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Antenatal corticosteroids for low and middle income countries
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Available online at www.sciencedirect.com
Seminars in Perinatology www.seminperinat.com
Antenatal corticosteroids for low and middle income countriesI Alan H. Jobea,b,*, Matthew W. Kempb,c,d, Beena Kamath-Raynea, and Augusto F. Schmidte a
Cincinnati Children’s Hospital Medical Center, University of Cincinnati, 3333 Burnet Avenue, MLC 7029, Cincinnati, OH 45248, USA University of Western Australia, Perth, Australia c Tohoku University Hospital, Sendai, Japan d Murdock University, Perth, Australia e University of Miami, Coral Gables, FL, USA b
A R T I C L E I N F O
AB STR ACT
Keywords:
Antenatal corticosteroids (ACS) are sporadically used in low and middle income countries
Infant mortality
(LMIC), although their use is considered by the World Health Organization (WHO) as essen-
Prematurity
tial for decreasing infant mortality. Presently the WHO recommends the use of ACS only
Low and middle income countries
when gestational age is known, delivery is imminent, and the delivery will be in a facility
Dexamethasone
that can provide care for the mother and the infant. We review uncertainties about ACS in
Betamethasone
high income countries that are underappreciated for anticipating their effectiveness in LMIC. We discuss the implications of a large RCT that evaluated the use of ACS in LMIC and found no benefit for presumed preterm infants and increased mortality in larger infants. The treatment schedules for ACS have not been optimized and more is now known about how to improve treatment strategies to hopefully decrease risks such as neonatal hypoglycemia in LMIC. The benefits from ACS may depend on the patient populations and health care environment in which the therapy is used. Further trials are needed to evaluate the safety and efficacy of ACS in LMIC. Ó 2019 Elsevier Inc. All rights reserved.
Introduction Prematurity remains a major contributor to infant morbidity and mortality worldwide.1 In high-income countries (HCI) with advanced healthcare systems, antenatal corticosteroids (ACS) are considered to be the major treatment to improve outcomes. Their use for pregnancies at risk of preterm delivery between 24 and 34 weeks is the Standard of Care as endorsed by the World Health Organization (WHO) and national obstetrical societies world-wide.1,2 In HIC greater I
than 80% of these high-risk pregnancies receive ACS. An assumption about infant morbidity and mortality in LMIC has been that ACS are the lowest hanging and sweetest fruit as an intervention to improve outcomes of premature delivery. Is that assumption true? This review will focus on weaknesses in the clinical information to support current uses of ACS in HIC and how that information may translate to concerns about the use of ACS in low and middle income countries (LMIC). Weak health care systems for the support of preterm deliveries and subsequent care of the premature infants may change ACS risks and benefits. We will consider WHO to treat
Seminars in Perinatology: Global Health of Women and Children Edward A. Liechty, M.D. Editor. * Corresponding author at: Cincinnati Children’s Hospital Medical Center, University of Cincinnati, 3333 Burnet Avenue, MLC 7029, Cincinnati, OH 45248, USA. E-mail address: [email protected] (A.H. Jobe). https://doi.org/10.1053/j.semperi.2019.03.012 0146-0005/Ó 2019 Elsevier Inc. All rights reserved.
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in WHICH health care environment with WHICH drugs for WHAT benefits and risks.
Pregnancies at risk in LMIC ACS were identified in 2003 by the Bellagio Survival Study as a preventive intervention to save 264,000 lives in LMIC, but at the time only 5% of the target population received ACS.3 A 2008 report estimated that ACS were given to 9 73% of pregnancies <34 weeks in four South East Asian countries, and not surprisingly with widely variable use between hospitals.4 A more recent survey in 2014 reported that in 29 LMIC, 54% of at risk pregnancies received ACS, but tocolytics to delay delivery for ACS to be more beneficial were seldom used.5 Dexamethasone phosphate (Dex-P) was added to the WHO essential medicine list for the ACS indication. With coverage data of 41% for 75 countries as of 2014, an estimated 130,000 lives were saved by 2017.6 Although, under 5 year mortality has decreased greatly in LMIC, infant death from prematurity has no changed. Therefore, prematurity related deaths contribute a higher proportion of under 5 year deaths. Prematurity is now the target demographic to decrease overall under 5 year mortality.7 As infant mortality has not decreased, any benefit resulting from increased use of ACS in LMIC is not apparent in the international infant mortality statistics. ACS were recently described as the case history for underuse of effective strategies in LMIC.8 There has been relatively little discussion about the appropriate use of ACS for populations with very limited resources in LMIC. It is unknown if the WHO recommendation to give ANS for pregnancies at risk of preterm delivery at 24 34 weeks gestation is generalizable to LMIC. As gestational ages selected for ANS decrease in LMIC, the complex infrastructural needs to achieve survival of the more premature infants will increase exponentially. The efficacy of ACS to decrease mortality for populations depends on integrated and effective use of medical infrastructure.9 ANS use was documented primarily in deliveries occurring in urban settings and in central hospitals, but ANS were rarely used in clinic or home deliveries.10 For example, clinics without basic neonatal support infrastructure and no ability to quickly transfer very preterm infants will not be able to salvage many infants <32 weeks gestational age even with ACS. Births <28 weeks gestational age will seldom benefit from ACS even in facilities with some resources. ACS used as an isolated intervention are unlikely to improve outcomes very much. However, ACS could be very effective in LMIC with medical systems in transition to improving maternal and infant care.11 The neonatal care in Auckland, New Zealand in 1972 where ACS were first proved to be effective in relatively mature infants was more similar to some care environments in LMIC today than to advanced neonatal intensive care units.12 In HIC, infant mortality of infants of 34 37 weeks is extremely low and the respiratory problems can be easily managed in most cases. ANS for these late preterm infants have modest benefits related primarily to respiratory adaption shortly after birth as demonstrated by the Antenatal
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Steroids in Late Preterms (ALPS) trial.13 In LMIC, these respiratory problems may result in deaths without oxygen, continuous positive airway pressure, surfactant and the infrequent need for mechanical ventilation. An untested hypothesis is that ACS may have more benefit in LMIC than in HIC for the 6 8% deliveries that are late preterm. However, the unanticipated increase in newborn hypoglycemia with ACS treatments identified by the ALPS trial is an easily managed risk in HIC.14 Hypoglycemia may be undetected or more difficult to manage in LMIC. Such tradeoffs will complicate decisions about ANS use in LMIC.
