Opinion
VIEWPOINT
Catherine E. M. Aiken, PhD, MRCOG Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, United Kingdom. Abigail L. Fowden, PhD Centre for Trophoblast Research and Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom. Gordon C. S. Smith, MD, PhD, DSc Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, United Kingdom.
Antenatal Glucocorticoids Prior to Cesarean Delivery at Term Administration of glucocorticoids to pregnant women to accelerate fetal lung maturation prior to preterm birth is one of the most effective interventions in perinatal medicine. Its success led to the evaluation of glucocorticoid administration prior to prelabor cesarean delivery between 37 weeks 0 days and 38 weeks 6 days of gestational age. The Antenatal Steroids for Term Elective Caesarean Section (ASTECS) trial demonstrated that antenatal glucocorticoids reduced short-term respiratory morbidity.1 Based on this evidence, the Royal College of Obstetricians and Gynaecologists in the United Kingdom recommended antenatal glucocorticoids prior to all planned cesarean births before 39 weeks.2 Administration of antenatal glucocorticoids has become common practice in the United Kingdom and elsewhere. The long-term follow-up of the ASTECS trial by Stutchfield et al3 has recently been published. The authors concluded that “antenatal betamethasone did not result in any adverse outcomes… it should be considered for elective cesarean section at 37-38 weeks of gestation.”3(pF195) However, we believe that the long-term outcome data and the known pharmacologic effects of high doses of synthetic glucocorticoids indicate that this intervention should not be routinely recommended.
Results of Long-term Follow-up of the ASTECS Trial
Corresponding Author: Gordon C. S. Smith, MD, PhD, DSc, Department of Obstetrics and Gynaecology, University of Cambridge, The Rosie Hospital, Cambridge, CB2 0SW, United Kingdom (gcss2@cam .ac.uk).
The long-term follow-up of the ASTECS trial consisted of questionnaire data from 407 of 862 participants from the original trial. In addition, school performance data were available for 352 children. Among this subset of the trial cohort, the glucocorticoid-exposed children experienced a lower rate of respiratory morbidity (2%) than the control group (9%). However, when the long-term health of both groups of children was compared, the rate of any experience of a medical problem was identical (36%). In addition, there were no significant differences in hospital admissions or asthma-related morbidity. The only statistically significant difference between the 2 groups was in the assessments of academic ability by their schools. Glucocorticoid-exposed children were twice as likely to be identified as being in the lowest achievement group at school compared with the control group (33 of 186 [17.7%] vs 14 of 164 [8.5%], relative risk, 2.1; 95% CI, 1.1-3.7; P = .01). 3 The authors commented that this result “appeared a discordant finding.”3(pF199) No objective testing of academic ability was performed within the trial. Results from national standardized assessments were available, and although there was no statistical difference between the scores for each group, the trends consistently favored the control group. Despite the difference in the assessments of academic ability, the ASTECS trial authors concluded “no adverse effect was seen on health,
behavior and academic achievement of children born following a single course of antenatal betamethasone at term.”3(pF195) When considering the results of the long-term follow-up of the ASTECS trial, the authors reported that a previous follow-up study of individuals exposed to antenatal glucocorticoids had failed to demonstrate any long-term cognitive impairment.4 However, that study followed up children whose mothers had received glucocorticoids for threatened preterm birth, of which twothirds had been delivered preterm. Meta-analysis of randomized clinical trials of glucocorticoids in the context of preterm birth have shown multiple short-term beneficial effects, including a 34% reduction in the risk of respiratory distress syndrome, a 46% reduction in the risk of cerebral intraventricular hemorrhage, a 54% reduction in the risk of necrotizing enterocolitis, and a 44% reduction in the risk of early systemic infection.5 Given that preterm infants have much higher rates of severe neonatal morbidity and that glucocorticoids are effective in reducing these risks, it may be that glucocorticoids have a beneficial effect on later cognitive function by reducing the risk of short-term severe morbidity in the preterm infant. However, it is possible that there is an underlying harmful effect of glucocorticoids, which is compensated for in preterm infants. Infants delivered by cesarean delivery at term do not have high risks of these complications. Consequently, a lack of effect of glucocorticoids on cognitive function following birth at term cannot safely be inferred by the apparent absence of an adverse effect in the context of preterm birth.
