial included only singleton pregnancy, but this is suggested by the equal numbers of women and infants reported. We have included data from this study in the singleton subgroup.

For the mother

There is no evidence that singleton or multiple pregnancy led to different rates of chorioamnionitis (Analysis 2.1) in women exposed to corticosteroids. Maternal death and endometritis were not reported separately by multiple pregnancy in any study, and so we did not conduct these subgroup analysis.

For the child

There is no evidence that singleton or multiple pregnancy led to different rates of death (perinatal (Analysis 2.2); neonatal (Analysis 2.3); or fetal (Analysis 2.4)), RDS (Analysis 2.5), IVH (Analysis 2.6) or birthweight (Analysis 2.7) in infants exposed to corticosteroids.

Chronic lung disease and moderate/severe RDS were not reported separately by multiple pregnancy in any study, and so we did not conduct these subgroup analysis.

3. Antenatal corticosteroids versus placebo or no treatment (by presence or absence of ruptured membranes)

Discrete outcome data from women with intact membranes at the first dose of study medication were available from six studies (Amorim 1999; Attawattanakul 2015; Collaborative 1981; Garite 1992; Kari 1994; Liggins 1972b), discrete outcome data from women with ruptured membranes at the first dose of study medication were available from 12 studies (Cararach 1991; Carlan 1991; Dexiprom 1999; Fekih 2002; Lewis 1996; Liggins 1972b; Lopez 1989; Morales 1989; Nelson 1985; Parsons 1988; Qublan 2001; Schutte 1980), with the remainder of the studies not reporting rupture of membrane status or reporting combined data from women with intact and ruptured membranes.

Relevant subgroups compared below are: 1. pregnant women with intact membranes, 2. with ruptured membranes, and 3. pregnant women for whom membrane status was not reported separately or mixed populations. Analyses with small amounts of data missing are the following: 3.2. Endometritis (Schutte 1980); 3.3 Perinatal death (Liggins 1972b); 3.4. Neonatal death (Liggins 1972b); 3.5. Fetal death (Liggins 1972b; Schutte 1980); 3.6. RDS (Liggins 1972b); 3.7. IVH (Liggins 1972b); and 3.8. Birthweight (Liggins 1972b). Overall totals for these outcomes will not match our main analyses in Comparison 1 due to missing data. We have conducted sensitivity analysis with imputed data and found no difference in results for any outcome (analyses not shown). We have added footnotes to the forest plots where data used for specific trials do not match those in the main analyses due to missing data. We were unable to investigate the impact of missing data for the continuous outcome of birthweight.

For the mother

Women with rupture of membranes who were exposed to corticosteroids did not show different rates of chorioamnionitis (Analysis 3.1) or endometritis (Analysis 3.2) from women without rupture of membranes. Maternal death was zero in the treatment and control arms in relevant studies of women with ruptured membranes, thus this subgroup analysis was not undertaken.

For the child

There is no evidence that rupture of membrane status led to different rates of death (perinatal (Analysis 3.3); neonatal (Analysis 3.4); or fetal (Analysis 3.5)), RDS (Analysis 3.6), IVH Analysis 3.7() or birthweight (Analysis 3.8) in infants exposed to corticosteroids. Chronic lung disease and moderate/severe RDS were not reported separately by rupture of membrane status in any study, and so we did not conduct these subgroup analyses.

4. Antenatal corticosteroids versus placebo or no treatment (for women with hypertension syndrome)

Meaningful analysis was not possible for several primary outcomes due to the small number of trials reporting results by presence or absence of hypertension syndromes.

For the mother

For maternal death, only one trial with events was eligible for the hypertension group (Amorim 1999); no study that was eligible for the 'not reported' or 'no hypertension or hypertension syndromes excluded' subgroups had any events, and we did not conduct analysis.

For chorioamnionitis and endometritis, there were too few trials reporting on hypertension to produce meaningful subgroup analyses. For chorioamnionitis there were two trials; for endometritis there was one trial.

For the child

There was no evidence that maternal hypertension status led to different rates of death (perinatal (Analysis 4.2); fetal (Analysis 4.3); or neonatal (Analysis 4.4)) in infants exposed to corticosteroids.

Corticosteroids were effective at preventing RDS in infants of women with and without hypertension syndromes (Analysis 4.1).

There were too few trials eligible for the hypertension syndrome subgroup (one study) to conduct subgroup analysis for the outcome of chronic lung disease.

5. Antenatal corticosteroids versus placebo or no treatment (by type of corticosteroid)

Seven (Attawattanakul 2015; Collaborative 1981; Dexiprom 1999; Kari 1994; Qublan 2001; Silver 1996; Taeusch 1979) of the included studies used dexamethasone as the corticosteroid in the treatment arm (1585 women and 1708 infants), while 21 (Amorim 1999; Balci 2010; Block 1977; Carlan 1991; Doran 1980; Fekih 2002; Gamsu 1989; Garite 1992; Goodner 1979; Gyamfi‐Bannerman 2016; Khazardoust 2012; Lewis 1996; Liggins 1972b; Lopez 1989; Mansouri 2010; Morales 1989; Nelson 1985; Parsons 1988; Porto 2011; Schutte 1980; Teramo 1980) studies used betamethasone (6133 women and 6314 infants). One study did not specify the corticosteroid used (Cararach 1991; 18 women and infants), and one study used either betamethasone or dexamethasone (Shanks 2010; 32 women and infants).

For the mother

For maternal death, there was insufficient event data to conduct subgroup analysis by type of corticosteroid.

There was no evidence that type of corticosteroid used led to different rates of endometritis (Analysis 5.2). Betamethasone appeared to result in less maternal chorioamnionitis (RR 0.67, 95% CI 0.50 to 0.90; participants = 4777; studies = 10) than dexamethasone (RR 1.35, 95% CI 0.89 to 2.05; participants = 769; studies = 5) (Test for subgroup differences: Chi² = 7.16, df = 1 (P = 0.007), I² = 86.0%; Analysis 5.1).

For the child

There was no evidence that type of corticosteroid used led to different rates of death (perinatal (Analysis 5.3); neonatal (Analysis 5.4); or fetal (Analysis 5.5)), RDS (Analysis 5.6), IVH (Analysis 5.7), birthweight (Analysis 5.8), moderate/severe RDS (Analysis 5.9), or chronic lung disease (Analysis 5.10).

6. Antenatal corticosteroids versus placebo or no treatment (by decade of trial)

The subgroup tests in RevMan 5 are not ideal to test whether or not there were trends across decades; the test can only indicate if decades differ. We advise caution when interpreting the findings below, especially regarding survival across decades. We also wonder if the trials from the 1980s that stand out for having worse findings are actually first‐wave trials with less impressive results that were published later.

For the mother

There was no evidence that the decade of study enrolment led to different rates of chorioamnionitis (Analysis 6.1) or endometritis (Analysis 6.2) in women exposed to corticosteroids. Maternal death was zero in the treatment and control arms of all but one relevant study, thus we did not undertake this subgroup analysis.

For the child

There was no evidence that the decade of study enrolment led to different rates of IVH (Analysis 6.7) or birthweight (Analysis 6.8) in infants exposed to corticosteroids.

There was evidence that the decade of study enrolment may have led to different rates of perinatal death (perinatal death, with random‐effects model: test for subgroup differences: Chi² = 10.73, df = 4 (P = 0.03), I² = 62.7%) (Analysis 6.3). This was predominantly due to differences in neonatal deaths (neonatal death: test for subgroup differences: Chi² = 12.40, df = 4 (P = 0.01), I² = 67.8%) (Analysis 6.4) rather than fetal deaths (Analysis 6.5). Neonatal deaths were reduced in infants exposed to corticosteroids in studies conducted in the 1970s, 1990s and 2000s, but not the 1980s or 2010s (Analysis 6.4). Only one study (Gyamfi‐Bannerman 2016), the largest in the review, contributed data to the decade of the 2010s. This study was conducted solely in infants born after 33 weeks, when neonatal deaths are rare, with the control arm having zero events in 1400 participants (two deaths in the treatment arm).

There was evidence that the decade of study enrolment may have led to different rates of RDS in infants exposed to corticosteroids (RDS: test for subgroup differences: Chi² = 14.30, df = 4 (P = 0.006), I² = 72.0%) (Analysis 6.6). We carried out a sensitivity analysis removing each decade from the overall analysis set and repeating the test for subgroup differences without the decade removed. Removal of all decades apart from the 2000s resulted in significant subgroup differences, suggesting that data from studies conducted in the 2000s contributed significantly to the finding that the decade of study enrolment led to different rates of RDS in infants exposed to corticosteroids. Studies conducted during the 2000s had the greatest efficacy in reducing RDS in infants exposed to corticosteroids (RR 0.39, 95% CI 0.26 to 0.59; participants = 839; studies = 5; I2 = 22%) (Analysis 6.6). RDS was reduced in infants exposed to corticosteroids in studies conducted in the 1970s, 1980s, and 1990s, but not in the 2010s (Analysis 6.6).

There was no evidence of a difference in rates of moderate/severe RDS or chronic lung disease across decades; there were single trials in many subgroups and therefore we have not shown this analysis.

7. Antenatal corticosteroids versus placebo or no treatment (by presence or absence in protocol of weekly repeat doses of corticosteroid)

Nine of the included studies allowed weekly repeat courses of study medication in their study protocols (Amorim 1999; Carlan 1991; Fekih 2002; Garite 1992; Lewis 1996; Morales 1989; Parsons 1988; Qublan 2001; Silver 1996) (932 women and 946 infants).

For the mother

There was no evidence that protocols that allowed weekly repeat doses of corticosteroids led to different rates of chorioamnionitis (Analysis 7.1) or endometritis (Analysis 7.2) in women exposed to corticosteroids. Maternal death was zero in the treatment and control arms of all but one relevant study, thus we did not undertake this subgroup analysis.

For the child

There was no evidence that protocols that allowed weekly repeat doses of corticosteroids led to different rates of death (perinatal (Analysis 7.3); neonatal (Analysis 7.4); fetal (Analysis 7.5)), RDS (Analysis 7.6), IVH (Analysis 7.7) or birthweight (Analysis 7.8) in infants exposed to corticosteroids. For chronic lung disease, only one trial contributed data to the single‐course subgroup and we did not conduct analysis.

8. Gestational age at trial entry (less than or equal to 35 weeks + 0 days; greater than or equal to 34 weeks + 0 days)

We have split studies according to the gestational age at which pregnant women entered trials to receive their first dose of corticosteroids and have considered two, slightly overlapping subgroups: 1) women less than, and including, 35 weeks and 0 days and 2) women greater than, and including, 34 weeks and 0 days. Twenty studies (Amorim 1999; Cararach 1991; Carlan 1991; Dexiprom 1999; Doran 1980; Fekih 2002; Gamsu 1989; Garite 1992; Goodner 1979; Kari 1994; Khazardoust 2012; Lewis 1996; Lopez 1989; Morales 1989; Nelson 1985; Parsons 1988; Qublan 2001; Schutte 1980; Silver 1996; Taeusch 1979) contributed data to the younger gestational age group and six studies (Attawattanakul 2015; Balci 2010; Gyamfi‐Bannerman 2016; Mansouri 2010; Porto 2011; Shanks 2010) contributed data to the older gestational age group. Of these 26 studies, 17 (Amorim 1999; Attawattanakul 2015; Balci 2010; Carlan 1991; Dexiprom 1999; Doran 1980; Fekih 2002; Gamsu 1989; Gyamfi‐Bannerman 2016; Lewis 1996; Khazardoust 2012; Lopez 1989; Morales 1989; Nelson 1985; Porto 2011; Qublan 2001; Shanks 2010) have data in the overlapping 34 weeks + 0 days to 34 weeks + 6 days gestational age group between the two groups. A further four studies could be analysed in either group (Block 1977; Collaborative 1981; Liggins 1972b; Teramo 1980). We addressed these issues as follows: data from Liggins 1972b were available for women entering trials at less than 35 weeks + 0 days and from between 35 weeks + 0 days and 37 weeks + 0 days. The majority of women in the remaining three studies (Block 1977; Collaborative 1981; Teramo 1980) were of less than 34 weeks + 0 days gestation, therefore we included these studies in the younger‐gestational‐age grouping for the analysis (women less than and including 35 weeks and 0 days), but we undertook a sensitivity analysis with the studies' data removed.

For the mother

There was no evidence that gestational age at trial entry led to different rates of chorioamnionitis (Analysis 8.1) in women exposed to corticosteroids. There were insufficient studies in the later gestational age group to evaluate endometritis. Maternal death was zero in the treatment and control arms of all but one relevant study, thus this subgroup analysis was not undertaken.

For the infant

There was no evidence that gestational age at trial entry led to different rates of death (perinatal (Analysis 8.2); neonatal (Analysis 8.3); fetal (Analysis 8.4)), RDS (Analysis 8.5), IVH (Analysis 8.6) or birthweight (Analysis 8.7) in infants exposed to corticosteroids.

Chronic lung disease and moderate/severe RDS were not reported by studies occurring in later gestations, and so we did not conduct these subgroup analyses.

Discussion

Summary of main results

The results of the 30 studies included in this updated review support the conclusion of the previous review (Roberts 2006), that treatment with antenatal corticosteroids reduces perinatal death, neonatal death, RDS, and IVH in preterm infants. Treatment with antenatal corticosteroids is not associated with changes in the rates of maternal death, maternal endometritis or chorioamnionitis, fetal death, neonatal chronic lung disease, or birthweight. Treatment with antenatal corticosteroids is associated with a reduction in the incidence of neonatal necrotising enterocolitis and systemic infections in the first 48 hours of life, as well as a reduction in the need for respiratory support and NICU admission.