Current status of ACS in HIC Although ACS are efficiently used to treat women at risk of preterm delivery at 24 34 weeks, there remain substantial uncertainties about ACS that are not generally acknowledged.15 Liggins and Howie used a 1:1 mixture of betamethasone phosphate (Beta-P) and betamethasone acetate (BetaAc) for a 2 dose treatment for the 1972 trial demonstrating efficacy of ACS.12 Other early trials used Dex-P as 4 doses of 6 mg given every 12 h. The drug choice or dosing strategies have never been optimized or approved by the FDA for antenatal treatments.16 The single treatment trials for efficacy were done almost entirely in HIC prior to 1990 for pregnancies at risk for preterm delivery, with most randomized treatments for >28 week gestational age deliveries.17 While outcomes of adults who were randomized as fetuses are reassuring,18 the current populations of concern are for more premature deliveries who are receiving greatly different obstetric and neonatal care strategies. Current large epidemiology and network studies of outcomes of very premature infant support large beneficial effects on infant morbidities and mortality.19,20 However, without randomization to ACS and with treatment rates >80%, attribution of benefits are suspect.15 There is not current information about the magnitude of treatment effects for ACS for deliveries between 24 and 34 weeks gestational age within the context of modern clinical care in HIC. The use of ACS is expanding in HIC to 34 366 weeks late preterm infants and to elective cesarean deliveries to decrease the relatively infrequent respiratory morbidities.21 ACS are also being used for periviable at risk pregnancies as early as 22 weeks gestational age.22 As the population of pregnancies to treat with ACS expands, the benefit to risk may change substantially. A concern is that more than 50% pregnancies treated with ACS in HIC do not deliver in the presumed window of benefit after initiation of treatment of 1 7 days.23 A number of preterm pregnancies are exposed to ACS but deliver at >34 weeks and at term, and these infants are seldom followed for outcomes. In one cohort study, there were no ACS effects on birth weights for preterm deliveries, but birth weights were decreased for pregnancies treated with ACS before 34 weeks and that delivered after 34 weeks gestational age.24 The research base for the translation of ACS use from HIC to LMIC has gaps based on the age of the research, and the populations studied.
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Studies of ACS in LMIC Although 30 trials were included in the 2017 Cochrane metaanalysis of ACS, only ten small studies were from middle income countries.18 The benefits of ACS for decreased respiratory distress syndrome, mortality, and other adverse neonatal outcomes for HIC have been used for estimates of the potential of ACS to decrease mortality in LMIC.9 To test the hypothesis that ACS would decrease mortality in LMIC, the National Institutes of Child Health and Human Development performed a cluster randomized controlled trial of a population based implementation of ACS in comparison to standard care in the ACT trial in 2014.25 The surprising and unanticipated outcomes were no benefit for infants <5th percentile birth weight and increased mortality for larger infants. The results disrupted a WHO sponsored roll-out of ACS for LMIC as the essential intervention to decrease mortality from prematurity. The current guidelines for ACS in these environments were changed to minimize the potential risks identified in the ACT trial with the 2015 WHO Recommendations on Interventions to improve Preterm Birth Outcomes1 (Box 1). The requirements for ACS limit the therapy primarily to urban hospital settings with substantial medical infrastructure and trained staff in LMIC, making ACS available to limited populations of women at risk. A restriction is accurate gestational age assessment, which can be done most accurately by early gestational age fetal ultrasound determinations a major hurdle for antenatal care provision.