Glucocorticoids at Term and Later Cognitive Function A key question when considering the poor school performance of glucocorticoid-exposed children is whether it is indeed a discordant finding. We believe that an adverse effect on the brain is biologically plausible on the basis of the physiological effects of in utero exposure to glucocorticoids. The benefit of antenatal glucocorticoids prior to preterm birth arises from iatrogenic mimicking of the physiological rise in fetal circulating concentrations of cortisol (from the fetal adrenals) in late gestation. Cortisol acts in the fetus, in part, by stimulating a general switch from growth and proliferation to differentiation and maturation. Earlier fetal exposure to cortisol from the maternal circulation is prevented by high levels of placental expression of the enzyme 11βhydroxysteroid dehydrogenase type 2 (11β-HDS-2), which converts cortisol to inactive 11-keto metabolites.6 However, when glucocorticoids are administered to accelerate fetal lung maturation, the synthetic agents used (principally betamethasone sodium phosphate and dexa-
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JAMA Pediatrics June 2014 Volume 168, Number 6
Copyright 2014 American Medical Association. All rights reserved.
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507
Opinion Viewpoint
methasone phosphate) are poorly inactivated by 11β-HDS-2 and consequently reach the fetal tissues in greater bioactive quantities.6 In general, expression of 11β-HDS-2 is low in fetal tissues relative to the reductase 11β-hydroxysteroid dehydrogenase type 1, which produces active corticosteroids from their inactive metabolites. This allows a response to the physiological elevation of cortisol at term. However, an exception to this is in the brain, where 11β-HDS-2 is highly expressed, particularly in the neurons of the cerebellar cortex and nuclei of the thalamus around the time of birth.6 Although the developing brain is particularly sensitive to the effects of glucocorticoids, high levels of 11β-HDS-2 in late gestation and, in some brain areas, in neonatal life as well,6 result in growth and proliferation during the perinatal period despite high levels of endogenous fetal cortisol. It follows, therefore, that exposing the fetus or neonate to potent synthetic glucocorticoids that are resistant to 11β-HDS-2 deactivation may cause an early switch to differentiation and maturation in the developing brain. It is plausible that this could result in adverse effects on long-term neurodevelopmental outcome. Randomized trials of postnatal synthetic glucocorticoids given to promote lung function in preterm infants are consistent with this model. Dexamethasone (11β-HSD-2–resistant) is significantly associated with the risk of later cerebral palsy (relative risk, 1.75; 95% CI,
Balancing the Risks of Glucocorticoids at Term All medical interventions ultimately involve a balance of risks and benefits. The initial findings regarding the risk of adverse cognitive outcomes for children exposed to glucocorticoids at term from the follow-up of the ASTECS trial require confirmation through objective standardized testing on a larger cohort. The benefit of administering glucocorticoids at term is to reduce the risk of short-term respiratory morbidity. To prevent one infant admission to special care 16 women at 37 weeks and 29 women at 38 weeks need to be treated. Most of these infants (approximately 80%) will not experience severe complications. The question facing obstetricians and neonatologists is whether this degree of reduction in short-term respiratory morbidity justifies the risk that glucocorticoids may have an adverse effect on cognitive function of the child in later life. Given the present evidence, we do not believe the risk is warranted.
ARTICLE INFORMATION
REFERENCES
Published Online: April 7, 2014. doi:10.1001/jamapediatrics.2014.9.
1. Stutchfield P, Whitaker R, Russell I; Antenatal Steroids for Term Elective Caesarean Section (ASTECS) Research Team. Antenatal betamethasone and incidence of neonatal respiratory distress after elective caesarean section: pragmatic randomised trial. BMJ. 2005;331(7518):662.