Whether antenatal corticosteroids are beneficial in the current era of advanced neonatal practice has been questioned on the basis that previous conclusions concerning their benefits drew on data from the 1970s. In this update, we have included nine trials published since 2000 (Attawattanakul 2015; Balci 2010; Fekih 2002; Gyamfi‐Bannerman 2016; Khazardoust 2012; Mansouri 2010; Porto 2011; Qublan 2001; Shanks 2010), as well as analyses for the previous decades. These more recent trials contributed 51% of the overall data to the review. Overall, the results show consistent benefits of steroid use, without any strong evidence that antenatal corticosteroids are not beneficial in the current era of advanced neonatal practice. In subgroup analysis two decades suggested heterogeneity of the results between decades for only one each of the eight primary outcomes analysed; studies conducted in the decade of the 2000s appeared to show that corticosteroids had a greater effect on reducing RDS, the opposite result to that expected if antenatal corticosteroids are not beneficial in the current era of advanced neonatal practice. Studies conducted in the 1980s appeared to show that corticosteroids had no effect in reducing neonatal death (removal of this group in sensitivity analysis explained subgroup heterogeneity), with no evidence of effect also seen in the most recent decade (2010s). However, as the sole study (Gyamfi‐Bannerman 2016) conducted in the 2010s was conducted in near term infants who have very low rates of neonatal death, and with studies conducted in the decades of the 1990s and 2000s showing a clear statistical and clinical benefit in terms of neonatal death, RDS and IVH, we conclude that antenatal corticosteroids continue to have a strong role in supporting current methods of obstetric and neonatal practice.

The gestational age range at which antenatal corticosteroids provide benefit has been subject to debate. Previous reviews have had difficulty demonstrating benefit at gestations less than 26 weeks and beyond 36 weeks (Roberts 2006). Once again it was not possible to test this adequately using trial level data; ideally this question should be investigated with individual patient data analysis using a priori agreed gestational age cut‐offs. In this update, we examined outcomes based on gestational age divisions of up to, and including, 35 weeks + 0 days and greater than, and including, 34 weeks + 0 days. Although this post hoc analysis is exploratory, and 17 studies have data in the overlapping 34 weeks + 0 days to 35 weeks + 0 days gestational age group, we found no evidence of a difference in effect of antenatal corticosteroids in the two gestational age groups for the seven primary outcomes analysed. The most recent study (Gyamfi‐Bannerman 2016) included in this review enrolled 2831 women from 34 weeks + 0 days until 36 weeks + 5 days, and found a clinical benefit in terms of a primary outcome of requirement for respiratory support in the first 72 hours of life (11.6% versus 14.4%), but with increased neonatal hypoglycaemia (24% versus 15%) for which the long‐term effects remain unknown. Consistent with this we have demonstrated a clear statistical and clinical benefit of corticosteroids on RDS in six studies providing data from 34 weeks + 0 days gestation, but not with other primary outcomes. Thus in very late preterm gestation women (from 35 weeks + 0 days) the use of antenatal corticosteroids needs to be considered in light of the balance of risks and benefits.

The relationship between the time interval from first dose to delivery and outcome, and how this is influenced by factors such as whether corticosteroids were given and how many doses a women received, can only be determined by an individual patient data analysis. We were not able to do this in this update. We were able to undertake an analysis comparing outcomes in mothers and children exposed to studies allowing only a single course versus study protocols allowing weekly repeats if infants remained undelivered. We found no differences between these two study protocol groups. The effect of repeated doses of antenatal corticosteroids is the subject of a separate Cochrane Review (Crowther 2015), which found that although repeated doses reduced the severity of neonatal lung disease, there were insufficient data to exclude other beneficial or harmful effects to the mother or infant. The Crowther review awaits the outcome of trials looking at the long‐term effects of repeated courses of antenatal corticosteroids.

We did not find any evidence that the effect of antenatal corticosteroids was different in the subgroups of women with multiple pregnancies, premature rupture of membranes and hypertension syndromes. However as discrete RDS data from infants of women with multiple pregnancies contributed to 4.1% of the total RDS data, and discrete data from infants of women with hypertension syndromes and premature rupture of membranes contributed to 4.9% and 14.5% of the total RDS data respectively, there needs to be caution in the interpretation of these findings. Further caution is required due to the number of studies in which subgroup classification data were not available.

In this update, we have included a comparison of studies using dexamethasone as a trial protocol with studies using betamethasone. We found no evidence of a difference in efficacy between the two types of corticosteroids, apart from less maternal chorioamnionitis occurring with betamethasone. Our analysis is subject to bias as allocation to one type of corticosteroid or the other was not subject to randomisation. However, consistent with our results a review by Brownfoot 2013 and colleagues (10 studies; 1089 women and 1161 infants) compared different corticosteroid regimens and found insufficient evidence to support the use of one corticosteroid over the other.

There are insufficient data from follow‐up studies into childhood (Collaborative 1981; Kari 1994; Liggins 1972b; Schutte 1980) and into adulthood (Liggins 1972b; Schutte 1980) included in this review. Just one small study reported neurodevelopmental delay in childhood (Kari 1994; n = 82). There are also limited data for developmental delay in childhood (two trials; n = 518). Five trials report potential improvement in rates of cerebral palsy in childhood, though confidence intervals are wide and cross the line of no effect. Just two included studies followed up into adulthood (Liggins 1972b; Schutte 1980) and found no differences in intellectual impairment or educational achievement between those exposed to a single course of antenatal corticosteroids and those exposed to placebo. This has largely contributed to dispelling previous concerns regarding decreased brain growth after antenatal corticosteroid exposure from animal studies (Huang 1999; Jobe 1998).

Exposure to excess corticosteroids before birth is a postulated mechanism underlying the fetal origins of adult disease hypothesis (Barker 1998; Benediktsson 1993). Increased insulin release has been found 30 minutes following a 75 g oral glucose tolerance test in one follow‐up study conducted at age 30 (Liggins 1972b). However, the same study found no difference in blood pressure, fasting lipids, body size, hypothalamo‐pituitary‐adrenal axis function or the prevalence of diabetes or cardiovascular disease. Thus, while the finding of increased insulin resistance in adulthood provides support for excess corticosteroids as a mechanism underlying the fetal origins of adult disease hypothesis, it should not be seen as a reason to withhold antenatal corticosteroids given the large and clinically substantial benefits seen in the neonatal period.

Overall completeness and applicability of evidence

We have attempted to identify all available published and unpublished randomised trial data for the use of antenatal corticosteroids for women at risk of preterm birth. Additional data have been obtained and included where possible. We feel that the data are comprehensive and relevant to women at risk of preterm birth. Comparisons of repeat antenatal corticosteroid regimens, of different antenatal corticosteroids and of the use of antenatal corticosteroids at term before elective birth are described in other Cochrane Reviews (Brownfoot 2013; Crowther 2015; Sotiriadis 2009).

The evidence here is applicable to most hospital settings in mid‐ or high‐income countries. More evidence from low‐income settings would help support the overall applicability of the data. For example, data in this review for RDS come from 15 different countries, but only one of these is a low‐income country (Tunisia). The issue of generalisability of the current evidence has also been highlighted in the recent cluster‐randomised trial (Althabe 2014). This trial suggested harms from better compliance with antenatal corticosteroid administration in women at risk of delivering preterm in communities of low‐resource settings (Althabe 2014).

Quality of the evidence

The evidence described in this review is based on 30 randomised controlled trials comparing antenatal corticosteroids with no antenatal corticosteroids. Overall the evidence is consistent. There are some limitations in 13 of the trials where there was no blinding of the intervention, and there was insufficient information in 14 trials to enable the review authors to make judgements on the processes of randomisation or allocation concealment. The lack of information is most likely due to the era in which the trials were conducted, when this information was not a requirement for publication.

We assessed seven outcomes with GRADE methodology, as shown in the 'Summary of findings' table (summary of findings Table 1). For pregnant women, evidence was graded as of moderate quality for three outcomes: maternal death, chorioamnionitis and endometritis. Downgrading in each case was for imprecision due to wide confidence intervals crossing the line of no effect. There were very few data for maternal death.

For infants, evidence for four outcomes was also graded to be of moderate quality. We downgraded evidence for perinatal death, RDS, IVH and birthweight for risks of bias in the included trials. A grade of moderate quality suggests we have some reservations about the available data and its quality due specifically to unclear risks of bias for allocation concealment or randomisation and unclear or high risks of bias for lack of blinding or incomplete outcome data in some trials included in the meta‐analyses.

Potential biases in the review process

We believe we have made sufficient attempts to reduce the potential bias of the review process. We have attempted to identify all relevant trials and two or more researchers have independently appraised the trial and extracted the data required. Where data were missing, we have contacted the original trialists and some additional data have been provided that enhances the content of this review.

Agreements and disagreements with other studies or reviews

Current systematic reviews of antenatal corticosteroids including the World Health Organization have used earlier versions of this review on which to base their recommendations (Hofmeyr 2009).

A systematic review conducted for a bi‐national clinical practice guideline for Australia and New Zealand in 2015 reported on the same maternal and neonatal benefits as the primary outcomes of this systematic review (Antenatal Corticosteroid CPG Panel 2015).

A recent systematic review of observational studies has analysed the use of antenatal corticosteroids in specific populations of pregnant women at risk of impending preterm birth (with gestational age 34 to 37 weeks); the authors considered evidence for pregnant women with gestational diabetes mellitus; pregnant women undergoing elective caesarean section (34 to 37 weeks' gestation; pregnant women with chorioamnionitis; and pregnant women with growth‐restricted fetuses) (Amiya 2016). There was no available evidence (randomised or observational) for women with gestational diabetes or for pregnant women undergoing elective caesarean section. For pregnant women with chorioamnionitis, pooled evidence from eight studies (1424 women) showed a benefit of steroid use for the outcomes of neonatal death, RDS, IVH and severe IVH; consistent with the conclusions of this review. There were no data available from these studies for maternal outcomes for women with chorioamnionitis. For pregnant women with growth‐restricted fetuses, the results were inconclusive. There were no clear benefits for growth‐restricted babies for outcomes measuring neonatal mortality or morbidity, including RDS, and the authors called for further research in this population. Using GRADE methods, review authors assessed all evidence for individual outcomes in the review as of low or very low quality, due to observational study design and, most often, imprecision due to wide confidence intervals (Amiya 2016).

As mentioned above, additional evidence is required to better understand the potential for adverse effects with steroid use in low‐resource settings (Althabe 2014; Azad 2014).

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

Figures and Tables -
Figure 1

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study

Figures and Tables -
Figure 2

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.2 Chorioamnionitis

Figures and Tables -
Figure 3

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.2 Chorioamnionitis

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.4 Perinatal deaths

Figures and Tables -
Figure 4

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.4 Perinatal deaths

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.5 Neonatal deaths

Figures and Tables -
Figure 5

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.5 Neonatal deaths

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.6 Fetal deaths

Figures and Tables -
Figure 6

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.6 Fetal deaths

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.7 Respiratory distress syndrome

Figures and Tables -
Figure 7

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.7 Respiratory distress syndrome

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.10 Intraventricular haemorrhage

Figures and Tables -
Figure 8

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.10 Intraventricular haemorrhage

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.11 Mean birthweight (g)

Figures and Tables -
Figure 9

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.11 Mean birthweight (g)

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.25 Need for mechanical ventilation/CPAP

Figures and Tables -
Figure 10

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.25 Need for mechanical ventilation/CPAP

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.30 Apgar < 7 at 5 minutes

Figures and Tables -
Figure 11

Funnel plot of comparison: 1 Corticosteroids versus placebo or no treatment, outcome: 1.30 Apgar < 7 at 5 minutes

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 1: Maternal death

Figures and Tables -
Analysis 1.1

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 1: Maternal death

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 2: Chorioamnionitis

Figures and Tables -
Analysis 1.2

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 2: Chorioamnionitis

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 3: Endometritis

Figures and Tables -
Analysis 1.3

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 3: Endometritis

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 4: Perinatal deaths

Figures and Tables -
Analysis 1.4

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 4: Perinatal deaths

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 5: Neonatal deaths

Figures and Tables -
Analysis 1.5

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 5: Neonatal deaths

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 6: Fetal deaths

Figures and Tables -
Analysis 1.6

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 6: Fetal deaths

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 7: Respiratory distress syndrome

Figures and Tables -
Analysis 1.7

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 7: Respiratory distress syndrome

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 8: Moderate/severe respiratory distress syndrome

Figures and Tables -
Analysis 1.8

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 8: Moderate/severe respiratory distress syndrome

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 9: Chronic lung disease

Figures and Tables -
Analysis 1.9

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 9: Chronic lung disease

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 10: Intraventricular haemorrhage

Figures and Tables -
Analysis 1.10

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 10: Intraventricular haemorrhage

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 11: Mean birthweight (g)

Figures and Tables -
Analysis 1.11

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 11: Mean birthweight (g)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 12: Death in childhood

Figures and Tables -
Analysis 1.12

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 12: Death in childhood

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 13: Neurodevelopmental delay in childhood

Figures and Tables -
Analysis 1.13

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 13: Neurodevelopmental delay in childhood

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 14: Death into adulthood

Figures and Tables -
Analysis 1.14

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 14: Death into adulthood

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 15: Fever in women after trial entry requiring the use of antibiotics

Figures and Tables -
Analysis 1.15

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 15: Fever in women after trial entry requiring the use of antibiotics

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 16: Intrapartum fever in woman requiring the use of antibiotics

Figures and Tables -
Analysis 1.16

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 16: Intrapartum fever in woman requiring the use of antibiotics

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 17: Side effects of therapy in women

Figures and Tables -
Analysis 1.17

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 17: Side effects of therapy in women