A closer look at the ACT trial This seminal and controversial trial was a population based assessment of ACS within a multifaceted strategy to improve outcomes for preterm infants in Argentina, Guatemala, India, Kenya, Pakistan and Zambia.25 The trial randomized clusters of communities to the intervention or to routine care. The intervention included health provider training for the identification of women at risk of preterm delivery, the initiation of treatment with an ACS kit containing 4 doses of 6 mg Dex-P to be given at 12 h intervals, and the recommendation to the
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women for delivery at a location that could provide maternal and infant care. The routine care was no change in prenatal care and delivery plans for clusters in countries with very low ACS use, based on assessments in the clusters prior to the trial. The trial enrolled almost 100,000 pregnant women with accurate information on the primary outcome of perinatal mortality (Table 1). The intervention increased ACS use from 2% to 12% for all women in the treatment clusters and from 10% to 45% in the presumed primarily premature population with birth weights <5th percentile, which was the surrogate for lack of accurate gestational age information. There was no mortality benefit and there was no change in location of delivery for the <5th percentile infants. Of more concern was the significantly increased mortality primarily in infants >2.5 kg which were presumed to be late preterm or term infants. The initial analysis suggested that the increased infant mortality might have resulted from increased maternal infection. Strengths of the trial were the number of study participants and the outcome assessments of birthweight and 28 day mortality that were done independently of the intervention. Of note, most trials of ACS only report outcomes for the randomized women who deliver preterm. The mortality difference in the ACT trial would not have been detected if all pregnancies had not been followed to delivery and to 28 days for survival. A weakness was imprecise gestational age information, but that flaw does not influence the increased mortality in the large infants. Many of the treated pregnancies likely were not preterm indicating overtreatment in the trial. A series of secondary analyses were reported by the trial investigators.26 ACS were given to 29% of infants who died and to 6% in the comparison group suggesting that the steroid exposure was contributing to the mortality.27 The presumed late preterm and term infants that died were delivered more frequently of mothers who received ACS within 7 days of delivery than the non-exposed infants, again suggesting a steroid exposure component to the increased mortality. No process differences in who assisted with deliveries, where the deliveries occurred, or in postnatal care were apparent. Infection in the mothers and infants was not an outcome for the trial, but a retrospective application of the WHO criteria for presumed severe bacterial infection (PSBI) to the data
Table 1 – Increase mortality in the antenatal corticosteroid trial. ACT trial Women who delivered <5th percentile birth weight infant
All women
Characteristics of population and outcomes
ACS intervention
Control
ACS treatment
Control
Number Delivery location Hospital (%) Clinic (%) Home (%) Cesarean section (%) ACS treated (%) Stillbirth per 1000 births Death to 28 days per 1000 births
2361
2094
48,219
51,523
51 26 23 16 45 229 226
58 19 23 17 10 247 232
49 28 22 15 12 27 27
53 23 24 15 2 24* 24*
*P < 0.02. Althabe25.
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indicated possible increased infection in the intervention clusters. A consequence of a multi-country trial in LMIC setting was the inevitable large differences in populations and health care available for managing prematurity.28 While site differences are a variable for any multicenter trial, the differences will be magnified across countries and cultures. Two of the 7 trial locations had statistically significant decreased mortality with ACS in the <5th percentile births and no increased mortality in overall births. In contrast, 3 of the 7 trial locations had statistically increased mortality with ACS in all births but no decreased mortality for the <5th percentile infants. There was no signal as to why the different outcomes occurred, but the increased mortality occurred primarily at African sites. Guatemala had decreased mortality for the <5th percentile infants concurrent with improvements in their obstetric and neonatal care which may explain the benefit.29
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sugars of infants born to small malnourished women with frequently growth restricted infants are unknown. Independent of trials, screening for low blood sugars in infants exposed to ACS and delivering within the window of efficacy to about 7 days should be routine. Further, effective treatments for low blood sugars caused by ACS will be a further challenge in LMIC. The Bill and Melinda Gates Foundation is supporting the WHO to conduct parallel trials in India in care environments that are not using ACS routinely but that can verify gestational age by ultrasound and can provide some care for the delivery and the infant.33 The trials will be randomized and controlled to test 4 doses of 6 mg Dex-P with placebo for preterm deliveries with gestational ages of 24 34 weeks and for the 35 37 week late preterm population. A concern is that any result may only be applicable to the context and location of the trials.
Lessons from the ACT trial
Future of ACS for LMIC This very large trial has resulted in targeted promotion of ACS in LMIC by WHO rather than a general recommendation to increase use and to avoid previously unappreciated risks (Box 1). The variability in the mortality outcomes between sites suggests that outcomes may depend greatly on the healthcare resources available to a target population and/or the characteristics of the population. A recently reported trial from Tanzania that included ACS for deliveries at 28 35 weeks gestational age as a component of a bundle of care maternal antibiotics, neonatal antibiotics and hypothermia avoidance decreased neonatal mortality by 26% relative to before the care bundle was introduced.30 The contribution of ACS to the outcome is not known but the trial demonstrated the potential for improving outcomes with a package of interventions rather than a single intervention. The introduction of ACS into a care system that is not capable of adequate care for the preterm may only increase risk. Assuming the result was real, the cause(s) for the unanticipated increased mortality in the higher birth weight infants can only be identified by new trials that follow all the trial participants to delivery and to 28 day outcomes with collection of more granular data on the pregnancies and outcomes. Given the difficulties with identification of causes of death in infants even under conditions of intensive study in LMIC,31 this will be a challenge. Important information to collect will be indicators of infection in the mother and the infant.27 Infectious complications may vary widely in populations based on maternal infections such as tuberculosis, malaria, HIV, and on maternal nutritional status. Another possible contribution to the increased mortality is the hypoglycemia associated with ACS identified in the ALPS trial for late preterm infants.13 Screening of all births for hypoglycemia in a future ACS trial will be essential. A concern is that the dose of ACS is the same independent of maternal size and BMI. In a perinatal unit in Chicago, women in preterm labor with a lower BMI had higher blood sugar values for longer than did women with a high BMI.32 However, the mean value of 30 for the lowest BMI category was high by international standards. Women in LMIC countries often will be short with a BMI closer to 20. The effects of ACS on blood