Conflict of Interest Disclosures: None reported. Funding/Support: Funding for this study was provided by the National Institute for Health Research Cambridge Comprehensive Biomedical Research Centre. Role of the Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: We are grateful to Edile M. Murdoch, MB, ChB (Department of Neonatology, Royal Infirmary of Edinburgh, UK), and Ian M. Goodyer, MD (Department of Psychiatry, University of Cambridge, Developmental Lifecourse Research Group), for their comments on the manuscript.
508
1.20-2.55) whereas hydrocortisone (oxidized to inactive cortisone by 11β-HSD-2) is not (0.97; 0.55-1.69).7,8 Consequently, for children exposed to glucocorticoids at term, low school achievement is not a discordant finding but could plausibly represent the long-term manifestation of unphysiological activation of the glucocorticoid receptor in the brain during a critical period of development.
2. Roberts D. Antenatal Corticosteroids to Reduce Neonatal Morbidity and Mortality. Royal College of Obstetricians and Gynaecologists; London, UK; 2010. 3. Stutchfield PR, Whitaker R, Gliddon AE, Hobson L, Kotecha S, Doull IJ. Behavioural, educational and respiratory outcomes of antenatal betamethasone for term caesarean section (ASTECS trial). Arch Dis Child Fetal Neonatal Ed. 2013;98(3):F195-F200. 4. Dalziel SR, Lim VK, Lambert A, et al. Antenatal exposure to betamethasone: psychological functioning and health related quality of life 31
years after inclusion in randomised controlled trial. BMJ. 2005;331(7518):665. 5. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2006; (3):CD004454. 6. Wyrwoll CS, Holmes MC, Seckl JR. 11β-hydroxysteroid dehydrogenases and the brain: from zero to hero, a decade of progress. Front Neuroendocrinol. 2011;32(3):265-286. 7. Halliday HL, Ehrenkranz RA, Doyle LW. Early (
VIEWPOINT
Catherine E. M. Aiken, PhD, MRCOG Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, United Kingdom. Abigail L. Fowden, PhD Centre for Trophoblast Research and Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom. Gordon C. S. Smith, MD, PhD, DSc Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, United Kingdom.
Antenatal Glucocorticoids Prior to Cesarean Delivery at Term Administration of glucocorticoids to pregnant women to accelerate fetal lung maturation prior to preterm birth is one of the most effective interventions in perinatal medicine. Its success led to the evaluation of glucocorticoid administration prior to prelabor cesarean delivery between 37 weeks 0 days and 38 weeks 6 days of gestational age. The Antenatal Steroids for Term Elective Caesarean Section (ASTECS) trial demonstrated that antenatal glucocorticoids reduced short-term respiratory morbidity.1 Based on this evidence, the Royal College of Obstetricians and Gynaecologists in the United Kingdom recommended antenatal glucocorticoids prior to all planned cesarean births before 39 weeks.2 Administration of antenatal glucocorticoids has become common practice in the United Kingdom and elsewhere. The long-term follow-up of the ASTECS trial by Stutchfield et al3 has recently been published. The authors concluded that “antenatal betamethasone did not result in any adverse outcomes… it should be considered for elective cesarean section at 37-38 weeks of gestation.”3(pF195) However, we believe that the long-term outcome data and the known pharmacologic effects of high doses of synthetic glucocorticoids indicate that this intervention should not be routinely recommended.
Results of Long-term Follow-up of the ASTECS Trial
Corresponding Author: Gordon C. S. Smith, MD, PhD, DSc, Department of Obstetrics and Gynaecology, University of Cambridge, The Rosie Hospital, Cambridge, CB2 0SW, United Kingdom (gcss2@cam .ac.uk).