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 18: Admission into adult intensive care unit

Figures and Tables -
Analysis 1.18

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 18: Admission into adult intensive care unit

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 19: Hypertension

Figures and Tables -
Analysis 1.19

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 19: Hypertension

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 20: Postnatal fever in woman

Figures and Tables -
Analysis 1.20

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 20: Postnatal fever in woman

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 21: Glucose intolerance

Figures and Tables -
Analysis 1.21

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 21: Glucose intolerance

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 22: Necrotising enterocolitis

Figures and Tables -
Analysis 1.22

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 22: Necrotising enterocolitis

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 23: Systemic infection in the first 48 hours of life

Figures and Tables -
Analysis 1.23

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 23: Systemic infection in the first 48 hours of life

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 24: Proven infection while in the neonatal intensive care unit

Figures and Tables -
Analysis 1.24

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 24: Proven infection while in the neonatal intensive care unit

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 25: Need for mechanical ventilation/CPAP

Figures and Tables -
Analysis 1.25

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 25: Need for mechanical ventilation/CPAP

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 26: Mean duration of mechanical ventilation/CPAP (days)

Figures and Tables -
Analysis 1.26

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 26: Mean duration of mechanical ventilation/CPAP (days)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 27: Mean duration of oxygen supplementation (days)

Figures and Tables -
Analysis 1.27

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 27: Mean duration of oxygen supplementation (days)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 28: Surfactant use

Figures and Tables -
Analysis 1.28

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 28: Surfactant use

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 29: Air leak syndrome

Figures and Tables -
Analysis 1.29

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 29: Air leak syndrome

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 30: Apgar < 7 at 5 minutes

Figures and Tables -
Analysis 1.30

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 30: Apgar < 7 at 5 minutes

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 31: Mean interval between trial entry and birth (days)

Figures and Tables -
Analysis 1.31

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 31: Mean interval between trial entry and birth (days)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 32: Small‐for‐gestational age

Figures and Tables -
Analysis 1.32

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 32: Small‐for‐gestational age

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 33: Mean infant HPA axis function (cortisol)

Figures and Tables -
Analysis 1.33

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 33: Mean infant HPA axis function (cortisol)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 34: Admission to neonatal intensive care unit

Figures and Tables -
Analysis 1.34

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 34: Admission to neonatal intensive care unit

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 35: Developmental delay in childhood

Figures and Tables -
Analysis 1.35

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 35: Developmental delay in childhood

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 36: Cerebral palsy in childhood

Figures and Tables -
Analysis 1.36

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 36: Cerebral palsy in childhood

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 37: Mean childhood weight (kg)

Figures and Tables -
Analysis 1.37

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 37: Mean childhood weight (kg)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 38: Mean childhood height (cm)

Figures and Tables -
Analysis 1.38

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 38: Mean childhood height (cm)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 39: Mean childhood head circumference (cm)

Figures and Tables -
Analysis 1.39

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 39: Mean childhood head circumference (cm)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 40: Mean childhood VC (% predicted)

Figures and Tables -
Analysis 1.40

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 40: Mean childhood VC (% predicted)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 41: Mean childhood FEV1 (% predicted)

Figures and Tables -
Analysis 1.41

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 41: Mean childhood FEV1 (% predicted)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 42: Mean childhood FEV1/VC

Figures and Tables -
Analysis 1.42

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 42: Mean childhood FEV1/VC

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 43: Mean childhood systolic blood pressure (mmHg)

Figures and Tables -
Analysis 1.43

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 43: Mean childhood systolic blood pressure (mmHg)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 44: Visual impairment in childhood

Figures and Tables -
Analysis 1.44

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 44: Visual impairment in childhood

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 45: Hearing impairment in childhood

Figures and Tables -
Analysis 1.45

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 45: Hearing impairment in childhood

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 46: Intellectual impairment in childhood

Figures and Tables -
Analysis 1.46

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 46: Intellectual impairment in childhood

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 47: Behavioural/learning difficulties in childhood

Figures and Tables -
Analysis 1.47

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 47: Behavioural/learning difficulties in childhood

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 48: Mean adult insulin (log values)

Figures and Tables -
Analysis 1.48

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 48: Mean adult insulin (log values)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 49: Mean adult glucose (mmol/L)

Figures and Tables -
Analysis 1.49

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 49: Mean adult glucose (mmol/L)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 50: Mean adult weight (kg)

Figures and Tables -
Analysis 1.50

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 50: Mean adult weight (kg)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 51: Mean adult height (cm)

Figures and Tables -
Analysis 1.51

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 51: Mean adult height (cm)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 52: Mean adult head circumference (cm)

Figures and Tables -
Analysis 1.52

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 52: Mean adult head circumference (cm)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 53: Mean adult skinfold thickness (log values)

Figures and Tables -
Analysis 1.53

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 53: Mean adult skinfold thickness (log values)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 54: Mean adult systolic blood pressure (mmHg)

Figures and Tables -
Analysis 1.54

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 54: Mean adult systolic blood pressure (mmHg)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 55: Mean adult HPA axis function (mean log fasting cortisol)

Figures and Tables -
Analysis 1.55

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 55: Mean adult HPA axis function (mean log fasting cortisol)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 56: Mean cholesterol in adulthood (mmol/L)

Figures and Tables -
Analysis 1.56

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 56: Mean cholesterol in adulthood (mmol/L)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 57: Mean age at puberty (years)

Figures and Tables -
Analysis 1.57

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 57: Mean age at puberty (years)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 58: Educational achievement by adulthood (university or polytechnic education)

Figures and Tables -
Analysis 1.58

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 58: Educational achievement by adulthood (university or polytechnic education)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 59: Visual impairment in adulthood

Figures and Tables -
Analysis 1.59

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 59: Visual impairment in adulthood

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 60: Hearing impairment in adulthood

Figures and Tables -
Analysis 1.60

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 60: Hearing impairment in adulthood

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 61: Intellectual impairment in adulthood

Figures and Tables -
Analysis 1.61

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 61: Intellectual impairment in adulthood

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 62: Mean adult FVC (% predicted)

Figures and Tables -
Analysis 1.62

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 62: Mean adult FVC (% predicted)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 63: Mean adult FEV1 (% predicted)

Figures and Tables -
Analysis 1.63

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 63: Mean adult FEV1 (% predicted)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 64: Mean adult FEV1/FVC

Figures and Tables -
Analysis 1.64

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 64: Mean adult FEV1/FVC

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 65: Mean adult PEF

Figures and Tables -
Analysis 1.65

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 65: Mean adult PEF

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 66: Mean adult F50

Figures and Tables -
Analysis 1.66

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 66: Mean adult F50

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 67: Mean adult F25

Figures and Tables -
Analysis 1.67

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 67: Mean adult F25

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 68: Mean adult FEF 25%‐75%

Figures and Tables -
Analysis 1.68

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 68: Mean adult FEF 25%‐75%

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 69: FEV1/FVC < 70%

Figures and Tables -
Analysis 1.69

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 69: FEV1/FVC < 70%

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 70: Asthma diagnosed by Doctor in lifetime

Figures and Tables -
Analysis 1.70

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 70: Asthma diagnosed by Doctor in lifetime

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 71: Wheezing in last 12 months

Figures and Tables -
Analysis 1.71

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 71: Wheezing in last 12 months

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 72: Current Asthma

Figures and Tables -
Analysis 1.72

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 72: Current Asthma

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 73: Further respiratory diagnosis (includes pneumonia, upper airway conditions and bronchitis)

Figures and Tables -
Analysis 1.73

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 73: Further respiratory diagnosis (includes pneumonia, upper airway conditions and bronchitis)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 74: Spontaneous pneumothorax

Figures and Tables -
Analysis 1.74

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 74: Spontaneous pneumothorax

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 75: Shortness of breath at anytime in the last 12 months

Figures and Tables -
Analysis 1.75

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 75: Shortness of breath at anytime in the last 12 months

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 76: Mean adult lumbar spine aBMD (g/cm2) areal bone mineral density

Figures and Tables -
Analysis 1.76

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 76: Mean adult lumbar spine aBMD (g/cm2) areal bone mineral density

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 77: Mean adult lumbar spine vBMD (g/cm3) volumetric bone mineral density

Figures and Tables -
Analysis 1.77

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 77: Mean adult lumbar spine vBMD (g/cm3) volumetric bone mineral density

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 78: Mean adult total body BMC (grams) bone mineral content

Figures and Tables -
Analysis 1.78

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 78: Mean adult total body BMC (grams) bone mineral content

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 79: Mean adult total body aBMD (g/cm3) areal bone mineral density

Figures and Tables -
Analysis 1.79

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 79: Mean adult total body aBMD (g/cm3) areal bone mineral density

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 80: Mean adult femoral neck aBMD (g/cm2) areal bone mineral density

Figures and Tables -
Analysis 1.80

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 80: Mean adult femoral neck aBMD (g/cm2) areal bone mineral density

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 81: Mean adult femoral trochanter aBMD (g/cm2) areal bone mineral density

Figures and Tables -
Analysis 1.81

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 81: Mean adult femoral trochanter aBMD (g/cm2) areal bone mineral density

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 82: Mean adult femoral shaft aBMD (g/cm2) areal bone mineral density

Figures and Tables -
Analysis 1.82

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 82: Mean adult femoral shaft aBMD (g/cm2) areal bone mineral density

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 83: Mean total proximal femur aBMD (g/cm2) areal bone mineral density

Figures and Tables -
Analysis 1.83

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 83: Mean total proximal femur aBMD (g/cm2) areal bone mineral density

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 84: Mean length of antenatal hospitalisation (days)

Figures and Tables -
Analysis 1.84

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 84: Mean length of antenatal hospitalisation (days)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 85: Mean length of postnatal hospitalisation (days)

Figures and Tables -
Analysis 1.85

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 85: Mean length of postnatal hospitalisation (days)

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 86: Mean length of neonatal hospitalisation (days)

Figures and Tables -
Analysis 1.86

Comparison 1: Corticosteroids versus placebo or no treatment, Outcome 86: Mean length of neonatal hospitalisation (days)

Comparison 2: Corticosteroids versus placebo or no treatment ‐ single or multiple pregnancy, Outcome 1: Chorioamnionitis ‐ single or multiple pregnancy

Figures and Tables -
Analysis 2.1

Comparison 2: Corticosteroids versus placebo or no treatment ‐ single or multiple pregnancy, Outcome 1: Chorioamnionitis ‐ single or multiple pregnancy

Comparison 2: Corticosteroids versus placebo or no treatment ‐ single or multiple pregnancy, Outcome 2: Perinatal death ‐ single or multiple pregnancy

Figures and Tables -
Analysis 2.2

Comparison 2: Corticosteroids versus placebo or no treatment ‐ single or multiple pregnancy, Outcome 2: Perinatal death ‐ single or multiple pregnancy

Comparison 2: Corticosteroids versus placebo or no treatment ‐ single or multiple pregnancy, Outcome 3: Neonatal death ‐ single or multiple pregnancy

Figures and Tables -
Analysis 2.3

Comparison 2: Corticosteroids versus placebo or no treatment ‐ single or multiple pregnancy, Outcome 3: Neonatal death ‐ single or multiple pregnancy

Comparison 2: Corticosteroids versus placebo or no treatment ‐ single or multiple pregnancy, Outcome 4: Fetal death ‐ single or multiple pregnancy

Figures and Tables -
Analysis 2.4

Comparison 2: Corticosteroids versus placebo or no treatment ‐ single or multiple pregnancy, Outcome 4: Fetal death ‐ single or multiple pregnancy

Comparison 2: Corticosteroids versus placebo or no treatment ‐ single or multiple pregnancy, Outcome 5: Respiratory distress syndrome ‐ single or multiple pregnancy

Figures and Tables -
Analysis 2.5

Comparison 2: Corticosteroids versus placebo or no treatment ‐ single or multiple pregnancy, Outcome 5: Respiratory distress syndrome ‐ single or multiple pregnancy

Comparison 2: Corticosteroids versus placebo or no treatment ‐ single or multiple pregnancy, Outcome 6: IVH ‐ single or multiple pregnancy

Figures and Tables -
Analysis 2.6

Comparison 2: Corticosteroids versus placebo or no treatment ‐ single or multiple pregnancy, Outcome 6: IVH ‐ single or multiple pregnancy

Comparison 2: Corticosteroids versus placebo or no treatment ‐ single or multiple pregnancy, Outcome 7: Birthweight ‐ single or multiple pregnancy

Figures and Tables -
Analysis 2.7

Comparison 2: Corticosteroids versus placebo or no treatment ‐ single or multiple pregnancy, Outcome 7: Birthweight ‐ single or multiple pregnancy

Comparison 3: Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose, Outcome 1: Chorioamnionitis ‐ intact or ruptured membranes

Figures and Tables -
Analysis 3.1

Comparison 3: Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose, Outcome 1: Chorioamnionitis ‐ intact or ruptured membranes

Comparison 3: Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose, Outcome 2: Endometritis ‐ intact or ruptured membranes

Figures and Tables -
Analysis 3.2

Comparison 3: Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose, Outcome 2: Endometritis ‐ intact or ruptured membranes

Comparison 3: Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose, Outcome 3: Perinatal death ‐ intact or ruptured membranes

Figures and Tables -
Analysis 3.3

Comparison 3: Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose, Outcome 3: Perinatal death ‐ intact or ruptured membranes

Comparison 3: Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose, Outcome 4: Neonatal deaths ‐ intact or ruptured membranes

Figures and Tables -
Analysis 3.4

Comparison 3: Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose, Outcome 4: Neonatal deaths ‐ intact or ruptured membranes

Comparison 3: Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose, Outcome 5: Fetal death ‐ intact or ruptured membranes