ACS were initially tested by Liggins and Howie in 1972 using an available preparation that would provide the exposure duration that Liggins had used experimentally for fetal infusions in sheep.34,12 That preparation of a 1:1 mixture of Beta-P and Beta-Ac given as two 12 mg maternal injections given 24 h apart at recognition of a risk of preterm delivery and 24 h later is the standard of care for much of the world but with limited availability in LMIC.15 An alternate treatment has been 4 doses at 12 h intervals of 6 mg Dex-P as this drug is more available, more stable and less expensive, as recommended by the WHO.1 The Beta-P and Beta-Ac mixture was used primarily for the RCTs for single treatment courses for ACS before 1990, and exclusively for the repeated treatment trials.18 However, the pharmacology studies to optimize dosing were never done, although there were indications that the treatment doses were higher than necessary.35 With support from the Bill and Melinda Gates Foundation and GalaxoSmithKlein, we have learned the fetal exposures to ACS that result in lung maturational responses in fetal sheep and Rhesus macaques. The phosphorylated Beta-P or Dex-P are prodrugs that when given by intramuscular injection are rapidly dephosphorylated to cause high maternal and fetal blood levels of Beta or Dex. We initially evaluated the clinical drugs as the 1:1 mixture Beta-P and Beta-Ac in comparison to the slowly deacetylated Beta-Ac alone. The Beta-Ac alone was as effective as the clinical drug and the high peak drug levels from Beta-P in the pregnant animal and fetus were avoided. The lack of a need for the high plasma drug levels was confirmed using maternal Beta-P infusions to achieve constant low maternal and fetal Beta levels that also caused lung maturation in fetal sheep.36 The target drug levels in sheep and primates are in the range of 1 4 ng/ml, but the levels need to be maintained for at least 48 h for a durable lung maturational effect.37 This fetal exposure can be achieved with two IM injections of Beta-Ac. However, Beta-Ac is not available as a single component drug. We have recently applied this knowledge of the minimal drug exposure to achieve a fetal lung maturational response
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to how ACS treatments could be optimized for LMIC (Box 2). The desired attributes of an ACS treatment should be low fetal drug exposures to presumably decrease risks, which are dose and treatment duration dependent for corticosteroids.38 The drug should be stable in harsh environments, available widely, easy to administer and inexpensive. A desirable quality would be easily adjusted dosing based on maternal weight. The solution may be Dex or Beta pills that are very inexpensive and widely available in different steroid amounts in LMIC. In experiments in progress in sheep and primates, oral absorption of either drug avoids the high peak drug levels from intramuscular treatments and prolongs clearance. More needs to be learned about oral dosing in humans, as this mode of dosing may be very attractive in LMIC.
ACS targeted to pregnancies that will benefit ACS may be deceptively safe in HIC. The acute adverse outcome is hypoglycemia, but most concerning ACS have been associated with brain injury in animal models and humans. Further, ACS are associated with the cardiovascular and metabolic abnormalities of the metabolic syndrome with transgenerational effects in animal models ranging from mice to baboons.39,40 Isolated observations have identified cardiovascular effects in human cohorts.41 Such effects are difficult to study as they may occur decades after the fetal exposure. In LMIC, the ACT trial identified increased infection and increased mortality as potential risk of ACS.27 A major problem for that trial was “off target” treatments of pregnancies >34 weeks gestation and very long intervals from treatment to delivery for some pregnancies. The problem is not unique to ACT trial as more than 50% of pregnancies in HIC deliver beyond the efficacy period of 7 days with deliveries at term for some pregnancies. These frequent off target treatments combined with two rules of drug therapy treat only patients who will benefit and use the lowest effective dose make ACS problematic for a therapy for the most vulnerable of patients the human fetus. As ACS are being evaluated in LMIC, more needs be learned about which pregnancies will benefit. Decreasing RDS should decrease mortality, but there may be adverse trade-offs that may be minimized by lower dosing strategies. More information is required about what may be quite varied maternal responses to and fetal effects of ACS in LMIC with different pregnancy problems and health care systems.
Conclusion In this review, we have identified a number of practical and pharmacologic variables that limit the generalizability of the potential benefits of ACS to LMIC. In these environments we do not know WHO to treat with any precision as causes of death in preterm infants are poorly described. The WHICH health care environment is a variable that will define the gestational ages that may benefit from ACS, depending on facilities available. The WHICH drug question awaits further research to minimize dose and explore new treatments routes such as oral dosing to minimize risks. We have not
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specifically addressed WHAT benefits ACS will provide in LMIC. The primary indication for ACS has been to decrease RDS which should decrease mortality. But the effects of these agents are pleotropic with multiple organ benefits in HIC gut effects decrease necrotizing enterocolitis, brain effects decrease intraventricular hemorrhage, kidney effects increase kidney maturation, for example.17 The benefits may differ depending on the patient and the environment and resources of the health care system in LMIC. The unknowns warrant further trials and the need to proceed with caution before widespread unmonitored use of ACS in LMIC. BOX 1. WHO recommendation for ACS Antenatal corticosteroids are recommended for pregnancies at risk of preterm birth from 24 to 34 week gestation if all the conditions are met: Gestational is accurately known to be 24 34 weeks. Preterm birth is imminent (within 1 7 days). No clinical evidence of maternal infection. Adequate labor and delivery care can be provided. Newborn care is available including resuscitation, thermal and feeding support, infection treatment and oxygen.
BOX 2. Optimal ACS for LMIC Corticosteroid dosing schedule to minimize fetal exposure. Stable, available, inexpensive and easy corticosteroid dosing. Treatment with dosing based on maternal weight. Treatment of only pregnancies that will benefit.
Disclosures The authors have conflict of interest for this revise article.
