Should we take another look at antenatal corticosteroids?

Despite Liggins’ landmark paper in 1972 and more than 44 years of active research, we are still at a loss to define which pregnancies are most likely to benefit from antenatal corticosteroids (ACS) and which may be harmed.¹ While much attention has been focused on the impact of ACS on the preterm lung, the long-term impact of ACS on other organ systems has not been adequately studied in humans, even though glucocorticoids affect every human organ system. 

The efficacy and relative safety of a single course of ACS in pregnancies delivered prior to 32–34 weeks is well established and one of the most powerful interventions in obstetric medicine.^2,3 The value of ACS in late preterm pregnancies and before elective cesarean at term is less clear. Here I review the latest data from clinical trials on this topic and the risks of expanding use of ACS therapy.

What the evidence says

Use of ACS at ≥34 weeks’ gestation  was evaluated in a 2016 meta-analysis that included 6 randomized controlled trials (RCTs).⁴ The RCTs looked at 2 groups: women who were candidates for ACS with delivery anticipated between 35 and 37 weeks’ gestation (N=3204) and women undergoing planned elective cesarean at term (≥37 weeks’ gestation, N=2498). The primary outcome of all the RCTs in the meta-analysis was neonatal respiratory outcomes and/or NICU admissions. Only 3 trials were blinded and long-term outcomes are available from one study.^5,6 The group of women randomized between 34 and 36 6/7 weeks for “imminent preterm delivery” demonstrated statistically significant reductions in severe respiratory distress syndrome (1.4% vs 2.3%; RR 0.60, 95% CI 0.24–0.98) and transient tachypnea of the newborn (8.2% vs 10.9%; RR 0.72, 95% CI 0.50–0.98), but not RDS overall or mechanical ventilation. ACS treatment increased the risk for neonatal hypoglycemia (22.8% vs 14.2%; RR 1.61, 95% CI 1.16–2.12).⁴

The meta-analysis was dominated by the Antenatal Late Preterm Steroids Trial (ALPS),⁷ in which women at 34 0/7 to 36 5/7 weeks’ gestation at high risk for late preterm birth were randomly assigned to receive a first course of antenatal corticosteroids (2 injections of betamethasone 24 hrs apart) or placebo. No tocolytics were administered. The primary outcome was a composite of neonatal respiratory treatment in the first 72 hrs (continuous positive airway pressure [CPAP] or high-flow nasal cannula for ≥2 hours, supplemental oxygen with FIO2 ≥0.30 for ≥4 hrs, extracorporeal membrane oxygenation, or mechanical ventilation), stillbirth, or neonatal death within 72 hrs of delivery. See sidebar at left for major findings. 

No data are available about the long-term neurodevelopmental outcomes of children exposed to corticosteroids between 34 0/7 and 36 5/7 weeks. A 2-year follow-up study is currently being performed. 

Women randomized at term prior to cesarean received either betamethasone or dexamethasone administered 48 hrs before planned cesarean delivery at ≥37 weeks’ gestation. RDS (2.7% vs 6.7%; RR 0.40, 95% CI 0.27–0.59) and use of mechanical ventilation (0.7% vs 3.6%; RR 0.19, 95% CI 0.08–0.43) were reduced, as were time on oxygen, maximum inspired oxygen, and length of stay in the NICU.⁴

Long-term follow-up is available from the ASTECS (ACS for term cesarean section) and ASTECS2 trials.^5,6 In ASTECS2, 998 women undergoing planned cesarean delivery at term were randomly assigned to receive a course of betamethasone (12 mg IM q 24 hrs x2) or usual treatment prior to delivery.⁶ The primary outcome was admission to a special care unit with respiratory problems. 

The ASTECS-2 study provided follow-up data on participants of the ASTEC trial at ages 8 to 15 years.⁵ About 50% of participants were lost to follow-up; children available for study were disproportionately represented by the betamethasone group and those admitted to the special care nursery for respiratory complications (5% vs 2%, P=0.01). Long-term assessment was based on parental responses to the strengths and difficulties questionnaire (SDQ), standardized scholastic testing results, and teacher responses. Overall there was no difference in behavioral characteristics based on SDQ, school performance, health issues, asthma, or atopic disease. The authors concluded that “parents can be reassured that the administration of a single course of ACS is not only beneficial in the short term, but does not have any adverse long term consequences.” Based on these findings, use of ACS prior to term cesarean became accepted practice in the United Kingdom. 

Potentially exposing hundreds of thousands of late preterm or term pregnancies in the United States alone to ACS is a significant shift from limiting use of the drugs to pregnancies <34 weeks. Following the publication of the ALPS trial and despite the lack of long-term safety data, the Society for Maternal-Fetal Medicine (SMFM) endorsed use of a single course of ACS in late preterm if delivery appears to be imminent.⁸ They also opined that risk of hypoglycemia could be minimized by routine glucose testing in late-preterm infants as endorsed by the American Academy of Pediatrics.⁹ The American College of Obstetricians and Gynecologists then expanded their guidelines to include gestations from 23 to 37 weeks.² Neither organization has advocated for ACS use at term prior to cesarean delivery. 

