1. Background

• Complications of preterm birth (<37 weeks’ gestation) are the leading cause of neonatal death and deaths among children under the age of five years (1). Preterm newborns who survive are at increased risk of a wide range of respiratory, infectious, metabolic and neurological morbidities (2–10).
• Animal and human studies have shown that when glucocorticoids (such as dexamethasone or betamethasone) are administered to women at risk of preterm birth, they can cross the placenta and enhance the structural maturity of developing fetal lungs, including inducing differentiation of mesenchymal tissue, accelerating production and secretion of surfactant and decreasing vascular permeability, leading to increased compliance and maximal lung volume (11). These changes can prevent respiratory-related morbidity and mortality affecting preterm newborns.
• Fetal growth restriction is a pathological process that prevents the fetus from attaining its growth potential (12). The incidence is difficult to estimate, varying between populations, settings and definitions used (13). However, the prevalence of small-for-gestational-age (SGA) – many of whom are growth restricted – is nearly 20% in low- and middle-income countries (14). Despite the high prevalence, it is often not detected during routine antenatal care (14–17).

2. Question

Among pregnant women at risk of imminent preterm birth (P), is antenatal corticosteroid therapy (I), compared with no antenatal corticosteroid therapy or placebo (C), effective in reducing adverse newborn outcomes (O)? If so:

• Which population of pregnant women should be offered antenatal corticosteroids considering fetal growth restriction?

Problem: Adverse outcomes due to preterm birth

Perspective: Clinical practice recommendation – population perspective

Population (P): Pregnant women at risk of imminent preterm birth

Intervention (I): Antenatal corticosteroid therapy

Comparator (C): No antenatal corticosteroid therapy or placebo

Priority outcomes (O) ¹

Settings: Low- middle- and high-income settings

Subgroups: Populations of women with babies with fetal growth restriction or small-for-gestational-age babies, growth-restricted babies or small-for-gestational age babies

Critical outcomes

Critical maternal outcomes considered were:

• Severe maternal morbidity or death (e.g. maternal admission to intensive care unit or other markers of severe maternal illness)
• Maternal infectious morbidity (i.e. chorioamnionitis, puerperal sepsis, postnatal fever)
• Adverse effects of treatment
• Maternal well-being
• Maternal satisfaction

Critical newborn outcomes considered were:

• Perinatal death (fetal or early neonatal death)
• Neonatal death
• Fetal death or stillbirth
• Severe neonatal morbidity (i.e. an illness in the neonatal period that is associated with a high risk of death or severe long-term disability among survivors, e.g. respiratory distress syndrome (RDS), intraventricular haemorrhage, neonatal infection, necrotising enterocolitis, chronic lung disease, periventricular leukomalacia (PVL), and retinopathy of prematurity)
• Birth weight (mean; low or very low)
• Infant or childhood death
• Long-term morbidity (i.e. an illness occurring after the neonatal period that is associated with physical or behavioural impairment among survivors, e.g. cerebral palsy, developmental delay, intellectual, hearing, or visual impairment)

3. Assessment

3.1. Effects of interventions

Research evidence

It was not possible to use trial evidence to assess the effects of antenatal corticosteroids in women with growth-restricted fetuses, as the 2020 Cochrane review on antenatal corticosteroid efficacy did not conduct a subgroup analysis in this group. Any such subgroup analysis is unlikely to be informative as fetal growth restriction is often an exclusion criterion in many of these trials, but it is noteworthy that fetal growth restriction was not an exclusion criterion in the largest trial of this meta-analysis.

Evidence supporting the WHO 2015 recommendation was derived from a non-Cochrane systematic review of maternal and child outcomes following antenatal corticosteroid therapy of women in specific populations at risk of imminent preterm birth, which was subsequently published in 2016 (18). The review was updated in 2021 (19).