Figures and Tables -
Analysis 3.5

Comparison 3: Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose, Outcome 5: Fetal death ‐ intact or ruptured membranes

Comparison 3: Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose, Outcome 6: RDS ‐ intact or ruptured membranes

Figures and Tables -
Analysis 3.6

Comparison 3: Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose, Outcome 6: RDS ‐ intact or ruptured membranes

Comparison 3: Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose, Outcome 7: IVH ‐ intact or ruptured membranes

Figures and Tables -
Analysis 3.7

Comparison 3: Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose, Outcome 7: IVH ‐ intact or ruptured membranes

Comparison 3: Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose, Outcome 8: Birthweight ‐ intact or ruptured membranes

Figures and Tables -
Analysis 3.8

Comparison 3: Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose, Outcome 8: Birthweight ‐ intact or ruptured membranes

Comparison 4: Corticosteroids versus placebo or no treatment ‐ hypertension syndrome versus all other trials, Outcome 1: RDS

Figures and Tables -
Analysis 4.1

Comparison 4: Corticosteroids versus placebo or no treatment ‐ hypertension syndrome versus all other trials, Outcome 1: RDS

Comparison 4: Corticosteroids versus placebo or no treatment ‐ hypertension syndrome versus all other trials, Outcome 2: Perinatal deaths

Figures and Tables -
Analysis 4.2

Comparison 4: Corticosteroids versus placebo or no treatment ‐ hypertension syndrome versus all other trials, Outcome 2: Perinatal deaths

Comparison 4: Corticosteroids versus placebo or no treatment ‐ hypertension syndrome versus all other trials, Outcome 3: Fetal deaths

Figures and Tables -
Analysis 4.3

Comparison 4: Corticosteroids versus placebo or no treatment ‐ hypertension syndrome versus all other trials, Outcome 3: Fetal deaths

Comparison 4: Corticosteroids versus placebo or no treatment ‐ hypertension syndrome versus all other trials, Outcome 4: Neonatal deaths

Figures and Tables -
Analysis 4.4

Comparison 4: Corticosteroids versus placebo or no treatment ‐ hypertension syndrome versus all other trials, Outcome 4: Neonatal deaths

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 1: Chorioamnionitis ‐ type of steroid

Figures and Tables -
Analysis 5.1

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 1: Chorioamnionitis ‐ type of steroid

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 2: Endometritis ‐ type of steroid

Figures and Tables -
Analysis 5.2

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 2: Endometritis ‐ type of steroid

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 3: Perinatal death ‐ type of steroid

Figures and Tables -
Analysis 5.3

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 3: Perinatal death ‐ type of steroid

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 4: Neonatal deaths by steroid type

Figures and Tables -
Analysis 5.4

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 4: Neonatal deaths by steroid type

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 5: Fetal death ‐ type of steroid

Figures and Tables -
Analysis 5.5

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 5: Fetal death ‐ type of steroid

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 6: Respiratory distress syndrome ‐ type of steroid

Figures and Tables -
Analysis 5.6

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 6: Respiratory distress syndrome ‐ type of steroid

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 7: IVH ‐ type of steroid

Figures and Tables -
Analysis 5.7

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 7: IVH ‐ type of steroid

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 8: Birthweight ‐ type of steroid

Figures and Tables -
Analysis 5.8

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 8: Birthweight ‐ type of steroid

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 9: Moderate/severe respiratory distress syndrome ‐ type of steroid

Figures and Tables -
Analysis 5.9

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 9: Moderate/severe respiratory distress syndrome ‐ type of steroid

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 10: Chronic lung disease ‐ type of steroid

Figures and Tables -
Analysis 5.10

Comparison 5: Corticosteroids versus placebo or no treatment ‐ type of steroid, Outcome 10: Chronic lung disease ‐ type of steroid

Comparison 6: Corticosteroids versus placebo or no treatment ‐ decade of trial, Outcome 1: Chorioamnionitis ‐ decade of trial

Figures and Tables -
Analysis 6.1

Comparison 6: Corticosteroids versus placebo or no treatment ‐ decade of trial, Outcome 1: Chorioamnionitis ‐ decade of trial

Comparison 6: Corticosteroids versus placebo or no treatment ‐ decade of trial, Outcome 2: Endometritis ‐ decade of trial

Figures and Tables -
Analysis 6.2

Comparison 6: Corticosteroids versus placebo or no treatment ‐ decade of trial, Outcome 2: Endometritis ‐ decade of trial

Comparison 6: Corticosteroids versus placebo or no treatment ‐ decade of trial, Outcome 3: Perinatal deaths ‐ decade of trial

Figures and Tables -
Analysis 6.3

Comparison 6: Corticosteroids versus placebo or no treatment ‐ decade of trial, Outcome 3: Perinatal deaths ‐ decade of trial

Comparison 6: Corticosteroids versus placebo or no treatment ‐ decade of trial, Outcome 4: Neonatal deaths decade of trial

Figures and Tables -
Analysis 6.4

Comparison 6: Corticosteroids versus placebo or no treatment ‐ decade of trial, Outcome 4: Neonatal deaths decade of trial

Comparison 6: Corticosteroids versus placebo or no treatment ‐ decade of trial, Outcome 5: Fetal death ‐ decade of trial

Figures and Tables -
Analysis 6.5

Comparison 6: Corticosteroids versus placebo or no treatment ‐ decade of trial, Outcome 5: Fetal death ‐ decade of trial

Comparison 6: Corticosteroids versus placebo or no treatment ‐ decade of trial, Outcome 6: RDS ‐ decade of trial

Figures and Tables -
Analysis 6.6

Comparison 6: Corticosteroids versus placebo or no treatment ‐ decade of trial, Outcome 6: RDS ‐ decade of trial

Comparison 6: Corticosteroids versus placebo or no treatment ‐ decade of trial, Outcome 7: IVH ‐ decade of trial

Figures and Tables -
Analysis 6.7

Comparison 6: Corticosteroids versus placebo or no treatment ‐ decade of trial, Outcome 7: IVH ‐ decade of trial

Comparison 6: Corticosteroids versus placebo or no treatment ‐ decade of trial, Outcome 8: Birthweight ‐ decade of trial

Figures and Tables -
Analysis 6.8

Comparison 6: Corticosteroids versus placebo or no treatment ‐ decade of trial, Outcome 8: Birthweight ‐ decade of trial

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 1: Chorioamnionitis ‐ Protocol with weekly repeats

Figures and Tables -
Analysis 7.1

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 1: Chorioamnionitis ‐ Protocol with weekly repeats

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 2: Endometritis ‐ protocol with weekly repeats

Figures and Tables -
Analysis 7.2

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 2: Endometritis ‐ protocol with weekly repeats

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 3: Perinatal death ‐ protocol with weekly repeats

Figures and Tables -
Analysis 7.3

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 3: Perinatal death ‐ protocol with weekly repeats

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 4: Neonatal death ‐ protocol with weekly repeats

Figures and Tables -
Analysis 7.4

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 4: Neonatal death ‐ protocol with weekly repeats

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 5: Fetal death ‐ protocol with weekly repeats

Figures and Tables -
Analysis 7.5

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 5: Fetal death ‐ protocol with weekly repeats

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 6: RDS ‐ protocol with weekly repeats

Figures and Tables -
Analysis 7.6

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 6: RDS ‐ protocol with weekly repeats

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 7: IVH‐ protocol with weekly repeats

Figures and Tables -
Analysis 7.7

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 7: IVH‐ protocol with weekly repeats

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 8: Birthweight ‐ protocol with weekly repeats

Figures and Tables -
Analysis 7.8

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 8: Birthweight ‐ protocol with weekly repeats

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 9: Moderate/severe respiratory distress syndrome

Figures and Tables -
Analysis 7.9

Comparison 7: Corticosteroids versus placebo or no treatment ‐ weekly repeats, Outcome 9: Moderate/severe respiratory distress syndrome

Comparison 8: Corticosteroids versus placebo or no treatment ‐ gestational age at trial entry, Outcome 1: Chorioamnionitis ‐ gestational age at trial entry

Figures and Tables -
Analysis 8.1

Comparison 8: Corticosteroids versus placebo or no treatment ‐ gestational age at trial entry, Outcome 1: Chorioamnionitis ‐ gestational age at trial entry

Comparison 8: Corticosteroids versus placebo or no treatment ‐ gestational age at trial entry, Outcome 2: Perinatal death ‐ gestational age at trial entry

Figures and Tables -
Analysis 8.2

Comparison 8: Corticosteroids versus placebo or no treatment ‐ gestational age at trial entry, Outcome 2: Perinatal death ‐ gestational age at trial entry

Comparison 8: Corticosteroids versus placebo or no treatment ‐ gestational age at trial entry, Outcome 3: Neonatal death ‐ gestational age at trial engry

Figures and Tables -
Analysis 8.3

Comparison 8: Corticosteroids versus placebo or no treatment ‐ gestational age at trial entry, Outcome 3: Neonatal death ‐ gestational age at trial engry

Comparison 8: Corticosteroids versus placebo or no treatment ‐ gestational age at trial entry, Outcome 4: Fetal death ‐ gestational age at trial entry

Figures and Tables -
Analysis 8.4

Comparison 8: Corticosteroids versus placebo or no treatment ‐ gestational age at trial entry, Outcome 4: Fetal death ‐ gestational age at trial entry

Comparison 8: Corticosteroids versus placebo or no treatment ‐ gestational age at trial entry, Outcome 5: RDS‐ gestational age at trial entry

Figures and Tables -
Analysis 8.5

Comparison 8: Corticosteroids versus placebo or no treatment ‐ gestational age at trial entry, Outcome 5: RDS‐ gestational age at trial entry

Comparison 8: Corticosteroids versus placebo or no treatment ‐ gestational age at trial entry, Outcome 6: IVH ‐ gestational age at trial entry

Figures and Tables -
Analysis 8.6

Comparison 8: Corticosteroids versus placebo or no treatment ‐ gestational age at trial entry, Outcome 6: IVH ‐ gestational age at trial entry

Comparison 8: Corticosteroids versus placebo or no treatment ‐ gestational age at trial entry, Outcome 7: Birthweight ‐ gestational age at trial entry

Figures and Tables -
Analysis 8.7

Comparison 8: Corticosteroids versus placebo or no treatment ‐ gestational age at trial entry, Outcome 7: Birthweight ‐ gestational age at trial entry

Summary of findings 1. Corticosteroids versus placebo or no treatment

Corticosteroids versus placebo or no treatment

Patient or population: pregnant women at high risk of preterm birth receiving a corticosteroid or placebo/no treatment; women with singleton and multiple pregnancy and intact and ruptured membranes
Setting: hospital settings in high‐income countries. For example, data for RDS come from 28 trials in 15 different countries, but only one of these countries is of lower income (Tunisia)
Intervention: corticosteroids (dexamethasone or betamethasone) according to various doses and regimens; some trials with weekly repeats
Comparison: placebo (usually normal saline) or no treatment

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with placebo or no treatment

Risk with corticosteroids

Maternal death

Study population

RR 0.98
(0.06 to 15.50)

3392
(5 RCTs)

⊕⊕⊕⊝
Moderate1

RR based on 2 deaths in a single trial (1 death in each group). Four trials reported zero events

1 per 1000

1 per 1000
(0 to 9)

Chorioamnionitis

Study population

RR 0.83
(0.66 to 1.06)

5546
(15 RCTs)

⊕⊕⊕⊝
Moderate2

48 per 1000

40 per 1000
(32 to 51)

Endometritis (infections)

Study population

RR 1.20
(0.87 to 1.63)

4030
(10 RCTs)

⊕⊕⊕⊝
Moderate2,3

7 of 10 trials reported endometritis; the remaining trials report 'infections'

33 per 1000

39 per 1000
(27 to 59)

Perinatal deaths

Study population

average RR 0.72
(0.58 to 0.89)

6729
(15 RCTs)

⊕⊕⊕
Moderate4

102 per 1000

73 per 1000
(59 to 91)

Respiratory distress syndrome

Study population

average RR 0.66
(0.56 to 0.77)

7764
(28 RCTs)

⊕⊕⊕
Moderate5

176 per 1000

116 per 1000
(98 to 135)

Intraventricular haemorrhage

Study population

average RR 0.55
(0.40 to 0.76)

6093
(16 RCTs)

⊕⊕⊕
Moderate6

51 per 1000

28 per 1000
(20 to 39)

Mean birthweight (grams)

(less is worse)

Absolute risks not calculated

The mean birthweight was 18.47g less (40.83g less to 3.90g more)

6182
(16 RCTs)

⊕⊕⊕
Moderate7

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: we are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect
Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect

1Few events and wide confidence interval led to a downgrade for imprecision (‐1). Because maternal death is a rare event and the total population is over 3000 women, we have opted for (‐1) rather than (‐2).
2Wide confidence interval crossing the line of no effect (‐1).
3Value of I2 = 34% with random‐effects model. We have not downgraded evidence for heterogeneity.
4Value of I2 = 37% with random‐effects model. We have not downgraded for heterogeneity. Result downgraded once for risks of bias in included trials (‐1).
5Value of I2 = 47% with random‐effects model. We have not downgraded for heterogeneity. Result downgraded once for risks of bias in included trials (‐1).
6Value of I2 = 33% with random‐effects model. We have not downgraded for heterogeneity. Result downgraded once for risks of bias in included trials (‐1).
7The confidence interval showed a difference at most on average of 40 g in weight; because this is less than 10% of the lightest average for babies in any trial, we have not downgraded evidence for imprecision. We have downgraded the result for risks of bias concerns in included trials (‐1).