The long-term follow-up of the ASTECS trial consisted of questionnaire data from 407 of 862 participants from the original trial. In addition, school performance data were available for 352 children. Among this subset of the trial cohort, the glucocorticoid-exposed children experienced a lower rate of respiratory morbidity (2%) than the control group (9%). However, when the long-term health of both groups of children was compared, the rate of any experience of a medical problem was identical (36%). In addition, there were no significant differences in hospital admissions or asthma-related morbidity. The only statistically significant difference between the 2 groups was in the assessments of academic ability by their schools. Glucocorticoid-exposed children were twice as likely to be identified as being in the lowest achievement group at school compared with the control group (33 of 186 [17.7%] vs 14 of 164 [8.5%], relative risk, 2.1; 95% CI, 1.1-3.7; P = .01). 3 The authors commented that this result “appeared a discordant finding.”3(pF199) No objective testing of academic ability was performed within the trial. Results from national standardized assessments were available, and although there was no statistical difference between the scores for each group, the trends consistently favored the control group. Despite the difference in the assessments of academic ability, the ASTECS trial authors concluded “no adverse effect was seen on health,
behavior and academic achievement of children born following a single course of antenatal betamethasone at term.”3(pF195) When considering the results of the long-term follow-up of the ASTECS trial, the authors reported that a previous follow-up study of individuals exposed to antenatal glucocorticoids had failed to demonstrate any long-term cognitive impairment.4 However, that study followed up children whose mothers had received glucocorticoids for threatened preterm birth, of which twothirds had been delivered preterm. Meta-analysis of randomized clinical trials of glucocorticoids in the context of preterm birth have shown multiple short-term beneficial effects, including a 34% reduction in the risk of respiratory distress syndrome, a 46% reduction in the risk of cerebral intraventricular hemorrhage, a 54% reduction in the risk of necrotizing enterocolitis, and a 44% reduction in the risk of early systemic infection.5 Given that preterm infants have much higher rates of severe neonatal morbidity and that glucocorticoids are effective in reducing these risks, it may be that glucocorticoids have a beneficial effect on later cognitive function by reducing the risk of short-term severe morbidity in the preterm infant. However, it is possible that there is an underlying harmful effect of glucocorticoids, which is compensated for in preterm infants. Infants delivered by cesarean delivery at term do not have high risks of these complications. Consequently, a lack of effect of glucocorticoids on cognitive function following birth at term cannot safely be inferred by the apparent absence of an adverse effect in the context of preterm birth.
Glucocorticoids at Term and Later Cognitive Function A key question when considering the poor school performance of glucocorticoid-exposed children is whether it is indeed a discordant finding. We believe that an adverse effect on the brain is biologically plausible on the basis of the physiological effects of in utero exposure to glucocorticoids. The benefit of antenatal glucocorticoids prior to preterm birth arises from iatrogenic mimicking of the physiological rise in fetal circulating concentrations of cortisol (from the fetal adrenals) in late gestation. Cortisol acts in the fetus, in part, by stimulating a general switch from growth and proliferation to differentiation and maturation. Earlier fetal exposure to cortisol from the maternal circulation is prevented by high levels of placental expression of the enzyme 11βhydroxysteroid dehydrogenase type 2 (11β-HDS-2), which converts cortisol to inactive 11-keto metabolites.6 However, when glucocorticoids are administered to accelerate fetal lung maturation, the synthetic agents used (principally betamethasone sodium phosphate and dexa-
jamapediatrics.com
JAMA Pediatrics June 2014 Volume 168, Number 6
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Birmingham User on 05/28/2015
507
Opinion Viewpoint