R E F E R E N C E S
1. WHO. WHO Recommendations on Interventions to Improve Preterm Birth Outcomes. Geneva: WHO Publication; 2015. 2. Committee Opinion No. 713 Summary. Antenatal corticosteroid therapy for fetal maturation. Obstet Gynecol. 2017;130(2): 493–494. 3. Jones G, Steketee RW, Black RE, Bhutta ZA, Morris SS. Bellagio Child Survival Study Group. How many child deaths can we prevent this year? Lancet. 2003;362(9377):65–71. 4. Pattanittum P, Ewens MR, Laopaiboon M, et al. Use of antenatal corticosteroids prior to preterm birth in four South East Asian countries within the SEA-ORCHID project. BMC Pregnancy Childbirth. 2008;8:47. 5. Vogel JP, Souza JP, Gulmezoglu AM, et al. Use of antenatal corticosteroids and tocolytic drugs in preterm births in 29 countries: an analysis of the WHO Multicountry Survey on Maternal and Newborn Health. Lancet. 2014;384(9957):1869– 1877. 6. Bhutta ZA, Das JK, Bahl R, et al. Can available interventions end preventable deaths in mothers, newborn babies, and stillbirths, and at what cost? Lancet. 2014;384(9940):347–370.
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Available online at www.sciencedirect.com
Seminars in Perinatology www.seminperinat.com
Antenatal corticosteroids for low and middle income countriesI Alan H. Jobea,b,*, Matthew W. Kempb,c,d, Beena Kamath-Raynea, and Augusto F. Schmidte a
Cincinnati Children’s Hospital Medical Center, University of Cincinnati, 3333 Burnet Avenue, MLC 7029, Cincinnati, OH 45248, USA University of Western Australia, Perth, Australia c Tohoku University Hospital, Sendai, Japan d Murdock University, Perth, Australia e University of Miami, Coral Gables, FL, USA b
A R T I C L E I N F O
AB STR ACT
Keywords:
Antenatal corticosteroids (ACS) are sporadically used in low and middle income countries
Infant mortality
(LMIC), although their use is considered by the World Health Organization (WHO) as essen-
Prematurity
tial for decreasing infant mortality. Presently the WHO recommends the use of ACS only
Low and middle income countries
when gestational age is known, delivery is imminent, and the delivery will be in a facility
Dexamethasone
that can provide care for the mother and the infant. We review uncertainties about ACS in
Betamethasone
high income countries that are underappreciated for anticipating their effectiveness in LMIC. We discuss the implications of a large RCT that evaluated the use of ACS in LMIC and found no benefit for presumed preterm infants and increased mortality in larger infants. The treatment schedules for ACS have not been optimized and more is now known about how to improve treatment strategies to hopefully decrease risks such as neonatal hypoglycemia in LMIC. The benefits from ACS may depend on the patient populations and health care environment in which the therapy is used. Further trials are needed to evaluate the safety and efficacy of ACS in LMIC. Ó 2019 Elsevier Inc. All rights reserved.
Introduction Prematurity remains a major contributor to infant morbidity and mortality worldwide.1 In high-income countries (HCI) with advanced healthcare systems, antenatal corticosteroids (ACS) are considered to be the major treatment to improve outcomes. Their use for pregnancies at risk of preterm delivery between 24 and 34 weeks is the Standard of Care as endorsed by the World Health Organization (WHO) and national obstetrical societies world-wide.1,2 In HIC greater I
than 80% of these high-risk pregnancies receive ACS. An assumption about infant morbidity and mortality in LMIC has been that ACS are the lowest hanging and sweetest fruit as an intervention to improve outcomes of premature delivery. Is that assumption true? This review will focus on weaknesses in the clinical information to support current uses of ACS in HIC and how that information may translate to concerns about the use of ACS in low and middle income countries (LMIC). Weak health care systems for the support of preterm deliveries and subsequent care of the premature infants may change ACS risks and benefits. We will consider WHO to treat
Seminars in Perinatology: Global Health of Women and Children Edward A. Liechty, M.D. Editor. * Corresponding author at: Cincinnati Children’s Hospital Medical Center, University of Cincinnati, 3333 Burnet Avenue, MLC 7029, Cincinnati, OH 45248, USA. E-mail address: [email protected] (A.H. Jobe). https://doi.org/10.1053/j.semperi.2019.03.012 0146-0005/Ó 2019 Elsevier Inc. All rights reserved.
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in WHICH health care environment with WHICH drugs for WHAT benefits and risks.
Pregnancies at risk in LMIC ACS were identified in 2003 by the Bellagio Survival Study as a preventive intervention to save 264,000 lives in LMIC, but at the time only 5% of the target population received ACS.3 A 2008 report estimated that ACS were given to 9 73% of pregnancies <34 weeks in four South East Asian countries, and not surprisingly with widely variable use between hospitals.4 A more recent survey in 2014 reported that in 29 LMIC, 54% of at risk pregnancies received ACS, but tocolytics to delay delivery for ACS to be more beneficial were seldom used.5 Dexamethasone phosphate (Dex-P) was added to the WHO essential medicine list for the ACS indication. With coverage data of 41% for 75 countries as of 2014, an estimated 130,000 lives were saved by 2017.6 Although, under 5 year mortality has decreased greatly in LMIC, infant death from prematurity has no changed. Therefore, prematurity related deaths contribute a higher proportion of under 5 year deaths. Prematurity is now the target demographic to decrease overall under 5 year mortality.7 As infant mortality has not decreased, any benefit resulting from increased use of ACS in LMIC is not apparent in the international infant mortality statistics. ACS were recently described as the case history for underuse of effective strategies in LMIC.8 There has been relatively little discussion about the appropriate use of ACS for populations with very limited resources in LMIC. It is unknown if the WHO recommendation to give ANS for pregnancies at risk of preterm delivery at 24 34 weeks gestation is generalizable to LMIC. As gestational ages selected for ANS decrease in LMIC, the complex infrastructural needs to achieve survival of the more premature infants will increase exponentially. The efficacy of ACS to decrease mortality for populations depends on integrated and effective use of medical infrastructure.9 ANS use was documented primarily in deliveries occurring in urban settings and in central hospitals, but ANS were rarely used in clinic or home deliveries.10 For example, clinics without basic neonatal support infrastructure and no ability to quickly transfer very preterm infants will not be able to salvage many infants <32 weeks gestational age even with ACS. Births <28 weeks gestational age will seldom benefit from ACS even in facilities with some resources. ACS used as an isolated intervention are unlikely to improve outcomes very much. However, ACS could be very effective in LMIC with medical systems in transition to improving maternal and infant care.11 The neonatal care in Auckland, New Zealand in 1972 where ACS were first proved to be effective in relatively mature infants was more similar to some care environments in LMIC today than to advanced neonatal intensive care units.12 In HIC, infant mortality of infants of 34 37 weeks is extremely low and the respiratory problems can be easily managed in most cases. ANS for these late preterm infants have modest benefits related primarily to respiratory adaption shortly after birth as demonstrated by the Antenatal
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Steroids in Late Preterms (ALPS) trial.13 In LMIC, these respiratory problems may result in deaths without oxygen, continuous positive airway pressure, surfactant and the infrequent need for mechanical ventilation. An untested hypothesis is that ACS may have more benefit in LMIC than in HIC for the 6 8% deliveries that are late preterm. However, the unanticipated increase in newborn hypoglycemia with ACS treatments identified by the ALPS trial is an easily managed risk in HIC.14 Hypoglycemia may be undetected or more difficult to manage in LMIC. Such tradeoffs will complicate decisions about ANS use in LMIC.