Figures and Tables -
Summary of findings 1. Corticosteroids versus placebo or no treatment
Table 1. Gestational age parameters for included trials

Trial

Year

Minimum

(weeks+days)

Maximum

(weeks+days)

Amorim 1999

1999

28+0

34+6

Attawattanakul 2015

2015

34+0

36+6

Balci 2010

2010

34+0

36+6

Block 1977

1976

Not reported

36+6

Carlan 1991

1991

24+0

34+6

Cararach 1991

1994

28+0

30+6

Collaborative 1981

1981

26+0

37+0

Dexiprom 1999

1999

28+0

34+6

Doran 1980

1980

24+0

34+6

Fekih 2002

2002

26+0

34+6

Gamsu 1989

1989

Not reported

34+6

Garite 1992

1992

24+0

27+6

Goodner 1979

1979

Not reported

33+6

Gyamfi‐Bannerman 2016

2016

34+0

36+6

Kari 1994

1994

24+0

31+6

Khazardoust 2012

(no outcome data)

2012

34+0

37+0

Lewis 1996

1996

24+0

34+6

Liggins 1972b

1972

24+0

36+6

Lopez 1989

1989

27+0

35+0

Mansouri 2010

2010

35+0

36+6

Morales 1989

1989

26+0

34+6

Nelson 1985

1985

28+0

34+6

Parsons 1988

1988

25+0

32+6

Porto 2011

2011

34+0

36+6

Qublan 2001

2001

27+0

34+6

Schutte 1980

1980

26+0

32+6

Shanks 2010

2010

34+0

36+6

Silver 1996

1996

24+0

29+6

Taeusch 1979

1979

Not reported

33+6

Teramo 1980

1980

28+0

35+6

Figures and Tables -
Table 1. Gestational age parameters for included trials
Comparison 1. Corticosteroids versus placebo or no treatment

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1.1 Maternal death Show forest plot

5

3392

Risk Ratio (M‐H, Fixed, 95% CI)

0.98 [0.06, 15.50]

1.2 Chorioamnionitis Show forest plot

15

5546

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.66, 1.06]

1.3 Endometritis Show forest plot

10

4030

Risk Ratio (M‐H, Fixed, 95% CI)

1.20 [0.87, 1.63]

1.4 Perinatal deaths Show forest plot

15

6729

Risk Ratio (M‐H, Random, 95% CI)

0.72 [0.58, 0.89]

1.5 Neonatal deaths Show forest plot

22

7188

Risk Ratio (M‐H, Fixed, 95% CI)

0.69 [0.59, 0.81]

1.6 Fetal deaths Show forest plot

15

6729

Risk Ratio (M‐H, Fixed, 95% CI)

0.98 [0.74, 1.30]

1.7 Respiratory distress syndrome Show forest plot

28

7764

Risk Ratio (M‐H, Random, 95% CI)

0.66 [0.56, 0.77]

1.8 Moderate/severe respiratory distress syndrome Show forest plot

6

1686

Risk Ratio (M‐H, Random, 95% CI)

0.59 [0.38, 0.91]

1.9 Chronic lung disease Show forest plot

6

818

Risk Ratio (M‐H, Random, 95% CI)

0.86 [0.42, 1.79]

1.10 Intraventricular haemorrhage Show forest plot

16

6093

Risk Ratio (M‐H, Random, 95% CI)

0.55 [0.40, 0.76]

1.11 Mean birthweight (g) Show forest plot

16

6182

Mean Difference (IV, Fixed, 95% CI)

‐18.47 [‐40.83, 3.90]

1.12 Death in childhood Show forest plot

4

1010

Risk Ratio (M‐H, Fixed, 95% CI)

0.68 [0.36, 1.27]

1.13 Neurodevelopmental delay in childhood Show forest plot

1

82

Risk Ratio (M‐H, Fixed, 95% CI)

0.64 [0.14, 2.98]

1.14 Death into adulthood Show forest plot

1

988

Risk Ratio (M‐H, Fixed, 95% CI)

1.00 [0.56, 1.81]

1.15 Fever in women after trial entry requiring the use of antibiotics Show forest plot

4

481

Risk Ratio (M‐H, Random, 95% CI)

0.95 [0.43, 2.06]

1.16 Intrapartum fever in woman requiring the use of antibiotics Show forest plot

2

319

Risk Ratio (M‐H, Random, 95% CI)

0.66 [0.09, 4.89]

1.17 Side effects of therapy in women Show forest plot

6

3572

Risk Ratio (M‐H, Fixed, 95% CI)

0.69 [0.59, 0.82]

1.18 Admission into adult intensive care unit Show forest plot

2

319

Risk Ratio (M‐H, Fixed, 95% CI)

0.74 [0.26, 2.05]

1.19 Hypertension Show forest plot

1

220

Risk Ratio (M‐H, Fixed, 95% CI)

1.00 [0.36, 2.76]

1.20 Postnatal fever in woman Show forest plot

5

1323

Risk Ratio (M‐H, Fixed, 95% CI)

0.92 [0.64, 1.33]

1.21 Glucose intolerance Show forest plot

1

123

Risk Ratio (M‐H, Fixed, 95% CI)

2.71 [1.14, 6.46]

1.22 Necrotising enterocolitis Show forest plot

10

4702

Risk Ratio (M‐H, Fixed, 95% CI)

0.50 [0.32, 0.78]

1.23 Systemic infection in the first 48 hours of life Show forest plot

8

1753

Risk Ratio (M‐H, Fixed, 95% CI)

0.60 [0.41, 0.88]

1.24 Proven infection while in the neonatal intensive care unit Show forest plot

13

5707

Risk Ratio (M‐H, Random, 95% CI)

0.77 [0.55, 1.08]

1.25 Need for mechanical ventilation/CPAP Show forest plot

9

1368

Risk Ratio (M‐H, Fixed, 95% CI)

0.68 [0.56, 0.84]

1.26 Mean duration of mechanical ventilation/CPAP (days) Show forest plot

3

471

Mean Difference (IV, Random, 95% CI)

‐1.91 [‐4.59, 0.76]

1.27 Mean duration of oxygen supplementation (days) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

1.28 Surfactant use Show forest plot

5

3556

Risk Ratio (M‐H, Fixed, 95% CI)

0.68 [0.51, 0.90]

1.29 Air leak syndrome Show forest plot

2

2965

Risk Ratio (M‐H, Fixed, 95% CI)

0.76 [0.32, 1.80]

1.30 Apgar < 7 at 5 minutes Show forest plot

10

2419

Risk Ratio (M‐H, Fixed, 95% CI)

0.81 [0.67, 0.98]

1.31 Mean interval between trial entry and birth (days) Show forest plot

3

1513

Mean Difference (IV, Fixed, 95% CI)

0.23 [‐1.86, 2.32]

1.32 Small‐for‐gestational age Show forest plot

5

3478

Risk Ratio (M‐H, Fixed, 95% CI)

1.11 [0.96, 1.28]

1.33 Mean infant HPA axis function (cortisol) Show forest plot

1

27

Mean Difference (IV, Fixed, 95% CI)

3.94 [‐3.12, 11.00]

1.33.1 In babies born < 24 hours after 1st dose

1

6

Mean Difference (IV, Fixed, 95% CI)

9.00 [‐11.93, 29.93]

1.33.2 In babies born 24‐48 hours after 1st dose

1

10

Mean Difference (IV, Fixed, 95% CI)

0.00 [‐8.68, 8.68]

1.33.3 In babies born > 48 hours after 1st dose

1

11

Mean Difference (IV, Fixed, 95% CI)

13.00 [‐1.90, 27.90]

1.34 Admission to neonatal intensive care unit Show forest plot

7

3803

Risk Ratio (M‐H, Fixed, 95% CI)

0.90 [0.84, 0.97]

1.35 Developmental delay in childhood Show forest plot

2

518

Risk Ratio (M‐H, Fixed, 95% CI)

0.49 [0.24, 1.00]

1.36 Cerebral palsy in childhood Show forest plot

5

904

Risk Ratio (M‐H, Fixed, 95% CI)

0.60 [0.34, 1.03]

1.37 Mean childhood weight (kg) Show forest plot

2

333

Mean Difference (IV, Fixed, 95% CI)

0.30 [‐0.39, 1.00]

1.37.1 Liggins

1

250

Mean Difference (IV, Fixed, 95% CI)

0.40 [‐0.32, 1.12]

1.37.2 Schutte (females)

1

39

Mean Difference (IV, Fixed, 95% CI)

‐2.40 [‐6.55, 1.75]

1.37.3 Schutte (males)

1

44

Mean Difference (IV, Fixed, 95% CI)

‐0.10 [‐3.88, 3.68]

1.38 Mean childhood height (cm) Show forest plot

2

334

Mean Difference (IV, Fixed, 95% CI)

1.02 [‐0.26, 2.29]

1.38.1 Liggins

1

250

Mean Difference (IV, Fixed, 95% CI)

1.00 [‐0.39, 2.39]

1.38.2 Schutte (females)

1

39

Mean Difference (IV, Fixed, 95% CI)

1.70 [‐3.08, 6.48]

1.38.3 Schutte (males)

1

45

Mean Difference (IV, Fixed, 95% CI)

0.60 [‐3.79, 4.99]

1.39 Mean childhood head circumference (cm) Show forest plot

2

328

Mean Difference (IV, Fixed, 95% CI)

0.27 [‐0.08, 0.63]

1.39.1 Liggins

1

250

Mean Difference (IV, Fixed, 95% CI)

0.30 [‐0.11, 0.71]

1.39.2 Schutte (females)

1

36

Mean Difference (IV, Fixed, 95% CI)

‐0.10 [‐1.05, 0.85]

1.39.3 Schutte (males)

1

42

Mean Difference (IV, Fixed, 95% CI)

0.60 [‐0.51, 1.71]

1.40 Mean childhood VC (% predicted) Show forest plot

2

150

Mean Difference (IV, Fixed, 95% CI)

‐1.68 [‐5.12, 1.75]

1.40.1 Liggins

1

75

Mean Difference (IV, Fixed, 95% CI)

0.70 [‐5.12, 6.52]

1.40.2 Schutte (females)

1

36

Mean Difference (IV, Fixed, 95% CI)

‐2.60 [‐8.65, 3.45]

1.40.3 Schutte (males)

1

39

Mean Difference (IV, Fixed, 95% CI)

‐3.30 [‐9.27, 2.67]

1.41 Mean childhood FEV1 (% predicted) Show forest plot

1

75

Mean Difference (IV, Fixed, 95% CI)

‐4.73 [‐10.13, 0.67]

1.41.1 Schutte (females)

1

36

Mean Difference (IV, Fixed, 95% CI)

‐2.50 [‐11.24, 6.24]

1.41.2 Schutte (males)

1

39

Mean Difference (IV, Fixed, 95% CI)

‐6.10 [‐12.96, 0.76]

1.42 Mean childhood FEV1/VC Show forest plot

2

150

Mean Difference (IV, Random, 95% CI)

‐0.94 [‐3.63, 1.76]

1.42.1 Liggins

1

75

Mean Difference (IV, Random, 95% CI)

1.00 [‐2.57, 4.57]

1.42.2 Schutte (females)

1

36

Mean Difference (IV, Random, 95% CI)

0.00 [‐5.56, 5.56]

1.42.3 Schutte (males)

1

39

Mean Difference (IV, Random, 95% CI)

‐3.00 [‐6.14, 0.14]

1.43 Mean childhood systolic blood pressure (mmHg) Show forest plot

1

223

Mean Difference (IV, Fixed, 95% CI)

‐1.60 [‐4.06, 0.86]

1.44 Visual impairment in childhood Show forest plot

2

166

Risk Ratio (M‐H, Fixed, 95% CI)

0.55 [0.24, 1.23]

1.45 Hearing impairment in childhood Show forest plot

2

166

Risk Ratio (M‐H, Fixed, 95% CI)

0.64 [0.04, 9.87]

1.46 Intellectual impairment in childhood Show forest plot

3

778

Risk Ratio (M‐H, Fixed, 95% CI)

0.86 [0.44, 1.69]

1.47 Behavioural/learning difficulties in childhood Show forest plot

1

90

Risk Ratio (M‐H, Fixed, 95% CI)

0.86 [0.35, 2.09]

1.48 Mean adult insulin (log values) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

1.48.1 Fasting

1

435

Mean Difference (IV, Fixed, 95% CI)

0.08 [‐0.03, 0.19]

1.48.2 30 minutes following a 75 g oral glucose tolerance test

1

412

Mean Difference (IV, Fixed, 95% CI)

0.16 [0.04, 0.28]

1.48.3 120 minutes following a 75 g oral glucose tolerance test

1

428

Mean Difference (IV, Fixed, 95% CI)

‐0.10 [‐0.27, 0.07]

1.49 Mean adult glucose (mmol/L) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

1.49.1 Fasting

1

432

Mean Difference (IV, Fixed, 95% CI)

0.01 [‐0.09, 0.11]

1.49.2 30 minutes following a 75 g oral glucose tolerance test

1

413

Mean Difference (IV, Fixed, 95% CI)

0.19 [‐0.14, 0.52]

1.49.3 120 minutes following a 75 g oral glucose tolerance test

1

410

Mean Difference (IV, Fixed, 95% CI)

‐0.27 [‐0.52, ‐0.02]

1.50 Mean adult weight (kg) Show forest plot

2

538

Mean Difference (IV, Random, 95% CI)

‐0.83 [‐6.41, 4.76]

1.50.1 Schutte (females)

1

37

Mean Difference (IV, Random, 95% CI)

‐6.00 [‐12.93, 0.93]

1.50.2 Schutte (males)

1

43

Mean Difference (IV, Random, 95% CI)

‐1.00 [‐9.91, 7.91]

1.50.3 Liggins

1

458

Mean Difference (IV, Random, 95% CI)

2.57 [‐0.72, 5.86]

