By John C. Hobbins, MD

Professor, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora

Dr. Hobbins reports no financial relationships relevant to this field of study.

SYNOPSIS: A large European multicenter study has shown that antenatal corticosteroid administration in patients at risk for imminent very early preterm birth (24 to 31 weeks) will decrease perinatal mortality and morbidity substantially, even after only three hours of exposure.

SOURCE: Norman M, et al. Association of short antenatal corticosteroid administration-to-birth intervals with survival and morbidity among very preterm infants: Results from the EPICE cohort. JAMA Pediatr 2017;171:678-686. doi:10.1001/jamapediatrics.2017.0602.

Corticosteroids perhaps have had a greater beneficial effect on perinatal outcomes than any other in utero treatment method. Since antenatal steroids consistently have been shown to reduce the incidence of respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), and necrotizing enterocolitis (NEC) in preterm infants, they have become a staple in the management of patients with evidence of imminent preterm delivery. Even the dosage and timing of administration have become standard. However, it has been unclear as to when the protective effects on the fetal lung and brain kick in along the 48-hour course.

Norman and colleagues undertook an ambitious multicenter study to try to answer this question in very preterm fetuses. The authors analyzed data from 123 participating hospitals in 11 European countries (The Effect of Perinatal Intensive Care in Europe study). From 2011 through 2012, the authors identified 4,594 preterm singleton pregnancies in which mothers delivered between 24 and 31 weeks. Anomalous pregnancies and those exposed to multiple courses of steroids were excluded. The standard dose in 85% of hospitals consisted of two injections of 12 mg of betamethasone 24 hours apart. The remaining patients had an assortment of similar regimens. Dexamethasone was used in only 5% of patients.

Pregnancies were categorized according to the time between when antenatal steroids were initiated and when the patients delivered. For example, one group of 662 of infants (14.4%) received no in utero treatment; another 1,111 patients (24%) had antenatal steroids on board for less than 24 hours; another group of 1,871 patients (40%) delivered one to seven days after receiving antenatal steroids; and the last group of 950 infants (20.7%) delivered more than seven days after receiving antenatal steroids. Outcome measures most emphasized were in-hospital deaths and composite severe neonatal morbidity (grade 3 or higher IVH, cystic periventricular leukomalacia, surgical NEC, or stage III retinopathy).

The average gestational age at delivery in the entire group was 28 weeks, with a mean birth weight of 1,213 g. The greatest reduction in mortality after antenatal steroids were administered (50%) was attained with deliveries occurring within 18 to 36 hours after the first dose. Interestingly, although there was a similar trend in timeline with composite morbidity, severe brain injury appeared to occur most frequently when delivery occurred after 48 hours post first injection. Also, the benefit of antenatal steroids to diminish mortality and severe morbidity was similar after 12 hours to that noted between 18 and 48 hours. In addition, there was a reduction of 24% after only three hours.

COMMENTARY

The amazing story of the evolution of antenatal steroids needs re-telling. In the late 1960s, Dr. G.C. Liggins, a New Zealand obstetrician, was exploring mechanisms of labor in the readily available sheep model and noted that some lambs born before 130 days (term is 150 days) survived when they all should have succumbed to RDS. The only difference was that their mothers had been on an experimental steroid regimen to initiate labor. This led to a randomized, clinical trial (RCT), published in 1972, which suggested that antenatal steroids diminished the chances of RDS.1 The drug, dosage, and timeline (betamethasone 12 mg q 12h x 2) were said to be chosen arbitrarily by Dr. Liggins. However, through the years this regimen appears to have been cast in stone.

Since then, antenatal steroids have been shown in many RCTs to be beneficial in pregnancies ending in preterm birth prior to 34 weeks. However, its efficacy had been in question in patients delivering at or after 34 weeks — until the Antenatal Late Preterm Steroids (ALPS) study emerged.2 This well-designed RCT suggested significant, but modest, benefit in composite neonatal outcome in late preterm pregnancies (34/1 to 36/6 weeks), when a standard dose of betamethasone was given to patients in preterm labor with cervical dilation of > 2 cm or in whom there was a compelling reason to deliver. The control group was given a double injection of placebo 12 hours apart. Forty percent delivered within 24 hours of their first injection. The authors calculated that 35 patients would need to be treated to show benefit in the composite neonatal score and 200 would need to be treated to prevent a serious complication of prematurity. Almost immediately following this publication, the American College of Obstetricians and Gynecologists and the Society for Maternal–Fetal Medicine responded by suggesting that patients less than 37 weeks who are at risk for imminent delivery be given antenatal steroids.3

Now that the initial wave of antenatal steroids enthusiasm has settled, some voices of caution have surfaced. As articulated by a few authors,4,5 the risk of neonatal hypoglycemia and later effects on insulin response should be considered, and by preventing mild RDS, antenatal steroids actually might cause preterm infants to be discharged before other insidious problems could surface. Also, although some studies have suggested no obvious neurological sequelae,6 the possible effect on the fetal hippocampus7 cannot be ignored.

There is ample evidence to indicate the benefit of antenatal steroids in pregnancies about to deliver prior to 35 weeks, and in late preterm births (34 to 37 weeks), antenatal steroids appear to afford some protection against RDS in those patients having cesarean delivery.8 However, in the remainder of late preterm births, the small benefit could be outweighed by the potential long-term risks, especially in those patients at the upper end (35/1 to 36/6) of that window. Also, since the above study on very preterm birth showed a 24% reduction in mortality after only three hours post first injection and maximum (50%) benefit after about 12 hours, one injection easily could be enough in late preterm patients.

In most patients in preterm labor, there has been a tendency to delay delivery to attain the maximum benefit of antenatal steroids (thought to be about 48 hours). This new information will allow us more flexibility in making management decisions in these patients.

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;50:515-525.
  2. Gyamfi-Bannerman C, et al; NICHD Maternal–Fetal Medicine Units Network. Antenatal betamethasone for women at risk for late preterm delivery. N Engl J Med 2016;374:1311-1320.
  3. American College of Obstetricians and Gynecologists’ Committee on Obstetrics Practice; Society for Maternal–Fetal Medicine. Committee Opinion No. 677: Antenatal corticosteroid therapy for fetal maturation. Obstet Gynecol 2016;128:e187-e194.
  4. Kamath-Rayne BD, et al. Antenatal corticosteroids beyond 34 weeks gestation: What do we do now? Am J Obstet Gynecol 2016;215:423-430.
  5. Vidaeff AC, et al. Antenatal corticosteroids: A time for more careful scrutiny of the indications? BJ0G 2016;123:1067-1069.
  6. Dalziel SR, et al. Antenatal exposure to betamethasone: Psychological functioning and health-related quality of life 31 years after inclusion and randomised controlled trial. BMJ 2005;331:665.
  7. Velisek L. Prenatal corticosteroid impact on the hippocampus: Implications for postnatal outcomes. Epilepsy Behav 2006;7:57-67.
  8. Stutchfield P, et al; Antenatal Steroids for Term Elective Caesarean Section (ASTECS) Research Team. Antenatal betamethasone and incidence of neonatal respiratory distress syndrome after elective caesarean section: A pragmatic randomised trial. BMJ 2005;331:662.