Current status of ACS in HIC Although ACS are efficiently used to treat women at risk of preterm delivery at 24 34 weeks, there remain substantial uncertainties about ACS that are not generally acknowledged.15 Liggins and Howie used a 1:1 mixture of betamethasone phosphate (Beta-P) and betamethasone acetate (BetaAc) for a 2 dose treatment for the 1972 trial demonstrating efficacy of ACS.12 Other early trials used Dex-P as 4 doses of 6 mg given every 12 h. The drug choice or dosing strategies have never been optimized or approved by the FDA for antenatal treatments.16 The single treatment trials for efficacy were done almost entirely in HIC prior to 1990 for pregnancies at risk for preterm delivery, with most randomized treatments for >28 week gestational age deliveries.17 While outcomes of adults who were randomized as fetuses are reassuring,18 the current populations of concern are for more premature deliveries who are receiving greatly different obstetric and neonatal care strategies. Current large epidemiology and network studies of outcomes of very premature infant support large beneficial effects on infant morbidities and mortality.19,20 However, without randomization to ACS and with treatment rates >80%, attribution of benefits are suspect.15 There is not current information about the magnitude of treatment effects for ACS for deliveries between 24 and 34 weeks gestational age within the context of modern clinical care in HIC. The use of ACS is expanding in HIC to 34 366 weeks late preterm infants and to elective cesarean deliveries to decrease the relatively infrequent respiratory morbidities.21 ACS are also being used for periviable at risk pregnancies as early as 22 weeks gestational age.22 As the population of pregnancies to treat with ACS expands, the benefit to risk may change substantially. A concern is that more than 50% pregnancies treated with ACS in HIC do not deliver in the presumed window of benefit after initiation of treatment of 1 7 days.23 A number of preterm pregnancies are exposed to ACS but deliver at >34 weeks and at term, and these infants are seldom followed for outcomes. In one cohort study, there were no ACS effects on birth weights for preterm deliveries, but birth weights were decreased for pregnancies treated with ACS before 34 weeks and that delivered after 34 weeks gestational age.24 The research base for the translation of ACS use from HIC to LMIC has gaps based on the age of the research, and the populations studied.
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Studies of ACS in LMIC Although 30 trials were included in the 2017 Cochrane metaanalysis of ACS, only ten small studies were from middle income countries.18 The benefits of ACS for decreased respiratory distress syndrome, mortality, and other adverse neonatal outcomes for HIC have been used for estimates of the potential of ACS to decrease mortality in LMIC.9 To test the hypothesis that ACS would decrease mortality in LMIC, the National Institutes of Child Health and Human Development performed a cluster randomized controlled trial of a population based implementation of ACS in comparison to standard care in the ACT trial in 2014.25 The surprising and unanticipated outcomes were no benefit for infants <5th percentile birth weight and increased mortality for larger infants. The results disrupted a WHO sponsored roll-out of ACS for LMIC as the essential intervention to decrease mortality from prematurity. The current guidelines for ACS in these environments were changed to minimize the potential risks identified in the ACT trial with the 2015 WHO Recommendations on Interventions to improve Preterm Birth Outcomes1 (Box 1). The requirements for ACS limit the therapy primarily to urban hospital settings with substantial medical infrastructure and trained staff in LMIC, making ACS available to limited populations of women at risk. A restriction is accurate gestational age assessment, which can be done most accurately by early gestational age fetal ultrasound determinations a major hurdle for antenatal care provision.