1.51 Mean adult height (cm) Show forest plot

2

537

Mean Difference (IV, Fixed, 95% CI)

0.91 [‐0.28, 2.10]

1.51.1 Schutte (females)

1

36

Mean Difference (IV, Fixed, 95% CI)

‐1.00 [‐5.37, 3.37]

1.51.2 Schutte (males)

1

43

Mean Difference (IV, Fixed, 95% CI)

3.00 [‐2.30, 8.30]

1.51.3 Liggins (females)

1

234

Mean Difference (IV, Fixed, 95% CI)

1.17 [‐0.65, 2.99]

1.51.4 Liggins (males)

1

224

Mean Difference (IV, Fixed, 95% CI)

0.75 [‐1.03, 2.53]

1.52 Mean adult head circumference (cm) Show forest plot

2

537

Mean Difference (IV, Fixed, 95% CI)

0.03 [‐0.33, 0.38]

1.52.1 Schutte (females)

1

37

Mean Difference (IV, Fixed, 95% CI)

0.00 [‐1.03, 1.03]

1.52.2 Schutte (males)

1

42

Mean Difference (IV, Fixed, 95% CI)

‐0.20 [‐1.37, 0.97]

1.52.3 Liggins

1

458

Mean Difference (IV, Fixed, 95% CI)

0.06 [‐0.34, 0.46]

1.53 Mean adult skinfold thickness (log values) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

1.53.1 Triceps

1

456

Mean Difference (IV, Fixed, 95% CI)

‐0.02 [‐0.11, 0.07]

1.53.2 Biceps

1

456

Mean Difference (IV, Fixed, 95% CI)

‐0.01 [‐0.11, 0.09]

1.53.3 Subscapular

1

441

Mean Difference (IV, Fixed, 95% CI)

0.01 [‐0.08, 0.10]

1.53.4 Suprailiac

1

452

Mean Difference (IV, Fixed, 95% CI)

‐0.01 [‐0.12, 0.10]

1.54 Mean adult systolic blood pressure (mmHg) Show forest plot

2

545

Mean Difference (IV, Random, 95% CI)

‐1.53 [‐4.50, 1.44]

1.54.1 Schutte (females)

1

38

Mean Difference (IV, Random, 95% CI)

‐4.00 [‐9.12, 1.12]

1.54.2 Schutte (males)

1

52

Mean Difference (IV, Random, 95% CI)

‐3.00 [‐7.17, 1.17]

1.54.3 Liggins

1

455

Mean Difference (IV, Random, 95% CI)

0.55 [‐1.88, 2.98]

1.55 Mean adult HPA axis function (mean log fasting cortisol) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

1.56 Mean cholesterol in adulthood (mmol/L) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

1.57 Mean age at puberty (years) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

1.57.1 Schutte (females)

1

38

Mean Difference (IV, Fixed, 95% CI)

0.00 [‐0.94, 0.94]

1.58 Educational achievement by adulthood (university or polytechnic education) Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.59 Visual impairment in adulthood Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.60 Hearing impairment in adulthood Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.61 Intellectual impairment in adulthood Show forest plot

2

273

Risk Ratio (M‐H, Fixed, 95% CI)

0.24 [0.01, 4.95]

1.62 Mean adult FVC (% predicted) Show forest plot

1

383

Mean Difference (IV, Fixed, 95% CI)

‐0.70 [‐3.16, 1.76]

1.63 Mean adult FEV1 (% predicted) Show forest plot

1

383

Mean Difference (IV, Fixed, 95% CI)

0.40 [‐2.31, 3.11]

1.64 Mean adult FEV1/FVC Show forest plot

1

383

Mean Difference (IV, Fixed, 95% CI)

0.01 [‐0.01, 0.03]

1.65 Mean adult PEF Show forest plot

1

383

Mean Difference (IV, Fixed, 95% CI)

2.20 [‐0.77, 5.17]

1.66 Mean adult F50 Show forest plot

1

383

Mean Difference (IV, Fixed, 95% CI)

3.00 [‐1.57, 7.57]

1.67 Mean adult F25 Show forest plot

1

383

Mean Difference (IV, Fixed, 95% CI)

0.40 [‐3.82, 4.62]

1.68 Mean adult FEF 25%‐75% Show forest plot

1

383

Mean Difference (IV, Fixed, 95% CI)

2.20 [‐2.10, 6.50]

1.69 FEV1/FVC < 70% Show forest plot

1

383

Risk Ratio (M‐H, Fixed, 95% CI)

0.87 [0.49, 1.57]

1.70 Asthma diagnosed by Doctor in lifetime Show forest plot

1

534

Risk Ratio (M‐H, Fixed, 95% CI)

0.98 [0.74, 1.30]

1.71 Wheezing in last 12 months Show forest plot

1

534

Risk Ratio (M‐H, Fixed, 95% CI)

1.06 [0.84, 1.35]

1.72 Current Asthma Show forest plot

1

534

Risk Ratio (M‐H, Fixed, 95% CI)

1.05 [0.74, 1.48]

1.73 Further respiratory diagnosis (includes pneumonia, upper airway conditions and bronchitis) Show forest plot

1

534

Risk Ratio (M‐H, Fixed, 95% CI)

1.33 [0.69, 2.59]

1.74 Spontaneous pneumothorax Show forest plot

1

534

Risk Ratio (M‐H, Fixed, 95% CI)

1.11 [0.07, 17.66]

1.75 Shortness of breath at anytime in the last 12 months Show forest plot

1

534

Risk Ratio (M‐H, Fixed, 95% CI)

1.02 [0.80, 1.31]

1.76 Mean adult lumbar spine aBMD (g/cm2) areal bone mineral density Show forest plot

1

174

Mean Difference (IV, Fixed, 95% CI)

0.00 [‐0.04, 0.04]

1.77 Mean adult lumbar spine vBMD (g/cm3) volumetric bone mineral density Show forest plot

1

174

Mean Difference (IV, Fixed, 95% CI)

0.00 [‐0.01, 0.01]

1.78 Mean adult total body BMC (grams) bone mineral content Show forest plot

1

174

Mean Difference (IV, Fixed, 95% CI)

18.00 [‐151.30, 187.30]

1.79 Mean adult total body aBMD (g/cm3) areal bone mineral density Show forest plot

1

174

Mean Difference (IV, Fixed, 95% CI)

0.00 [‐0.03, 0.03]

1.80 Mean adult femoral neck aBMD (g/cm2) areal bone mineral density Show forest plot

1

174

Mean Difference (IV, Fixed, 95% CI)

0.02 [‐0.03, 0.07]

1.81 Mean adult femoral trochanter aBMD (g/cm2) areal bone mineral density Show forest plot

1

174

Mean Difference (IV, Fixed, 95% CI)

0.02 [‐0.02, 0.06]

1.82 Mean adult femoral shaft aBMD (g/cm2) areal bone mineral density Show forest plot

1

174

Mean Difference (IV, Fixed, 95% CI)

0.01 [‐0.04, 0.06]

1.83 Mean total proximal femur aBMD (g/cm2) areal bone mineral density Show forest plot

1

174

Mean Difference (IV, Fixed, 95% CI)

0.02 [‐0.03, 0.07]

1.84 Mean length of antenatal hospitalisation (days) Show forest plot

1

218

Mean Difference (IV, Fixed, 95% CI)

0.50 [‐1.40, 2.40]

1.85 Mean length of postnatal hospitalisation (days) Show forest plot

1

218

Mean Difference (IV, Fixed, 95% CI)

0.00 [‐1.72, 1.72]

1.86 Mean length of neonatal hospitalisation (days) Show forest plot

5

788

Mean Difference (IV, Fixed, 95% CI)

0.18 [‐0.51, 0.87]

Figures and Tables -
Comparison 1. Corticosteroids versus placebo or no treatment
Comparison 2. Corticosteroids versus placebo or no treatment ‐ single or multiple pregnancy

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

2.1 Chorioamnionitis ‐ single or multiple pregnancy Show forest plot

15

5546

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.66, 1.06]

2.1.1 In women delivering singleton pregnancies

7

4682

Risk Ratio (M‐H, Fixed, 95% CI)

0.75 [0.56, 1.01]

2.1.2 In women delivering multiple pregnancies

1

74

Risk Ratio (M‐H, Fixed, 95% CI)

0.42 [0.04, 4.49]

2.1.3 Mixed population

8

790

Risk Ratio (M‐H, Fixed, 95% CI)

1.05 [0.70, 1.57]

2.2 Perinatal death ‐ single or multiple pregnancy Show forest plot

15

6729

Risk Ratio (M‐H, Random, 95% CI)

0.72 [0.59, 0.89]

2.2.1 In babies born from singleton pregnancies

6

5182

Risk Ratio (M‐H, Random, 95% CI)

0.75 [0.54, 1.05]

2.2.2 In babies born from multiple pregnancies

2

252

Risk Ratio (M‐H, Random, 95% CI)

0.74 [0.37, 1.47]

2.2.3 Mixed population

9

1295

Risk Ratio (M‐H, Random, 95% CI)

0.68 [0.49, 0.94]

2.3 Neonatal death ‐ single or multiple pregnancy Show forest plot

22

7188

Risk Ratio (M‐H, Fixed, 95% CI)

0.69 [0.59, 0.81]

2.3.1 In babies born from singleton pregnancies

9

5335

Risk Ratio (M‐H, Fixed, 95% CI)

0.75 [0.61, 0.92]

2.3.2 In babies born from multiple pregnancies

2

236

Risk Ratio (M‐H, Fixed, 95% CI)

0.79 [0.39, 1.61]

2.3.3 Mixed population

13

1617

Risk Ratio (M‐H, Fixed, 95% CI)

0.60 [0.46, 0.78]

2.4 Fetal death ‐ single or multiple pregnancy Show forest plot

15

6729

Risk Ratio (M‐H, Fixed, 95% CI)

0.97 [0.73, 1.29]

2.4.1 In babies born from singleton pregnancies

6

5182

Risk Ratio (M‐H, Fixed, 95% CI)

1.04 [0.75, 1.45]

2.4.2 In babies born from multiple pregnancies

2

252

Risk Ratio (M‐H, Fixed, 95% CI)

0.53 [0.20, 1.40]

2.4.3 Mixed population

9

1295

Risk Ratio (M‐H, Fixed, 95% CI)

0.99 [0.50, 1.99]

2.5 Respiratory distress syndrome ‐ single or multiple pregnancy Show forest plot

28

7762

Risk Ratio (M‐H, Random, 95% CI)

0.68 [0.59, 0.78]

2.5.1 In babies born from singleton pregnancies

15

6081

Risk Ratio (M‐H, Random, 95% CI)

0.62 [0.50, 0.77]

2.5.2 In babies born from multiple pregnancies

4

320

Risk Ratio (M‐H, Random, 95% CI)

0.90 [0.67, 1.22]

2.5.3 Mixed population

13

1361

Risk Ratio (M‐H, Random, 95% CI)

0.69 [0.53, 0.89]

2.6 IVH ‐ single or multiple pregnancy Show forest plot

16

6093

Risk Ratio (M‐H, Fixed, 95% CI)

0.56 [0.44, 0.70]

2.6.1 In babies born from singleton pregnancies

8

4782

Risk Ratio (M‐H, Fixed, 95% CI)

0.52 [0.36, 0.75]

2.6.2 In babies born from multiple pregnancies

1

137

Risk Ratio (M‐H, Fixed, 95% CI)

0.39 [0.07, 2.06]

2.6.3 Mixed population

8

1174

Risk Ratio (M‐H, Fixed, 95% CI)

0.60 [0.44, 0.81]

2.7 Birthweight ‐ single or multiple pregnancy Show forest plot

16

6182

Mean Difference (IV, Fixed, 95% CI)

‐17.61 [‐39.95, 4.74]

2.7.1 In babies born from singleton pregnancy

9

4948

Mean Difference (IV, Fixed, 95% CI)

‐24.12 [‐48.27, 0.03]

2.7.2 In babies born from multiple pregnancies

1

150

Mean Difference (IV, Fixed, 95% CI)

82.36 [‐146.23, 310.95]

2.7.3 Mixed population

7

1084

Mean Difference (IV, Fixed, 95% CI)

16.77 [‐44.16, 77.69]

Figures and Tables -
Comparison 2. Corticosteroids versus placebo or no treatment ‐ single or multiple pregnancy
Comparison 3. Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

3.1 Chorioamnionitis ‐ intact or ruptured membranes Show forest plot

15

5517

Risk Ratio (M‐H, Fixed, 95% CI)

0.85 [0.67, 1.07]

3.1.1 In women with intact membranes at 1st dose

5

1437

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.50, 1.40]

3.1.2 In women with ruptured membranes at 1st dose

7

959

Risk Ratio (M‐H, Fixed, 95% CI)

0.98 [0.69, 1.40]

3.1.3 Not reported or mixed population

4

3121

Risk Ratio (M‐H, Fixed, 95% CI)

0.71 [0.47, 1.06]

3.2 Endometritis ‐ intact or ruptured membranes Show forest plot

10

4030

Risk Ratio (M‐H, Random, 95% CI)

1.20 [0.80, 1.80]

3.2.1 In women with intact membranes at 1st dose

2

289

Risk Ratio (M‐H, Random, 95% CI)

1.21 [0.37, 4.01]

3.2.2 In women with ruptured membranes at 1st dose

4

477

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.35, 2.97]

3.2.3 Not reported or mixed population

5

3264

Risk Ratio (M‐H, Random, 95% CI)

1.31 [0.81, 2.13]

3.3 Perinatal death ‐ intact or ruptured membranes Show forest plot

15

6700

Risk Ratio (M‐H, Random, 95% CI)

0.74 [0.60, 0.90]