The updated review included a total of 18 cohort studies (8464 women and neonates) involving women with babies that were small for gestational age (SGA) and/or had fetal growth-restriction (FGR), who received antenatal corticosteroids compared to those who did not receive them. Additional unpublished data on one of the studies was obtained from a previous review paper identified through the search strategy.

Studies were conducted exclusively in high-income settings – three in the Netherlands, two each in Israel, Italy, the Republic of Korea and the United States of America; one each in Canada, China, France, Japan and Sweden; one study in Australia and New Zealand; and one study in Canada and the United States of America.

All women recruited into the studies were expected to give birth preterm (≤35 weeks) due to either spontaneous preterm labour, preterm prelabour rupture of the membranes or provider-initiated preterm birth due to fetal or maternal indications.

Three studies included babies with fetal growth restriction or who were small for gestational age (see Table 2), 12 studies included only small-for-gestational-age babies (see Table 3) and two included only babies with fetal growth restriction (see Table 4). One study reported fetal growth restriction and small-for-gestational-age separately. Where heterogeneity between the three sub-groups (i.e. SGA/FGR, SGA only, FGR only) was low, sub-group data were combined and total odds ratios calculated (see Table 1).

The studies all evaluated the use of a corticosteroid compared with no treatment. Eight studies used betamethasone in the treatment arm (1366 infants), one used dexamethasone (82 infants) and three studies used either betamethasone or dexamethasone (789 infants). The remaining six studies did not specify the type of corticosteroid used (6127 infants).

Sixteen studies specified that the comparison group comprised women who did not receive antenatal corticosteroids, one study compared antenatal corticosteroids to saline placebo and one compared to ‘no treatment’, without further explanation.

Antenatal corticosteroids versus placebo or no treatment — all growth-restricted babies (i.e. 18 studies: fetal growth restriction, small-for-gestational-age, and fetal growth restriction or small-for-gestational-age)

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Maternal outcomes

• Maternal infectious morbidity: The evidence on the effect of antenatal corticosteroids on risk of chorioamnionitis among women with growth restricted babies is very uncertain No data were available for other maternal outcomes (maternal severe morbidity or death, adverse effects, well-being, satisfaction).

Infant outcomes

• Fetal and neonatal death: The evidence on the effect of antenatal corticosteroids on risk of neonatal death before discharge among growth-restricted babies is very uncertain. No data were available on fetal death or perinatal death.
• Severe neonatal morbidity: Among growth-restricted babies, antenatal corticosteroid therapy may increase the risk of neonatal hypoglycaemia² (OR 2.06 95% CI 1.27 to 3.32; 2 studies; low certainty) and may reduce the risk of severe intraventricular haemorrhage (OR 0.54 95% CI 0.43 to 0.68; 9 studies; low certainty) and duration of hospital stay (MD −2.32 95% CI −3.81 to −0.83; 2 studies; low certainty).
  The evidence on the effect of antenatal corticosteroid therapy on risk of intraventricular haemorrhage, neonatal infection, necrotizing enterocolitis, chronic lung disease/bronchopulmonary dysplasia, patent ductus arteriosus, retinopathy of prematurity and major brain lesion (IVH, Intracerebral haemorrhage [ICH] or PVL) among growth-restricted babies is very uncertain. No data were available on respiratory distress syndrome, moderate/severe respiratory distress syndrome, periventricular leukomalacia, surfactant use, admission to neonatal intensive care, use of mechanical ventilation, mean duration of mechanical ventilation.
• Birth weight: No data were available for mean birth weight or low birth weight.
• Long-term morbidity: The evidence on the effect of antenatal corticosteroid therapy and risk of cerebral palsy among growth-restricted babies is very uncertain. No data were available for other childhood or long-term outcomes (infant, child or adult death, developmental delay, intellectual, hearing or visual impairment, behavioural/learning difficulties).