A closer look at the ACT trial This seminal and controversial trial was a population based assessment of ACS within a multifaceted strategy to improve outcomes for preterm infants in Argentina, Guatemala, India, Kenya, Pakistan and Zambia.25 The trial randomized clusters of communities to the intervention or to routine care. The intervention included health provider training for the identification of women at risk of preterm delivery, the initiation of treatment with an ACS kit containing 4 doses of 6 mg Dex-P to be given at 12 h intervals, and the recommendation to the
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women for delivery at a location that could provide maternal and infant care. The routine care was no change in prenatal care and delivery plans for clusters in countries with very low ACS use, based on assessments in the clusters prior to the trial. The trial enrolled almost 100,000 pregnant women with accurate information on the primary outcome of perinatal mortality (Table 1). The intervention increased ACS use from 2% to 12% for all women in the treatment clusters and from 10% to 45% in the presumed primarily premature population with birth weights <5th percentile, which was the surrogate for lack of accurate gestational age information. There was no mortality benefit and there was no change in location of delivery for the <5th percentile infants. Of more concern was the significantly increased mortality primarily in infants >2.5 kg which were presumed to be late preterm or term infants. The initial analysis suggested that the increased infant mortality might have resulted from increased maternal infection. Strengths of the trial were the number of study participants and the outcome assessments of birthweight and 28 day mortality that were done independently of the intervention. Of note, most trials of ACS only report outcomes for the randomized women who deliver preterm. The mortality difference in the ACT trial would not have been detected if all pregnancies had not been followed to delivery and to 28 days for survival. A weakness was imprecise gestational age information, but that flaw does not influence the increased mortality in the large infants. Many of the treated pregnancies likely were not preterm indicating overtreatment in the trial. A series of secondary analyses were reported by the trial investigators.26 ACS were given to 29% of infants who died and to 6% in the comparison group suggesting that the steroid exposure was contributing to the mortality.27 The presumed late preterm and term infants that died were delivered more frequently of mothers who received ACS within 7 days of delivery than the non-exposed infants, again suggesting a steroid exposure component to the increased mortality. No process differences in who assisted with deliveries, where the deliveries occurred, or in postnatal care were apparent. Infection in the mothers and infants was not an outcome for the trial, but a retrospective application of the WHO criteria for presumed severe bacterial infection (PSBI) to the data
Table 1 – Increase mortality in the antenatal corticosteroid trial. ACT trial Women who delivered <5th percentile birth weight infant
All women
Characteristics of population and outcomes
ACS intervention
Control
ACS treatment
Control
Number Delivery location Hospital (%) Clinic (%) Home (%) Cesarean section (%) ACS treated (%) Stillbirth per 1000 births Death to 28 days per 1000 births
2361
2094
48,219
51,523
51 26 23 16 45 229 226
58 19 23 17 10 247 232
49 28 22 15 12 27 27
53 23 24 15 2 24* 24*
*P < 0.02. Althabe25.
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indicated possible increased infection in the intervention clusters. A consequence of a multi-country trial in LMIC setting was the inevitable large differences in populations and health care available for managing prematurity.28 While site differences are a variable for any multicenter trial, the differences will be magnified across countries and cultures. Two of the 7 trial locations had statistically significant decreased mortality with ACS in the <5th percentile births and no increased mortality in overall births. In contrast, 3 of the 7 trial locations had statistically increased mortality with ACS in all births but no decreased mortality for the <5th percentile infants. There was no signal as to why the different outcomes occurred, but the increased mortality occurred primarily at African sites. Guatemala had decreased mortality for the <5th percentile infants concurrent with improvements in their obstetric and neonatal care which may explain the benefit.29
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sugars of infants born to small malnourished women with frequently growth restricted infants are unknown. Independent of trials, screening for low blood sugars in infants exposed to ACS and delivering within the window of efficacy to about 7 days should be routine. Further, effective treatments for low blood sugars caused by ACS will be a further challenge in LMIC. The Bill and Melinda Gates Foundation is supporting the WHO to conduct parallel trials in India in care environments that are not using ACS routinely but that can verify gestational age by ultrasound and can provide some care for the delivery and the infant.33 The trials will be randomized and controlled to test 4 doses of 6 mg Dex-P with placebo for preterm deliveries with gestational ages of 24 34 weeks and for the 35 37 week late preterm population. A concern is that any result may only be applicable to the context and location of the trials.
Lessons from the ACT trial
Future of ACS for LMIC This very large trial has resulted in targeted promotion of ACS in LMIC by WHO rather than a general recommendation to increase use and to avoid previously unappreciated risks (Box 1). The variability in the mortality outcomes between sites suggests that outcomes may depend greatly on the healthcare resources available to a target population and/or the characteristics of the population. A recently reported trial from Tanzania that included ACS for deliveries at 28 35 weeks gestational age as a component of a bundle of care maternal antibiotics, neonatal antibiotics and hypothermia avoidance decreased neonatal mortality by 26% relative to before the care bundle was introduced.30 The contribution of ACS to the outcome is not known but the trial demonstrated the potential for improving outcomes with a package of interventions rather than a single intervention. The introduction of ACS into a care system that is not capable of adequate care for the preterm may only increase risk. Assuming the result was real, the cause(s) for the unanticipated increased mortality in the higher birth weight infants can only be identified by new trials that follow all the trial participants to delivery and to 28 day outcomes with collection of more granular data on the pregnancies and outcomes. Given the difficulties with identification of causes of death in infants even under conditions of intensive study in LMIC,31 this will be a challenge. Important information to collect will be indicators of infection in the mother and the infant.27 Infectious complications may vary widely in populations based on maternal infections such as tuberculosis, malaria, HIV, and on maternal nutritional status. Another possible contribution to the increased mortality is the hypoglycemia associated with ACS identified in the ALPS trial for late preterm infants.13 Screening of all births for hypoglycemia in a future ACS trial will be essential. A concern is that the dose of ACS is the same independent of maternal size and BMI. In a perinatal unit in Chicago, women in preterm labor with a lower BMI had higher blood sugar values for longer than did women with a high BMI.32 However, the mean value of 30 for the lowest BMI category was high by international standards. Women in LMIC countries often will be short with a BMI closer to 20. The effects of ACS on blood
