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.
• The risk of preterm birth is greater for women with multiple pregnancies than with singleton pregnancies – up to 60% of twins and >90% of higher-order multiples are born preterm (12). An estimated 20% of the 14.84 million preterm births occurring worldwide are attributable to women with a multiple pregnancy (1).

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 single and multiple birth?

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: Population of women with singleton or multiple pregnancies.

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, intraventricular haemorrhage, neonatal infection, necrotising enterocolitis, chronic lung disease, periventricular leukomalacia, 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

Summary of evidence

Evidence on the effects of antenatal corticosteroids versus placebo or no treatment for reducing adverse effects of prematurity was derived from an updated 2020 Cochrane review (13). A subgroup analysis was conducted in the published review, based on singleton or multiple pregnancy.

Eighteen trials contributed to the subgroup analysis. Thirteen recruited women with singleton pregnancy only. Twelve recruited women with singleton or multiple pregnancy, of which five reported some outcome data separately for women with singleton or multiple pregnancy. This subgroup analysis includes a total of 10 245 infants – 9240 in the singleton group and 1005 infants in the multiple pregnancy group.

The trials came from a range of health care systems and settings. Six studies were conducted in the United States of America, two in Brazil and one each in Colombia, India, Iran, Jordan, New Zealand, Thailand, Turkey and the United Kingdom of Great Britain and Northern Ireland. One trial took place in the USA and Germany and another study took place in Bangladesh, India, Kenya, Nigeria and Pakistan.

The trials recruited women with a wide range of preterm gestational ages, from 24 to <37 weeks. One trial recruited women at <29 weeks, eight trials recruited women at <34 weeks, one at <35 weeks, two at <36 weeks, five at 34 weeks and 0 days to 36 weeks and 5 days or 36 weeks and 6 days and one at <37 weeks.

Antenatal corticosteroids used in the trials included in the subgroup analysis were betamethasone (11 trials; 5392 women and 5485 infants), dexamethasone (6 trials; 4265 women and 4565 infants) and hydrocortisone (1 trial; 196 women and infants).

Antenatal corticosteroids versus placebo or no treatment: singleton and multiple births

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Maternal outcomes

• No data were available for the pre-specified maternal outcomes (severe maternal morbidity or death, maternal infectious morbidity, maternal side effects, maternal well-being, maternal satisfaction).

Infant outcomes

• Fetal and neonatal death: In singleton pregnancies, antenatal corticosteroid therapy reduces the risk of perinatal death (RR 0.83, 95% CI 0.70 to 0.99; 7 trials, 5492 infants; high certainty). This is largely due to a probable reduction in neonatal deaths (RR 0.80, 95% CI 0.71 to 0.91; 13 trials, 8453 infants; moderate certainty) as they probably result in little or no difference in risk of fetal death (RR 1.06, 95% CI 0.76 to 1.46; 7 trials, 5492 infants; moderate certainty).
  In multiple pregnancies, there is probably little or no difference in risk of neonatal death (RR 0.76, 95% CI 0.57 to 1.02; 3 trials, 813 infants; moderate certainty) and there may be little or no difference in risk of perinatal deaths (RR 0.71, 95% CI 0.41 to 1.22; 2 trials, 252 infants; low certainty) or fetal death (RR 0.53, 95% CI 0.20 to 1.40; 2 trials, 252 infants; low certainty).
• Severe neonatal morbidity: In singleton pregnancies, antenatal corticosteroid therapy probably reduces the risk of respiratory distress syndrome (RR 0.65, 0.57 to 0.74; 17 trials, 6731 infants; moderate certainty) and intraventricular haemorrhage (RR 0.51, 95% CI 0.35 to 0.75; 6 trials, 4494 infants; moderate certainty). In multiple pregnancies, there may be little or no difference in effect on respiratory distress syndrome (RR 0.85, 95% CI 0.61 to 1.20; 4 trials, 323 infants; low certainty) and the evidence on intraventricular haemorrhage is very uncertain.
  No data were available for moderate/severe respiratory distress syndrome, systemic infection in the first 48 hours of life, necrotising enterocolitis, chronic lung disease, patent ductus arteriosus, periventricular leukomalacia, retinopathy of prematurity, surfactant use, admission to neonatal intensive care, infection in neonatal intensive care, mean duration of hospitalization, use of mechanical duration, mean duration of mechanical duration or neonatal hypoglycaemia.
• Birth weight: No data were available for mean birth weight, low birth weight, small for gestational age.
• Long-term morbidity: No data were available for infant or childhood death, cerebral palsy, developmental delay, intellectual impairment, hearing impairment, visual impairment, behavioural/learning difficulties in childhood.

Additional considerations

Subgroup analyses

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 (14). In this subgroup analysis, statistical tests for heterogeneity suggest that there are no differences in effect between singleton and multiples, for the available outcomes.