Perspective on safety

Do we have sufficient data to conclude that ACS administration to late preterm or term infants is safe? The field of medicine is full of examples of treatments that were introduced based on short-term outcomes and were later demonstrated to be harmful. In the SMFM consensus statement, 2 studies were cited as evidence of the safety of administering ACS in late preterm and term pregnancies.⁸ The first was ASTECS2 and the second was a 31-year follow-up of the original Liggins cohort.^6,10 Of note, few participants in the original trial were randomized near or at term and there is no mention of when ACS was administered relative to outcomes on follow-up. A total of 192 adults participated (87 betamethasone group and 105 control group). The results were reassuring with regard to perceived long-term health benefits, cognitive performance, and psychiatric illnesses. A larger cohort also participated in cardiovascular follow-up at age 30, which was not cited by SMFM.¹¹ At age 30, there were no major differences in cardiovascular health between betamethasone-exposed and control survivors, which is not surprising as most cardiovascular disease is seen in older adults. Risk factors for insulin resistance were significantly increased in betamethasone recipients. In these 2 studies,^5,10 304 cases were exposed to a single course of betamethasone from 24 to 41 weeks’ gestation compared to 295 controls. Those numbers are insufficient to conclude ACS exposure in late preterm infants as safe, a fact that was acknowledged by SMFM with the comment “there is always the potential for unintended consequences with any change in long term practice.”⁸

In the very low birthweight baby, the majority of data when a single course of ACS therapy was administered prior to 34 weeks’ gestation demonstrates significant benefits in the short term, including potential improvements in long-term neurologic handicap (eg, cerebral palsy).³ However, when all neonates exposed in utero to a single course of ACS at 24–34 weeks’ gestation are considered, follow-up data do not suggest that the positive effects seen in the nursery persist long-term.^10,11

The risk-benefit analysis for administering ACS at early gestational ages is not comparable to late preterm or term as the rates of morbidity and mortality are significantly lower at later gestational ages in non-anomalous fetuses. It should not be a surprise that administration of ACS prior to delivery near term or prior to cesarean at term decreased respiratory morbidity in both ASTECs and ALPS, as these studies had adequate power to detect small decreases in short-term respiratory problems in a low-risk population. The impact on a reduction in transient tachypnea of the newborn confirmed what was already known in animal models.¹²

The risks of administering ACS during late term and term remain unknown. Endogenous corticosteroids surge near term when the fetus is in a critical period of brain and other organ system development in preparation for parturition and transition to life ex utero.^12-15 Additional exposure to ACS during the period at or near term is likely to have far greater consequences for normal brain development than at any other time in development. Between 34 weeks’ gestation and term, in a normal human pregnancy, the brain grows by 35%. Cortical volume increases by 50% and 25% of cerebellum development occurs during that time.^3,14

Corticoids are crucial for normal development. “Overexposure of the fetus to ACS by using synthetic GC (betamethasone and dexamethasone) during certain stages of pregnancy can profoundly affect the development of the neuroendocrine system, which may lead to life-long effects on endocrine, behavioral, emotional, and cognitive function. These life-long effects on neuroendocrine function are associated with increased risks of developing a wide range or metabolic, cardiovascular, and brain disorders in later life.”^14-17

A study by Poggi Davis et al reinforces these concerns.¹⁸ They studied 54 children, aged 6 to 10, who had received a single course of betamethasone at a mean gestational age of 29.3 weeks (+/- 3 weeks), delivered at term, and matched 1:2 to term infants not exposed to ACS. There were very concerning findings with ACS exposure: widespread differences in cortical thickness associated with significant thinning of the cortex, particularly the rostral anterior cingulate cortex (rACC), which is strongly associated with development of affective disorders, as well as HPA axis dysregulation. 

These findings are consistent with every animal model of ACS exposure that has been studied.¹² In particular, they mirror the findings of Uno et al who used different dexamethasone dosing regimens administered similarly to ACS to preterm macaques.¹⁹ In unpublished data, they demonstrated significant changes in the hippocampus, and neural damage in the cere tarded growth of the cerebellum. The finding on the cerebellum has been confirmed.²⁰

Before endorsing the use of ACS at gestational ages when severe morbidity and mortality is low, the onus is on clinician-scientists and policy-makers to require long-term follow-up studies. ACS administration has always been enigmatic. We have gone from under-using it to abusing it with prophylactic weekly administration, to salvage therapy. Clinicians should avoid elective late-term deliveries and delay elective cesareans whenever possible to 39 weeks to reduce the morbidity associated with these deliveries. 

In 2013, SMFM published recommendations regarding early delivery for multiple maternal, fetal, and obstetrical complications.²¹ These recommendations were largely determined by consensus and not high-quality data. 

What are clinicians to do? Are we to deliver an increasing number of women late preterm to reduce the potential risks of expectant management and expose them to a single course of ACS all in an effort to avoid admission to the NICU and reduce short-term respiratory morbidity? Or should we avoid iatrogenic delivery prior to 39 weeks and thus obviate the need for ACS exposure but possibly increase fetal and maternal risk from continuing the pregnancy?