ACS were initially tested by Liggins and Howie in 1972 using an available preparation that would provide the exposure duration that Liggins had used experimentally for fetal infusions in sheep.34,12 That preparation of a 1:1 mixture of Beta-P and Beta-Ac given as two 12 mg maternal injections given 24 h apart at recognition of a risk of preterm delivery and 24 h later is the standard of care for much of the world but with limited availability in LMIC.15 An alternate treatment has been 4 doses at 12 h intervals of 6 mg Dex-P as this drug is more available, more stable and less expensive, as recommended by the WHO.1 The Beta-P and Beta-Ac mixture was used primarily for the RCTs for single treatment courses for ACS before 1990, and exclusively for the repeated treatment trials.18 However, the pharmacology studies to optimize dosing were never done, although there were indications that the treatment doses were higher than necessary.35 With support from the Bill and Melinda Gates Foundation and GalaxoSmithKlein, we have learned the fetal exposures to ACS that result in lung maturational responses in fetal sheep and Rhesus macaques. The phosphorylated Beta-P or Dex-P are prodrugs that when given by intramuscular injection are rapidly dephosphorylated to cause high maternal and fetal blood levels of Beta or Dex. We initially evaluated the clinical drugs as the 1:1 mixture Beta-P and Beta-Ac in comparison to the slowly deacetylated Beta-Ac alone. The Beta-Ac alone was as effective as the clinical drug and the high peak drug levels from Beta-P in the pregnant animal and fetus were avoided. The lack of a need for the high plasma drug levels was confirmed using maternal Beta-P infusions to achieve constant low maternal and fetal Beta levels that also caused lung maturation in fetal sheep.36 The target drug levels in sheep and primates are in the range of 1 4 ng/ml, but the levels need to be maintained for at least 48 h for a durable lung maturational effect.37 This fetal exposure can be achieved with two IM injections of Beta-Ac. However, Beta-Ac is not available as a single component drug. We have recently applied this knowledge of the minimal drug exposure to achieve a fetal lung maturational response
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to how ACS treatments could be optimized for LMIC (Box 2). The desired attributes of an ACS treatment should be low fetal drug exposures to presumably decrease risks, which are dose and treatment duration dependent for corticosteroids.38 The drug should be stable in harsh environments, available widely, easy to administer and inexpensive. A desirable quality would be easily adjusted dosing based on maternal weight. The solution may be Dex or Beta pills that are very inexpensive and widely available in different steroid amounts in LMIC. In experiments in progress in sheep and primates, oral absorption of either drug avoids the high peak drug levels from intramuscular treatments and prolongs clearance. More needs to be learned about oral dosing in humans, as this mode of dosing may be very attractive in LMIC.
ACS targeted to pregnancies that will benefit ACS may be deceptively safe in HIC. The acute adverse outcome is hypoglycemia, but most concerning ACS have been associated with brain injury in animal models and humans. Further, ACS are associated with the cardiovascular and metabolic abnormalities of the metabolic syndrome with transgenerational effects in animal models ranging from mice to baboons.39,40 Isolated observations have identified cardiovascular effects in human cohorts.41 Such effects are difficult to study as they may occur decades after the fetal exposure. In LMIC, the ACT trial identified increased infection and increased mortality as potential risk of ACS.27 A major problem for that trial was “off target” treatments of pregnancies >34 weeks gestation and very long intervals from treatment to delivery for some pregnancies. The problem is not unique to ACT trial as more than 50% of pregnancies in HIC deliver beyond the efficacy period of 7 days with deliveries at term for some pregnancies. These frequent off target treatments combined with two rules of drug therapy treat only patients who will benefit and use the lowest effective dose make ACS problematic for a therapy for the most vulnerable of patients the human fetus. As ACS are being evaluated in LMIC, more needs be learned about which pregnancies will benefit. Decreasing RDS should decrease mortality, but there may be adverse trade-offs that may be minimized by lower dosing strategies. More information is required about what may be quite varied maternal responses to and fetal effects of ACS in LMIC with different pregnancy problems and health care systems.
Conclusion In this review, we have identified a number of practical and pharmacologic variables that limit the generalizability of the potential benefits of ACS to LMIC. In these environments we do not know WHO to treat with any precision as causes of death in preterm infants are poorly described. The WHICH health care environment is a variable that will define the gestational ages that may benefit from ACS, depending on facilities available. The WHICH drug question awaits further research to minimize dose and explore new treatments routes such as oral dosing to minimize risks. We have not
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specifically addressed WHAT benefits ACS will provide in LMIC. The primary indication for ACS has been to decrease RDS which should decrease mortality. But the effects of these agents are pleotropic with multiple organ benefits in HIC gut effects decrease necrotizing enterocolitis, brain effects decrease intraventricular hemorrhage, kidney effects increase kidney maturation, for example.17 The benefits may differ depending on the patient and the environment and resources of the health care system in LMIC. The unknowns warrant further trials and the need to proceed with caution before widespread unmonitored use of ACS in LMIC. BOX 1. WHO recommendation for ACS Antenatal corticosteroids are recommended for pregnancies at risk of preterm birth from 24 to 34 week gestation if all the conditions are met: Gestational is accurately known to be 24 34 weeks. Preterm birth is imminent (within 1 7 days). No clinical evidence of maternal infection. Adequate labor and delivery care can be provided. Newborn care is available including resuscitation, thermal and feeding support, infection treatment and oxygen.
BOX 2. Optimal ACS for LMIC Corticosteroid dosing schedule to minimize fetal exposure. Stable, available, inexpensive and easy corticosteroid dosing. Treatment with dosing based on maternal weight. Treatment of only pregnancies that will benefit.
Disclosures The authors have conflict of interest for this revise article.
R E F E R E N C E S
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