3.3.1 In babies born from pregnancies with intact membranes at 1st dose

4

1332

Risk Ratio (M‐H, Random, 95% CI)

0.87 [0.70, 1.08]

3.3.2 In babies born from pregnancies with ruptured membranes at 1st dose

4

733

Risk Ratio (M‐H, Random, 95% CI)

0.59 [0.39, 0.90]

3.3.3 Not reported or mixed population

8

4635

Risk Ratio (M‐H, Random, 95% CI)

0.71 [0.49, 1.03]

3.4 Neonatal deaths ‐ intact or ruptured membranes Show forest plot

22

7163

Risk Ratio (M‐H, Fixed, 95% CI)

0.69 [0.59, 0.81]

3.4.1 In babies born from pregnancies with intact membranes at 1st dose

4

1236

Risk Ratio (M‐H, Fixed, 95% CI)

0.77 [0.58, 1.03]

3.4.2 In babies born from pregnancies with ruptured membranes at 1st dose

8

1024

Risk Ratio (M‐H, Fixed, 95% CI)

0.61 [0.46, 0.83]

3.4.3 Not reported or mixed population

11

4903

Risk Ratio (M‐H, Fixed, 95% CI)

0.68 [0.53, 0.88]

3.5 Fetal death ‐ intact or ruptured membranes Show forest plot

15

6634

Risk Ratio (M‐H, Fixed, 95% CI)

0.94 [0.71, 1.26]

3.5.1 In babies born from pregnancies with intact membranes at 1st dose

4

1332

Risk Ratio (M‐H, Fixed, 95% CI)

1.09 [0.73, 1.64]

3.5.2 In babies born from pregnancies with ruptured membranes at 1st dose

5

790

Risk Ratio (M‐H, Fixed, 95% CI)

0.86 [0.46, 1.61]

3.5.3 Not reported or mixed population

7

4512

Risk Ratio (M‐H, Fixed, 95% CI)

0.77 [0.44, 1.35]

3.6 RDS ‐ intact or ruptured membranes Show forest plot

28

7738

Risk Ratio (M‐H, Random, 95% CI)

0.65 [0.56, 0.76]

3.6.1 In babies born from pregnancies with intact membranes at 1st dose

6

1721

Risk Ratio (M‐H, Random, 95% CI)

0.63 [0.50, 0.80]

3.6.2 In babies born from pregnancies with ruptured membranes at 1st dose

12

1129

Risk Ratio (M‐H, Random, 95% CI)

0.70 [0.55, 0.90]

3.6.3 Not reported or mixed population

14

4888

Risk Ratio (M‐H, Random, 95% CI)

0.61 [0.46, 0.81]

3.7 IVH ‐ intact or ruptured membranes Show forest plot

15

5868

Risk Ratio (M‐H, Fixed, 95% CI)

0.56 [0.44, 0.70]

3.7.1 In babies born from pregnancies with intact membranes at 1st dose

5

1394

Risk Ratio (M‐H, Fixed, 95% CI)

0.50 [0.35, 0.72]

3.7.2 In babies born from pregnancies with ruptured membranes at 1st dose

5

895

Risk Ratio (M‐H, Fixed, 95% CI)

0.47 [0.28, 0.79]

3.7.3 Not reported or mixed population

6

3579

Risk Ratio (M‐H, Fixed, 95% CI)

0.72 [0.49, 1.07]

3.8 Birthweight ‐ intact or ruptured membranes Show forest plot

16

6153

Mean Difference (IV, Fixed, 95% CI)

‐19.52 [‐41.81, 2.78]

3.8.1 In babies born from pregnancies with intact membranes at 1st dose

4

1301

Mean Difference (IV, Fixed, 95% CI)

‐30.27 [‐100.43, 39.89]

3.8.2 In babies born from pregnancies with ruptured membranes at 1st dose

5

835

Mean Difference (IV, Fixed, 95% CI)

‐49.72 [‐113.91, 14.46]

3.8.3 Not reported or mixed population

8

4017

Mean Difference (IV, Fixed, 95% CI)

‐13.44 [‐38.71, 11.83]

Figures and Tables -
Comparison 3. Corticosteroids versus placebo or no treatment ‐ intact membranes versus ruptured membranes at first dose
Comparison 4. Corticosteroids versus placebo or no treatment ‐ hypertension syndrome versus all other trials

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

4.1 RDS Show forest plot

28

7764

Risk Ratio (M‐H, Fixed, 95% CI)

0.67 [0.60, 0.74]

4.1.1 Hypertension syndrome

5

382

Risk Ratio (M‐H, Fixed, 95% CI)

0.50 [0.35, 0.72]

4.1.2 No hypertension syndrome or hypertension syndromes excluded

9

2660

Risk Ratio (M‐H, Fixed, 95% CI)

0.58 [0.47, 0.71]

4.1.3 Hypertension not reported separately

18

4722

Risk Ratio (M‐H, Fixed, 95% CI)

0.75 [0.66, 0.85]

4.2 Perinatal deaths Show forest plot

15

6729

Risk Ratio (M‐H, Random, 95% CI)

0.74 [0.60, 0.92]

4.2.1 Hypertension syndrome

2

313

Risk Ratio (M‐H, Random, 95% CI)

0.94 [0.42, 2.10]

4.2.2 No hypertension syndrome or hypertension syndromes excluded

3

1394

Risk Ratio (M‐H, Random, 95% CI)

0.71 [0.39, 1.29]

4.2.3 Hypertension not reported separately

11

5022

Risk Ratio (M‐H, Random, 95% CI)

0.70 [0.52, 0.93]

4.3 Fetal deaths Show forest plot

15

6729

Risk Ratio (M‐H, Fixed, 95% CI)

0.98 [0.74, 1.30]

4.3.1 Women with hypertension syndrome

3

331

Risk Ratio (M‐H, Fixed, 95% CI)

1.73 [0.91, 3.28]

4.3.2 No hypertension syndrome or hypertension syndromes excluded

4

1644

Risk Ratio (M‐H, Fixed, 95% CI)

0.73 [0.49, 1.08]

4.3.3 Hypertension not reported separately

10

4754

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [0.67, 1.98]

4.4 Neonatal deaths Show forest plot

22

7188

Risk Ratio (M‐H, Fixed, 95% CI)

0.69 [0.59, 0.81]

4.4.1 Hypertension syndrome

2

278

Risk Ratio (M‐H, Fixed, 95% CI)

0.50 [0.29, 0.87]

4.4.2 No hypertension syndrome or hypertension syndromes excluded

3

1306

Risk Ratio (M‐H, Fixed, 95% CI)

0.81 [0.61, 1.09]

4.4.3 Hypertension not reported separately

18

5604

Risk Ratio (M‐H, Fixed, 95% CI)

0.66 [0.54, 0.82]

Figures and Tables -
Comparison 4. Corticosteroids versus placebo or no treatment ‐ hypertension syndrome versus all other trials
Comparison 5. Corticosteroids versus placebo or no treatment ‐ type of steroid

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

5.1 Chorioamnionitis ‐ type of steroid Show forest plot

15

5546

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.66, 1.06]

5.1.1 In women treated with dexamethasone

5

769

Risk Ratio (M‐H, Fixed, 95% CI)

1.35 [0.89, 2.05]

5.1.2 In women treated with betamethasone

10

4777

Risk Ratio (M‐H, Fixed, 95% CI)

0.67 [0.50, 0.90]

5.2 Endometritis ‐ type of steroid Show forest plot

10

4030

Risk Ratio (M‐H, Random, 95% CI)

1.20 [0.81, 1.80]

5.2.1 In women treated with dexamethasone

4

536

Risk Ratio (M‐H, Random, 95% CI)

1.71 [0.86, 3.43]

5.2.2 In women treated with betamethasone

6

3494

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.63, 1.45]

5.3 Perinatal death ‐ type of steroid Show forest plot

15

6729

Risk Ratio (M‐H, Random, 95% CI)

0.72 [0.58, 0.89]

5.3.1 In babies treated with dexamethasone

5

1420

Risk Ratio (M‐H, Random, 95% CI)

0.72 [0.46, 1.11]

5.3.2 In babies treated with betamethasone

10

5309

Risk Ratio (M‐H, Random, 95% CI)

0.73 [0.56, 0.94]

5.4 Neonatal deaths by steroid type Show forest plot

22

7188

Risk Ratio (M‐H, Fixed, 95% CI)

0.69 [0.59, 0.81]

5.4.1 In babies treated with dexamethasone

6

1468

Risk Ratio (M‐H, Fixed, 95% CI)

0.72 [0.55, 0.94]

5.4.2 In babies treated with betamethasone

16

5720

Risk Ratio (M‐H, Fixed, 95% CI)

0.68 [0.55, 0.83]

5.5 Fetal death ‐ type of steroid Show forest plot

15

6729

Risk Ratio (M‐H, Fixed, 95% CI)

0.98 [0.74, 1.30]

5.5.1 In babies treated with dexamethasone

5

1420

Risk Ratio (M‐H, Fixed, 95% CI)

0.88 [0.48, 1.60]

5.5.2 In babies treated with betamethasone

10

5309

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.73, 1.39]

5.6 Respiratory distress syndrome ‐ type of steroid Show forest plot

28

7764

Risk Ratio (M‐H, Random, 95% CI)

0.66 [0.56, 0.77]

5.6.1 In babies treated with dexamethasone

7

1651

Risk Ratio (M‐H, Random, 95% CI)

0.77 [0.61, 0.98]

5.6.2 In babies treated with betamethasone

20

6095

Risk Ratio (M‐H, Random, 95% CI)

0.60 [0.50, 0.73]

5.6.3 Steroid type not reported

1

18

Risk Ratio (M‐H, Random, 95% CI)

1.62 [0.08, 34.66]

5.7 IVH ‐ type of steroid Show forest plot

16

6093

Risk Ratio (M‐H, Random, 95% CI)

0.55 [0.40, 0.76]

5.7.1 In babies treated with dexamethasone

6

897

Risk Ratio (M‐H, Random, 95% CI)

0.48 [0.18, 1.26]

5.7.2 In babies treated with betamethasone

10

5196

Risk Ratio (M‐H, Random, 95% CI)

0.53 [0.40, 0.72]

5.8 Birthweight ‐ type of steroid Show forest plot

16

6182

Mean Difference (IV, Fixed, 95% CI)

‐18.47 [‐40.83, 3.90]

5.8.1 In babies treated with dexamethasone

4

686

Mean Difference (IV, Fixed, 95% CI)

‐17.04 [‐75.48, 41.41]

5.8.2 In babies treated with betamethasone

12

5496

Mean Difference (IV, Fixed, 95% CI)

‐18.71 [‐42.92, 5.50]

5.9 Moderate/severe respiratory distress syndrome ‐ type of steroid Show forest plot

6

1686

Risk Ratio (M‐H, Random, 95% CI)

0.59 [0.38, 0.91]

5.9.1 Dexamethasone

2

219

Risk Ratio (M‐H, Random, 95% CI)

0.82 [0.46, 1.44]

5.9.2 Betamethasone

4

1467

Risk Ratio (M‐H, Random, 95% CI)

0.49 [0.27, 0.90]

5.10 Chronic lung disease ‐ type of steroid Show forest plot

6

818

Risk Ratio (M‐H, Random, 95% CI)

0.86 [0.42, 1.79]

5.10.1 Dexamethasone

2

219

Risk Ratio (M‐H, Random, 95% CI)

1.17 [0.72, 1.90]

5.10.2 Betamethasone

4

599

Risk Ratio (M‐H, Random, 95% CI)

0.78 [0.26, 2.28]

Figures and Tables -
Comparison 5. Corticosteroids versus placebo or no treatment ‐ type of steroid
Comparison 6. Corticosteroids versus placebo or no treatment ‐ decade of trial

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

6.1 Chorioamnionitis ‐ decade of trial Show forest plot

15

5546

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.66, 1.06]

6.1.1 In women from trials conducted in 1970s

2

1237

Risk Ratio (M‐H, Fixed, 95% CI)

0.74 [0.46, 1.17]

6.1.2 In women from trials conducted in 1980s

3

276

Risk Ratio (M‐H, Fixed, 95% CI)

0.50 [0.25, 1.01]

6.1.3 In women from trials conducted in 1990s

6

755

Risk Ratio (M‐H, Fixed, 95% CI)

1.18 [0.80, 1.74]

6.1.4 in women from trials conducted in the 2000's

2

257

Risk Ratio (M‐H, Fixed, 95% CI)

2.02 [0.59, 6.95]

6.1.5 In trials from 2010s

2

3021

Risk Ratio (M‐H, Fixed, 95% CI)

0.61 [0.35, 1.07]

6.2 Endometritis ‐ decade of trial Show forest plot

10

4030

Risk Ratio (M‐H, Fixed, 95% CI)

1.20 [0.87, 1.63]

6.2.1 In women from trials conducted in 1970s

2

219

Risk Ratio (M‐H, Fixed, 95% CI)

1.86 [0.81, 4.27]

6.2.2 In women from trials conducted in 1980s

1

71

Risk Ratio (M‐H, Fixed, 95% CI)

2.30 [0.88, 6.06]

6.2.3 In women from trials conducted in 1990s

4

574

Risk Ratio (M‐H, Fixed, 95% CI)

0.87 [0.53, 1.44]

6.2.4 In women from trials conducted in the 2000's

3

3166

Risk Ratio (M‐H, Fixed, 95% CI)

1.18 [0.69, 2.01]

6.3 Perinatal deaths ‐ decade of trial Show forest plot

15

6729

Risk Ratio (M‐H, Random, 95% CI)

0.72 [0.58, 0.89]

6.3.1 In babies from trials conducted in 1970s

6

1994

Risk Ratio (M‐H, Random, 95% CI)