Observational evidence

A 2021 meta-analysis of observational studies investigated the effect of antenatal corticosteroids in women with multiple pregnancies (15). While available evidence was very low quality, the authors reported a reduced risk of neonatal death (RR 0.64, 95% CI 0.50 to 0.81; 11 studies), respiratory distress syndrome (OR 0.66, 95% CI 0.54 to 0.82; 14 studies), intraventricular haemorrhage (OR 0.67, 95% CI 0.54 to 0.83; 11 studies) and periventricular leukomalacia (OR 0.65, 95% CI 0.47 to 0.92; 8 studies). There was little or no difference in risk of necrotizing enterocolitis (OR 1.02, 95% CI 0.76 to 1.36; 7 studies), retinopathy of prematurity (OR 0.97, 95% CI 0.85 to 1.11; 7 studies) and bronchopulmonary dysplasia (OR 1.00, 95% CI 0.81 to 1.23; 8 studies). There was high heterogeneity in results for respiratory distress syndrome (p<0.001, I²=91.4%), mortality (p<0.001, I²=85.9%), intraventricular haemorrhage (p<0.001, I²=77.4%) and periventricular leukomalacia (p<0.001, I²=75.5%).

Desirable effects

How substantial are the desirable anticipated effects of antenatal corticosteroids, considering single and multiple births?

Judgement

Undesirable effects

How substantial are the undesirable anticipated effects of antenatal corticosteroids, considering single and multiple births?

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 single and multiple births?

Research evidence

Findings from a mixed methods systematic review (16) on the appropriate use of antenatal corticosteroids 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 considered antenatal corticosteroids to be beneficial, and preferred that they are only used when necessary and in the context of a positive relationship with a health care provider. They preferred that clear information is provided about treatment options, with adequate time to make shared decisions and ask questions.
• Most health care providers believed that the benefits of antenatal corticosteroids for women experiencing preterm birth mostly outweigh the risks, although some had concerns about safety in certain clinical situations.

No findings specific to plurality 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 benefits of antenatal corticosteroids on the risk of newborn death and serious morbidities, particularly because of higher baseline risk of preterm birth in multiple pregnancy. It is likely that mothers, health care providers and policy-makers in any setting will place a higher value on these benefits, even if modest, and will choose to use the intervention.

Judgement

Balance of effects

Does the balance between desirable and undesirable effects favour antenatal corticosteroids or the comparator, considering single and multiple birth?

Judgement

3.3. Resources

How large are the resource requirements (costs) of antenatal corticosteroids, considering single and multiple births?

Research evidence

The available evidence on the cost–effectiveness of antenatal corticosteroids for improving preterm birth outcomes was synthesized in a systematic review (17). 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 between singleton and multiple pregnancies.

Additional considerations

Antenatal corticosteroids are relatively cheap, easy to administer, and readily available in at least one preparation in all settings. It is feasible to include antenatal corticosteroid therapy into existing health structures and protocols that are designed to manage women at imminent risk of preterm birth with minimal cost. Given the known health benefits of antenatal corticosteroids, it is highly likely that the intervention is cost–effective.

Dexamethasone sodium phosphate (4 mg per mL) is available on the WHO Essential Medicines List (18). 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 (19) — 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 (19) — In the systematic review of cost–effectiveness studies (17), 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). Administration 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 treatment for women at risk of imminent preterm birth on health equity, considering single and multiple birth?

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 (20). 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 (21). 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 (22).

Evidence from trials demonstrates that antenatal corticosteroid use is effective, 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 from the protection offered by a relatively cheap and readily available medication in low-resource settings, thus increasing equity.

Judgement

3.5. Acceptability

Is a strategy of antenatal corticosteroid treatment for women at risk of imminent preterm birth acceptable to key stakeholders, considering single and multiple births?

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 treatment among key stakeholders (16).

In summary, the review found:

• 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 plurality were identified.

Judgement

3.6. Feasibility

Is a strategy of antenatal corticosteroid treatment for women at risk of imminent preterm birth feasible to implement, considering single and multiple births?

Research evidence

Findings from a mixed-methods systematic review (16) identified some evidence on the feasibility of implementing antenatal corticosteroid therapy for women at risk of imminent preterm birth.

In summary, the review found:

• 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 newborn 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 plurality were identified.

Judgement

4. Summary of judgements table

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5. Summary of findings table

Source: McGoldrick E, Stewart F, Parker R, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2020;12:CD004454.

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6. References

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van Dommelen P, Verkerk PH, van Straaten HL, Dutch Neonatal Intensive Care Unit Neonatal Hearing Screening Working Group. Hearing loss by week of gestation and birth weight in very preterm neonates. J Pediatr. 2015;166(4):840–3 e1. [PubMed: 25661409]

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O’Connor AR, Wilson CM, Fielder AR. Ophthalmological problems associated with preterm birth. Eye. 2007;21(10):1254–60. [PubMed: 17914427]

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McGoldrick E, Stewart F, Parker R, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2020;12:CD004454. [PMC free article: PMC8094626] [PubMed: 33368142]

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Lin D, Fan D, Chen G, Luo C, Guo X, Liu Z. Association of antenatal corticosteroids with morbidity and mortality among preterm multiple gestations: meta-analysis of observational studies. BMJ Open. 2021;11(9):e047651. [PMC free article: PMC8477320] [PubMed: 34580092]

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Zahroh RI, Hazfiarini A, Eddy KE, Vogel JP, Tuncalp Ö, Minckas N, et al Factors influencing the appropriate use of interventions for management of women experiencing preterm birth: a mixed-methods systematic review and narrative synthesis. Under review. [PMC free article: PMC9398034] [PubMed: 35998205]

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Sebastian E, Bykersma C, Egglestone A, Eddy KE, Chim ST, Zahroh RI, et al Cost-effectiveness of antenatal corticosteroids and tocolytics in the management of preterm birth: a systematic review. 2022;3;49:101496. [PMC free article: PMC9167884] [PubMed: 35747187]

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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.