methasone phosphate) are poorly inactivated by 11β-HDS-2 and consequently reach the fetal tissues in greater bioactive quantities.6 In general, expression of 11β-HDS-2 is low in fetal tissues relative to the reductase 11β-hydroxysteroid dehydrogenase type 1, which produces active corticosteroids from their inactive metabolites. This allows a response to the physiological elevation of cortisol at term. However, an exception to this is in the brain, where 11β-HDS-2 is highly expressed, particularly in the neurons of the cerebellar cortex and nuclei of the thalamus around the time of birth.6 Although the developing brain is particularly sensitive to the effects of glucocorticoids, high levels of 11β-HDS-2 in late gestation and, in some brain areas, in neonatal life as well,6 result in growth and proliferation during the perinatal period despite high levels of endogenous fetal cortisol. It follows, therefore, that exposing the fetus or neonate to potent synthetic glucocorticoids that are resistant to 11β-HDS-2 deactivation may cause an early switch to differentiation and maturation in the developing brain. It is plausible that this could result in adverse effects on long-term neurodevelopmental outcome. Randomized trials of postnatal synthetic glucocorticoids given to promote lung function in preterm infants are consistent with this model. Dexamethasone (11β-HSD-2–resistant) is significantly associated with the risk of later cerebral palsy (relative risk, 1.75; 95% CI,
Balancing the Risks of Glucocorticoids at Term All medical interventions ultimately involve a balance of risks and benefits. The initial findings regarding the risk of adverse cognitive outcomes for children exposed to glucocorticoids at term from the follow-up of the ASTECS trial require confirmation through objective standardized testing on a larger cohort. The benefit of administering glucocorticoids at term is to reduce the risk of short-term respiratory morbidity. To prevent one infant admission to special care 16 women at 37 weeks and 29 women at 38 weeks need to be treated. Most of these infants (approximately 80%) will not experience severe complications. The question facing obstetricians and neonatologists is whether this degree of reduction in short-term respiratory morbidity justifies the risk that glucocorticoids may have an adverse effect on cognitive function of the child in later life. Given the present evidence, we do not believe the risk is warranted.
ARTICLE INFORMATION
REFERENCES
Published Online: April 7, 2014. doi:10.1001/jamapediatrics.2014.9.
1. Stutchfield P, Whitaker R, Russell I; Antenatal Steroids for Term Elective Caesarean Section (ASTECS) Research Team. Antenatal betamethasone and incidence of neonatal respiratory distress after elective caesarean section: pragmatic randomised trial. BMJ. 2005;331(7518):662.
Conflict of Interest Disclosures: None reported. Funding/Support: Funding for this study was provided by the National Institute for Health Research Cambridge Comprehensive Biomedical Research Centre. Role of the Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: We are grateful to Edile M. Murdoch, MB, ChB (Department of Neonatology, Royal Infirmary of Edinburgh, UK), and Ian M. Goodyer, MD (Department of Psychiatry, University of Cambridge, Developmental Lifecourse Research Group), for their comments on the manuscript.
508
1.20-2.55) whereas hydrocortisone (oxidized to inactive cortisone by 11β-HSD-2) is not (0.97; 0.55-1.69).7,8 Consequently, for children exposed to glucocorticoids at term, low school achievement is not a discordant finding but could plausibly represent the long-term manifestation of unphysiological activation of the glucocorticoid receptor in the brain during a critical period of development.
2. Roberts D. Antenatal Corticosteroids to Reduce Neonatal Morbidity and Mortality. Royal College of Obstetricians and Gynaecologists; London, UK; 2010. 3. Stutchfield PR, Whitaker R, Gliddon AE, Hobson L, Kotecha S, Doull IJ. Behavioural, educational and respiratory outcomes of antenatal betamethasone for term caesarean section (ASTECS trial). Arch Dis Child Fetal Neonatal Ed. 2013;98(3):F195-F200. 4. Dalziel SR, Lim VK, Lambert A, et al. Antenatal exposure to betamethasone: psychological functioning and health related quality of life 31
years after inclusion in randomised controlled trial. BMJ. 2005;331(7518):665. 5. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2006; (3):CD004454. 6. Wyrwoll CS, Holmes MC, Seckl JR. 11β-hydroxysteroid dehydrogenases and the brain: from zero to hero, a decade of progress. Front Neuroendocrinol. 2011;32(3):265-286. 7. Halliday HL, Ehrenkranz RA, Doyle LW. Early (