Summary

If parents were informed of the low risk of severe respiratory complications in the majority of late preterm or term infants and the unknown risk for irreversible changes in the brain and the hypopituitary axis, the majority would likely choose to avoid ACS therapy.

ACS therapy should not be expanded until we fully understand the potential risk-benefit ratio of treatment, and better understand the long-term consequences of exposure to ACS late preterm or at term. <

References

1.  Liggins GC, Howie RN.  A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants.  Pediatrics 1972; 50: 515.

2.  ACOG Committee on practice bulletins-obstetrics.  ACOG practice bulletin no. 150:  management of preterm labor.  Obstet Gynecol 2016; 127 e29.

3. Sotiradis A, Tsiami A, Papatheodorou S, Baschat A, Sarafidis K, Makrydimas G. Neurodevelopmental outcome after a single course of antenatal steroids in children born preterm.  A systematic review and meta-analysis.  Obstet and Gynec 2015; 125 (6): 1385-

4. Saccone G, Berghella V.  Antenatal corticosteroids for maturity of term or near term fetuses:  systematic review and meta-analysis of randomized controlled trials.  BMJ 2016; 355:IS044  

5.  Stutchfield PR, Whitaker R, Gliddon AE, Hobson L, Kotecha S, Doull IJM.  Behavioural, educational and respiratory outcomes of antenatal betamethasone for term caesarean sect (ASTECS trial). Arch Dis Child Fetal Neonal Ed 2013; 98:F195-F200     

6. Stutchfield, P, Whiaker R, Russell I.  Antenatal betamethasone and incidence of neonatal respiratory distress after elective caesarean section:  pragmatic randomized trial.  BMK, doi:10.1135/bmj.38547.41693.06 (published 22 August 2005)  BMJ 2005; 331: 662.

7. Gyamfi-Bannerman C, Thom EA, Blackwell SC, Tita ATN, Reddy UM, et al.  Antenatal betamethasone for women at risk for late preterm delivery.  NEJM 2016 SMFM Publications Committee, SMFM statement:  implementation of the use of antenatal corticosteroids in the late preterm birth period in women at risk for preterm delivery.  Am J Obstet Gynec 2016: 

8. SMFM Publications Committee, SMFM statement: implementation of the use of antenatal corticosteroids in the late preterm birth period in women at risk for preterm delivery. Am J Obstet Gynecol. 2016:

9. Committee on Fetus and Newborn. Adarrkin DH. Postnatal glucose homeostasis in late-preterm and term infants. Pediatrics 2011;127:575-9

10. Dalziel SR, Lim VK, Lamber A, et al. Antenatal exposure to betamethasone: psychological functioning and health related quality of life 31 years after inclusion in randomized controlled trial. BMJ 2005;331 665.

11. Dalziel SR, Walker NK, Parag V, Mantell C, Rea H, et al. Cardiovascular risk factors after antenatal exposure to betamethasone: 30-year follow-up of a randomized controlled trial. Lancet 2005;365:1856-62. 

12. Kemp MW, Newnham JP, Challis JG, Jobe AH, Stock SJ. The clinical use of corticosteroids in pregnancy. Human Reproduction Update 2015;22(2):240-259

13. Kugelman A, Colin A. Late preterm infants: near term but still in a critical developmental time period. Pediatrics 2013:132(4):741-751.

14. Kinney J. The near-term (late preterm) human brain and risk for periventricular leukomalacia: A review. Semin Perinatol 2006;30:81-88

15. Chang YP. Evidence for adverse effect of perinatal glucocorticoid use on the developing brain. Korean J Pediatr 2014:57(3):101-109.

16. Champagne DL, de Kloet ER, Joels M. Fundamental aspects of the impact of glucocorticoids on the (immature) brain. Semin Fetal Neonatal Med 2009;14:136:142.

17. Tegethoff M, Pryce C, Meinlschmidt G. Effects of intrauterine exposure to synthetic glucocorticoids on fetal, newborn, and infant hypothalamic-pituitary adrenal axis function in humans: a systematic review. Endocr Rev 2009;30:753-759.

18. Davis EP, Sandman CA, Buss C, Wing DA, Head K. Fetal glucocorticoid exposure is associated with preadolescent brain development. Biol Psychiatry 2013;74(9)647-655. 

19. Uno H, Lohmiller L, Thieme C, Kemnitz JW, Engle MJ, et al. Brain damage induced by prenatal exposure to dexamethasone in fetal rhesus macaques. I. Hippocampus. Brain Res Dev Brain Res 1990;53(2):157-167.

20. Noguchi K, Walls K, Wozniak D, Olney JW, Roth KA, et al. Acute neonatal glucorcorticoid Cautioexposure produces selective and rapid cerebellar neural progenitor cell apoptotic death. Cell Death Differ 2008;15(10):1582-92

21. Medically indicated late preterm and early term deliveries. Committee opinion no 560. American College of Obstetricians and Gynecologists 2013;121:901-10