Antenatal corticosteroids versus placebo or no treatment – babies with fetal growth restriction or small-for-gestational-age babies³ (i.e. three studies)

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Maternal outcomes

• Maternal infectious morbidity: The evidence on the effect of antenatal corticosteroids on risk of chorioamnionitis among women with FGR or SGA babies is very uncertain. No data were available on other maternal outcomes (severe maternal morbidity or death, adverse effects, maternal well-being, maternal satisfaction).

Infant outcomes

• Fetal and neonatal death: The evidence on the effect of antenatal corticosteroids on risk of neonatal death among FGR or SGA babies is very uncertain. No data on perinatal death and fetal death were available.
• Severe neonatal morbidity: Among FGR or SGA babies, antenatal corticosteroid therapy may reduce use of surfactant (OR 0.38 95% CI 0.23 to 0.62; 3 studies; low certainty), mechanical ventilation (OR 0.42 95% CI 0.26 to 0.66; 2 studies; low certainty) and use of oxygen therapy (OR 0.48 95% CI 0.30 to 0.77; 2 studies; low certainty) and duration of hospital stay (MD −2.32 95% CI −3.81 to −0.83; 1 study; low certainty).
  The evidence on the effect of antenatal corticosteroids on risk of respiratory distress syndrome, intraventricular haemorrhage, severe intraventricular haemorrhage, neonatal infection, necrotizing enterocolitis, chronic lung disease/bronchopulmonary dysplasia, patent ductus arteriosus, retinopathy of prematurity, neonatal hypoglycaemia and admission to neonatal intensive care among FGR or SGA babies is very uncertain. No data were available for moderate/severe RDS or periventricular leukomalacia, admission to neonatal intensive care or mean duration of hospitalisation.
• Birth weight: The evidence on the effect of antenatal corticosteroid therapy on mean birth weight among FGR or SGA babies is very uncertain. No data were available for low birth weight or small-for-gestational age.
• Long-term morbidity: The evidence on the effect of antenatal corticosteroids therapy on survival free from disability and cerebral palsy among FGR or SGA babies is very uncertain. No data were available for other childhood or long-term outcomes (infant or child death, developmental delay, intellectual, hearing or visual impairment, behavioural/learning difficulties).

Antenatal corticosteroids versus placebo or no treatment – small-for-gestational-age babies only (i.e. 13 studies)

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Maternal outcomes

• Maternal infectious morbidity: The evidence on the effect of antenatal corticosteroid therapy on risk of chorioamnionitis among women with SGA babies is very uncertain.
  No data were available on other maternal outcomes (severe maternal morbidity or death, adverse effects, maternal well-being, maternal satisfaction).

Infant outcomes

• Fetal and neonatal death: Antenatal corticosteroid therapy may reduce the risk of neonatal death among SGA babies (OR 0.61 95% CI 0.49 to 0.78; 8 studies; low certainty). The evidence on the effect of antenatal corticosteroids on risk of death before discharge among SGA babies is very uncertain. No data were available on fetal death or perinatal death.
• Severe neonatal morbidity: Antenatal corticosteroid therapy may reduce the risk of severe intraventricular haemorrhage among SGA babies (OR 0.52 95% CI 0.41 to 0.66; 7 studies; low certainty). The evidence on the effect of antenatal corticosteroid therapy on risk of respiratory distress syndrome, intraventricular haemorrhage, neonatal infection, necrotizing enterocolitis, chronic lung disease/bronchopulmonary dysplasia, patent ductus arteriosus, periventricular leukomalacia, retinopathy of prematurity, neonatal hypoglycaemia, major brain lesion (IVH, ICH or PVL), surfactant use, use of mechanical ventilation and duration of hospital stay among SGA babies is very uncertain. No data were available on moderate/severe respiratory distress syndrome, admission to neonatal intensive care or mean duration of mechanical ventilation.
• Birth weight: The evidence on the effect of antenatal corticosteroids on mean birth weight among SGA babies is very uncertain. No data were available for low birth weight or small-for-gestational-age.
• Long-term morbidity: The evidence on the effect of antenatal corticosteroids on risk of cerebral palsy, severe hearing impairment and visual impairment among SGA babies is very uncertain. No data were available on other childhood or long-term outcomes (infant or childhood death, developmental delay, intellectual impairment, behavioural/learning difficulties).