0.71 [0.50, 1.00]

6.3.2 In babies from trials conducted in 1980s

3

879

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.74, 1.42]

6.3.3 In babies from trials conducted in 1990s

3

615

Risk Ratio (M‐H, Random, 95% CI)

0.63 [0.43, 0.93]

6.3.4 in babies from trials conducted in 2000's

2

414

Risk Ratio (M‐H, Random, 95% CI)

0.47 [0.31, 0.70]

6.3.5 In trials conducted in 2010s

1

2827

Risk Ratio (M‐H, Random, 95% CI)

4.91 [0.24, 102.09]

6.4 Neonatal deaths decade of trial Show forest plot

22

7188

Risk Ratio (M‐H, Fixed, 95% CI)

0.69 [0.59, 0.81]

6.4.1 In babies from trials conducted in 1970s

7

1968

Risk Ratio (M‐H, Fixed, 95% CI)

0.72 [0.56, 0.92]

6.4.2 In babies from trials conducted in 1980s

6

1096

Risk Ratio (M‐H, Fixed, 95% CI)

0.98 [0.70, 1.37]

6.4.3 In babies from trials conducted in 1990s

5

758

Risk Ratio (M‐H, Fixed, 95% CI)

0.55 [0.36, 0.84]

6.4.4 In babies from trials conducted in 2000s

3

539

Risk Ratio (M‐H, Fixed, 95% CI)

0.44 [0.31, 0.64]

6.4.5 In trials conducted in 2010s

1

2827

Risk Ratio (M‐H, Fixed, 95% CI)

4.91 [0.24, 102.09]

6.5 Fetal death ‐ decade of trial Show forest plot

15

6729

Risk Ratio (M‐H, Fixed, 95% CI)

0.98 [0.74, 1.30]

6.5.1 In babies from trials conducted in 1970s

6

1994

Risk Ratio (M‐H, Fixed, 95% CI)

0.95 [0.67, 1.34]

6.5.2 In babies from trials conducted in 1980s

3

879

Risk Ratio (M‐H, Fixed, 95% CI)

1.02 [0.52, 2.00]

6.5.3 In babies from trials conducted in 1990s

3

615

Risk Ratio (M‐H, Fixed, 95% CI)

1.07 [0.49, 2.36]

6.5.4 In babies from trials conducted in 2000's

2

414

Risk Ratio (M‐H, Fixed, 95% CI)

0.92 [0.19, 4.50]

6.5.5 In trials conducted in 2010s

1

2827

Risk Ratio (M‐H, Fixed, 95% CI)

Not estimable

6.6 RDS ‐ decade of trial Show forest plot

28

7764

Risk Ratio (M‐H, Fixed, 95% CI)

0.67 [0.60, 0.74]

6.6.1 In babies from trials conducted in 1970s

7

1939

Risk Ratio (M‐H, Fixed, 95% CI)

0.54 [0.43, 0.69]

6.6.2 In babies from trials conducted in 1980s

7

1167

Risk Ratio (M‐H, Fixed, 95% CI)

0.72 [0.59, 0.88]

6.6.3 In babies from trials conducted in 1990s

7

798

Risk Ratio (M‐H, Fixed, 95% CI)

0.77 [0.65, 0.91]

6.6.4 In babies from trials conducted in 2000s

5

839

Risk Ratio (M‐H, Fixed, 95% CI)

0.39 [0.26, 0.59]

6.6.5 In trials from 2010s

2

3021

Risk Ratio (M‐H, Fixed, 95% CI)

0.80 [0.61, 1.04]

6.7 IVH ‐ decade of trial Show forest plot

16

6093

Risk Ratio (M‐H, Fixed, 95% CI)

0.56 [0.44, 0.70]

6.7.1 In babies from trials conducted in 1970s

4

1646

Risk Ratio (M‐H, Fixed, 95% CI)

0.50 [0.29, 0.85]

6.7.2 In babies from trials conducted in 1980s

2

238

Risk Ratio (M‐H, Fixed, 95% CI)

0.61 [0.39, 0.94]

6.7.3 In babies from trials conducted in 1990s

5

722

Risk Ratio (M‐H, Fixed, 95% CI)

0.61 [0.42, 0.87]

6.7.4 In babies from trials conducted in 2000s

3

466

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.15, 0.73]

6.7.5 In trials from 2010s

2

3021

Risk Ratio (M‐H, Fixed, 95% CI)

4.91 [0.24, 102.09]

6.8 Birthweight ‐ decade of trial Show forest plot

16

6182

Mean Difference (IV, Fixed, 95% CI)

‐18.47 [‐40.83, 3.90]

6.8.1 In babies from trials conducted in 1970s

4

1739

Mean Difference (IV, Fixed, 95% CI)

‐9.54 [‐83.55, 64.47]

6.8.2 In babies from trials conducted in 1980s

3

280

Mean Difference (IV, Fixed, 95% CI)

‐19.60 [‐108.55, 69.35]

6.8.3 In babies from trials conducted in 1990s

4

569

Mean Difference (IV, Fixed, 95% CI)

‐33.13 [‐102.39, 36.13]

6.8.4 In babies from trials conducted in 2000s

3

573

Mean Difference (IV, Fixed, 95% CI)

‐20.77 [‐61.95, 20.41]

6.8.5 In trials in 2010s

2

3021

Mean Difference (IV, Fixed, 95% CI)

‐15.18 [‐48.66, 18.29]

Figures and Tables -
Comparison 6. Corticosteroids versus placebo or no treatment ‐ decade of trial
Comparison 7. Corticosteroids versus placebo or no treatment ‐ weekly repeats

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

7.1 Chorioamnionitis ‐ Protocol with weekly repeats Show forest plot

15

5546

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.66, 1.06]

7.1.1 In women treated with single courses only

7

4659

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.61, 1.11]

7.1.2 In women treated with courses including weekly repeats

8

887

Risk Ratio (M‐H, Fixed, 95% CI)

0.84 [0.57, 1.25]

7.2 Endometritis ‐ protocol with weekly repeats Show forest plot

10

4030

Risk Ratio (M‐H, Random, 95% CI)

1.20 [0.81, 1.80]

7.2.1 In women treated with single courses only

5

3450

Risk Ratio (M‐H, Random, 95% CI)

1.04 [0.66, 1.64]

7.2.2 In women treated with courses including weekly repeats

5

580

Risk Ratio (M‐H, Random, 95% CI)

1.46 [0.72, 2.95]

7.3 Perinatal death ‐ protocol with weekly repeats Show forest plot

15

6729

Risk Ratio (M‐H, Random, 95% CI)

0.72 [0.58, 0.89]

7.3.1 In babies treated with single course only

11

6250

Risk Ratio (M‐H, Random, 95% CI)

0.77 [0.61, 0.99]

7.3.2 In babies treated with courses including weekly repeats

4

479

Risk Ratio (M‐H, Random, 95% CI)

0.65 [0.44, 0.97]

7.4 Neonatal death ‐ protocol with weekly repeats Show forest plot

22

7188

Risk Ratio (M‐H, Fixed, 95% CI)

0.69 [0.59, 0.81]

7.4.1 In babies treated with single course only

14

6266

Risk Ratio (M‐H, Fixed, 95% CI)

0.78 [0.63, 0.95]

7.4.2 In babies treated with courses including weekly repeats

8

922

Risk Ratio (M‐H, Fixed, 95% CI)

0.55 [0.43, 0.72]

7.5 Fetal death ‐ protocol with weekly repeats Show forest plot

15

6729

Risk Ratio (M‐H, Fixed, 95% CI)

0.98 [0.74, 1.30]

7.5.1 In babies treated with single course only

11

6250

Risk Ratio (M‐H, Fixed, 95% CI)

0.92 [0.68, 1.25]

7.5.2 In babies treated with courses including weekly repeats

4

479

Risk Ratio (M‐H, Fixed, 95% CI)

1.36 [0.64, 2.87]

7.6 RDS ‐ protocol with weekly repeats Show forest plot

28

7764

Risk Ratio (M‐H, Fixed, 95% CI)

0.67 [0.60, 0.74]

7.6.1 In babies treated with single course only

19

6818

Risk Ratio (M‐H, Fixed, 95% CI)

0.69 [0.61, 0.79]

7.6.2 In babies treated with courses including weekly repeats

9

946

Risk Ratio (M‐H, Fixed, 95% CI)

0.61 [0.52, 0.72]

7.7 IVH‐ protocol with weekly repeats Show forest plot

16

6093

Risk Ratio (M‐H, Fixed, 95% CI)

0.56 [0.44, 0.70]

7.7.1 In babies treated with single course only

9

5216

Risk Ratio (M‐H, Fixed, 95% CI)

0.50 [0.33, 0.76]

7.7.2 In babies treated with courses including weekly repeats

7

877

Risk Ratio (M‐H, Fixed, 95% CI)

0.59 [0.45, 0.78]

7.8 Birthweight ‐ protocol with weekly repeats Show forest plot

16

6182

Mean Difference (IV, Fixed, 95% CI)

‐18.47 [‐40.83, 3.90]

7.8.1 In babies treated with single course only

12

5773

Mean Difference (IV, Fixed, 95% CI)

‐18.24 [‐42.12, 5.65]

7.8.2 In babies treated with courses including weekly repeats

4

409

Mean Difference (IV, Fixed, 95% CI)

‐20.10 [‐83.79, 43.60]

7.9 Moderate/severe respiratory distress syndrome Show forest plot

6

1686

Risk Ratio (M‐H, Random, 95% CI)

0.59 [0.38, 0.91]

7.9.1 Single course

3

1259

Risk Ratio (M‐H, Random, 95% CI)

0.60 [0.44, 0.83]

7.9.2 Weekly repeats

3

427

Risk Ratio (M‐H, Random, 95% CI)

0.41 [0.13, 1.32]

Figures and Tables -
Comparison 7. Corticosteroids versus placebo or no treatment ‐ weekly repeats
Comparison 8. Corticosteroids versus placebo or no treatment ‐ gestational age at trial entry

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

8.1 Chorioamnionitis ‐ gestational age at trial entry Show forest plot

15

5506

Risk Ratio (M‐H, Fixed, 95% CI)

0.82 [0.65, 1.05]

8.1.1 Less than or equal to 35 weeks + 0 days

13

2304

Risk Ratio (M‐H, Fixed, 95% CI)

0.91 [0.70, 1.19]

8.1.2 Greater than or equal to 34 weeks + 0 days

3

3202

Risk Ratio (M‐H, Fixed, 95% CI)

0.57 [0.33, 0.99]

8.2 Perinatal death ‐ gestational age at trial entry Show forest plot

15

6687

Risk Ratio (M‐H, Random, 95% CI)

0.72 [0.59, 0.88]

8.2.1 Less than or equal to 35 weeks + 0 days

13

3391

Risk Ratio (M‐H, Random, 95% CI)

0.71 [0.58, 0.87]

8.2.2 Greater than or equal to 34 weeks + 0 days

3

3296

Risk Ratio (M‐H, Random, 95% CI)

1.03 [0.29, 3.67]

8.3 Neonatal death ‐ gestational age at trial engry Show forest plot

22

7146

Risk Ratio (M‐H, Fixed, 95% CI)

0.67 [0.57, 0.79]

8.3.1 Less than or equal to 35 weeks + 0 days

20

3855

Risk Ratio (M‐H, Fixed, 95% CI)

0.67 [0.57, 0.79]

8.3.2 Greater than or equal to 34 weeks + 0 days

3

3291

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.22, 3.07]

8.4 Fetal death ‐ gestational age at trial entry Show forest plot

15

6687

Risk Ratio (M‐H, Fixed, 95% CI)

0.96 [0.72, 1.27]

8.4.1 Less than or equal to 35 weeks + 0 days

13

3391

Risk Ratio (M‐H, Fixed, 95% CI)

0.94 [0.71, 1.25]

8.4.2 Greater than or equal to 34 weeks + 0 days

3

3296

Risk Ratio (M‐H, Fixed, 95% CI)

1.62 [0.28, 9.37]

8.5 RDS‐ gestational age at trial entry Show forest plot

28

7722

Risk Ratio (M‐H, Fixed, 95% CI)

0.66 [0.60, 0.73]

8.5.1 Less than or equal to 35 weeks + 0 days

23

3939

Risk Ratio (M‐H, Fixed, 95% CI)

0.65 [0.58, 0.73]

8.5.2 Greater than or equal to 34 weeks + 0 days

6

3783

Risk Ratio (M‐H, Fixed, 95% CI)

0.71 [0.56, 0.91]

8.6 IVH ‐ gestational age at trial entry Show forest plot

16

6051

Risk Ratio (M‐H, Fixed, 95% CI)

0.55 [0.44, 0.70]

8.6.1 Less than or equal to 35 weeks + 0 days

13

2639

Risk Ratio (M‐H, Fixed, 95% CI)

0.54 [0.42, 0.68]

8.6.2 Greater than or equal to 34 weeks + 0 days

4

3412

Risk Ratio (M‐H, Fixed, 95% CI)

4.91 [0.24, 102.09]

8.7 Birthweight ‐ gestational age at trial entry Show forest plot

16

6140

Mean Difference (IV, Fixed, 95% CI)

‐17.45 [‐39.76, 4.86]

8.7.1 Less than or equal to 35 weeks + 0 days

11

2352

Mean Difference (IV, Fixed, 95% CI)

‐17.89 [‐63.14, 27.36]

8.7.2 Greater than or equal to 34 weeks + 0 days

6

3788

Mean Difference (IV, Fixed, 95% CI)

‐17.31 [‐42.96, 8.34]

Figures and Tables -
Comparison 8. Corticosteroids versus placebo or no treatment ‐ gestational age at trial entry