Antenatal corticosteroids versus placebo or no treatment – babies with fetal growth restriction only (i.e. three studies only)

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Maternal outcomes

• No data were available on maternal outcomes (severe maternal morbidity or death, maternal infectious morbidity, adverse effects, maternal well-being, maternal satisfaction).

Infant outcomes

• Fetal and neonatal death: The evidence on the effect of antenatal corticosteroids on risk of neonatal death and risk of death before discharge among FGR babies is very uncertain. No data were available for fetal death or neonatal death.
• Severe neonatal morbidity: The evidence on the effect of antenatal corticosteroids on risk of respiratory distress syndrome, intraventricular haemorrhage, severe intraventricular haemorrhage, neonatal sepsis, necrotizing enterocolitis, chronic lung disease/bronchopulmonary dysplasia, patent ductus arteriosus and major brain lesion (IVH, ICH or PVL), surfactant use and mean duration of mechanical ventilation among babies with fetal growth restriction is very uncertain. No data were available for moderate/severe respiratory distress syndrome, periventricular leukomalacia, retinopathy of prematurity, admission to neonatal intensive care, mean duration of hospitalization or use of mechanical ventilation.
• Birth weight: The evidence on the effect of antenatal corticosteroids on small-for-gestational-age (<2.3^rd percentile for gestational age) among FGR babies is very uncertain. No data were available for mean birth weight or low birth weight.
• Long-term morbidity: The evidence on abnormal behaviour at long-term follow-up at school age among FGR babies is very uncertain. No data were available for other childhood or long-term outcomes (child death, cerebral palsy, developmental delay, intellectual, hearing or visual impairment, learning difficulties).

Additional considerations

Subgroup analyses involve splitting available trials into different groups of participants. However, it should be acknowledged that subgroup analyses are not based on randomized comparisons and are therefore susceptible to possible biases affecting observational studies (20).

The largest efficacy trial of antenatal corticosteroids in low-resource countries (WHO ACTION-I Trial) enrolled 2852 women, including 189 women with known or suspected fetal growth restriction (21).

Desirable effects

How substantial are the desirable anticipated effects of antenatal corticosteroids, considering fetal growth restriction?

Judgement

Undesirable effects

How substantial are the undesirable anticipated effects of antenatal corticosteroids, considering fetal growth restriction?

Judgement

Certainty of the evidence

What is the overall certainty of the evidence on effects of antenatal corticosteroids on maternal outcomes?

What is the overall certainty of the evidence on effects of antenatal corticosteroids on neonatal outcomes?

3.2. Values

Is there important uncertainty about, or variability in, how much women (and their families) value the main outcomes associated with antenatal corticosteroids, considering fetal growth restriction?

Research evidence

Findings from a mixed methods systematic review (22) on the appropriate use of interventions in the management of women experiencing preterm birth show the following.

• Women and partners’ knowledge about antenatal corticosteroids varies across settings, with higher levels of knowledge in high-income countries than in low- and middle-income countries. Women generally consider antenatal corticosteroids to be beneficial, and prefer that they are only used when necessary and in the context of a positive relationship with a health care provider. They prefer that clear information is provided about treatment options, with adequate time to make shared decisions and ask questions.
• Most health care providers believe that the benefits of antenatal corticosteroids for women experiencing preterm birth mostly outweigh the risks, although some have concerns about safety in certain clinical situations.

No findings specific to presence of fetal growth restriction were identified.

Additional considerations

Health care providers, policy-makers, and pregnant women and their families in all settings are likely to place a high value on the potential benefits of antenatal steroids on babies’ survival without handicap and less value on potential effect on physical growth. It is likely that mothers, health care providers and policy-makers in any setting will invariably place a higher value on these benefits in the light of overall benefits of antenatal steroids for preterm population, and will chose to use the intervention.

Judgement

Balance of effects

Does the balance between desirable and undesirable effects favour antenatal corticosteroids or the comparator, considering fetal growth restriction?

Judgement

3.3. Resources

How large are the resource requirements (costs) of antenatal corticosteroids?

Research evidence

The available evidence on the cost–effectiveness of antenatal corticosteroids for improving preterm birth outcomes was synthesized in a systematic review (23). Evidence suggests antenatal corticosteroid use in early preterm period is cost–effective, but evidence for cost–effectiveness in the late preterm period is mixed.

The available studies did not explore differences in cost–effectiveness of antenatal corticosteroids for presence or absence of fetal growth restriction.

Additional considerations

Dexamethasone sodium phosphate (4 mg per mL) is available on the WHO Essential Medicines List (24). Injectable betamethasone preparations are not listed.

Main resource requirements

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Resource	Description
Staffing	Identifying women at risk of preterm birth requires skilled health personnel who can identify and diagnose preterm labour, excluding contraindications (such as maternal infection), prescribe and administer intramuscular (IM) antenatal corticosteroids and monitor women’s care. Accurate estimation of gestational age also requires personnel trained in the use of obstetric ultrasound. Preterm babies may require additional specialist care.
Training	Training for skilled health personnel to administer injections, and to monitor and manage any side-effects, is part of standard maternity staff training. Additional training would be required if antenatal corticosteroids were introduced in settings where they have not previously been available.
Supplies	Antenatal corticosteroids that are readily available in the maternity ward and emergency department. Antenatal corticosteroid indicative costs: Injectable dexamethasone (4mg/mL) — Median unitary price (2015) was USD$0.2358 per mL (25) — In the ACTION-1 cost–effectiveness analysis, price of 1 mL (4mg/mL) ampoule of dexamethasone ranged from USD$0.05 to USD$2.26. Injectable betamethasone (4mg/mL) — Median unitary price (2015) was USD$0.2950 per mL (25) — In the systematic review of cost–effectiveness studies (23), betamethasone unitary price ranged from USD$0.2503 for 4mg/1mL dose to USD$29.36 for 12mg dose. Other costs: IM administration: needle, syringe, antiseptic solution, swab, gloves, sharps disposal Women in preterm labour may require tocolysis with an effective agent (such as nifedipine) Women who are admitted for antenatal corticosteroid administration often require special investigations (such as blood tests, urinalysis or fetal heart monitoring).
Equipment and infrastructure	Obstetric ultrasound system, probes and ultrasound gel to assess gestational age (preferably in first trimester). Administering of antenatal corticosteroids requires inpatient admission of the woman. Babies born preterm often require additional care, including oxygen or respiratory support, feeding support, warmth, hygiene measures, diagnosis and treatment of infection, or admission to neonatal intensive care.
Time	IM administration of a single dose takes 2 minutes. Time for consultation between skilled health personnel and women about the risks and benefits of antenatal corticosteroids.
Supervision and monitoring	Supervision and monitoring to ensure appropriate use, stock availability and quality.

Resources required

Judgement

Certainty of the evidence on required resources

What is the certainty of the evidence on costs?

Judgement

Cost–effectiveness

Judgement

3.4. Equity

What would be the impact of a strategy of antenatal corticosteroid therapy for women at risk of imminent preterm birth on health equity, considering fetal growth restriction?

Research evidence

No direct evidence was identified.

Additional considerations

Preterm birth affects an estimated 10.6% of births worldwide, though rates are higher in many low- and middle-income countries (26). Similarly, preterm-associated newborn morbidity and mortality are generally higher in low- and middle-income countries due to the lack of good-quality health care services during pregnancy, childbirth and the postnatal period (27). It is likely that risks of preterm birth and its adverse consequences are worse for women and newborns living in disadvantaged circumstances: the poorest, least educated and those residing in rural areas, with poor access to quality antenatal and intrapartum care (28).

Evidence from trials demonstrates that antenatal corticosteroid use is effective in all settings, provided that a minimum level of maternal and preterm newborn care is available. Some women – such as women living in rural or remote areas, women with limited educational or employment opportunities, or women without access to higher levels of care – would be more likely to benefit to the protection offered by a relatively cheap and readily available medication in low-resource setting, thus increasing equity.

Judgement

3.5. Acceptability

Is a strategy of antenatal corticosteroid therapy for women at risk of imminent preterm birth acceptable to key stakeholders, considering fetal growth restriction?

Research evidence

A mixed-methods systematic review including 45 studies on appropriate use of maternal interventions in managing preterm birth identified some evidence on the acceptability of antenatal corticosteroid therapy among key stakeholders (22).

In summary, the review found the following:

• Providers may be uncertain about the benefits and risks of antenatal corticosteroids, and when to use them. Acceptability may be improved by providing high-quality evidence on effectiveness and safety (including in specific clinical situations), guidance on who can prescribe and administer them, training to improve administration skills, and promoting a multidisciplinary approach with clear role definitions and responsibilities.

No findings specifically relevant to presence of fetal growth restriction were identified.

Judgement

3.6. Feasibility

Is a strategy of antenatal corticosteroid therapy for women at risk of imminent preterm birth feasible to implement, considering fetal growth restriction?

Research evidence

Findings from a mixed-methods systematic review (22) which included 45 studies on appropriate use of maternal interventions in managing preterm birth identified some evidence on the feasibility of implementing antenatal corticosteroid therapy for women at risk of imminent preterm birth.

In summary, the review found the following.

• Evidence suggests that there is variation in current clinical guidance on when and how antenatal corticosteroids should be used. Feasibility may be impacted by varying levels of provider knowledge on safe and correct use, the unpredictability of preterm birth, and high staff workloads. Correct use of antenatal corticosteroids could be improved through provider education and training, clear guidelines and clinical protocols on when to use them, and ensuring facilities are well-stocked. Where pre-referral first dose administration is allowed in lower-level facilities (with basic emergency obstetric and neonatal care), implementation may be limited due to challenges around identifying preterm labour, limited knowledge about the importance of pre-referral dosing, and transportation issues.

No findings specifically relevant to presence of fetal growth restriction were identified.

Judgement

4. Summary of judgements table

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5. Summary of findings table

Source: Saito K, Nishimura E, Swa T, Cao J, Ramson JA, Namba F, et al. Antenatal corticosteroids for reducing adverse maternal and child outcomes in special populations of women at risk of imminent preterm birth: a systematic review and meta-analysis. Under review.

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6. References

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Amiya RM, Mlunde LB, Ota E, Swa T, Oladapo OT, Mori R. Antenatal corticosteroids for reducing adverse maternal and child outcomes in special populations of women at risk of imminent preterm birth: a systematic review and meta-analysis. PLoS One. 2016;11(2):e0147604. [PMC free article: PMC4740425] [PubMed: 26841022]

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Saito K, Nishimura E, Swa T, Namba F, Cao J, Ramson JA, et al Antenatal corticosteroids for reducing adverse maternal and child outcomes in special populations of women at risk of imminent preterm birth: a systematic review and meta-analysis. Under review. [PMC free article: PMC4740425] [PubMed: 26841022]

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Footnotes

1

These outcomes reflect the prioritized outcomes used for this recommendation in the WHO recommendations for interventions to improve preterm birth outcomes (2015). The outcomes “maternal well-being” and “maternal satisfaction” have been added as part of this update.

2

Neonatal hypoglycaemia is not a WHO priority outcome and was not reported in the 2020 Cochrane review. However, it is included here due to concerns about a possible increased risk among late preterm babies.

3

Only those studies that recruited “fetal growth restriction or small-for-gestational-age infants”