useful for pediatric and obstetrics

1. ANTENATAL STEROIDS
Dr. Satish D

2. INTRODUCTION:
• Liggins and Howie - single course of antenatal corticosteroid
therapy administered to women at risk for preterm delivery
(PTD) reduced the incidence and severity of respiratory
distress syndrome (RDS) and mortality in offspring
• Antenatal corticosteroid therapy improves circulatory stability
in preterm neonates, resulting in less IVH or NEC
• NIH ,ACOG, RCP - recommended ACS treatment for women
at risk - 34 weeks of gestation to reduce the morbidity and
mortality associated with preterm birth.

3. MECHANISM OF ACTION :
•Architectural and biochemical changes that improve both lung
mechanics and gas exchange.
•Accelerated morphologic development of type 1 and type 2
pneumocytes
•Type 1 pneumocytes - gas exchange in the alveoli
•Type 2 pneumocytes - production and secretion of surfactant

4. EVIDENCE OF SHORT-TERM CLINICAL EFFICACY:
Reduction of RDS
•Study by Liggins and Howie
•Preterm delivery < 37 weeks GA - randomly received
betamethasone.
•Lower incidence of RDS (9.0 versus 25.8 percent in controls).
•The maximum benefit - subgroup of infants delivered > 48 hours
but < 7 days after maternal treatment
•Incidence of RDS: 3.6 versus 33.3 percent in controls
•Given between 26 and 32 weeks of gestation incidence of RDS:
11.8 versus 69.6 percent in controls

5. •Subsequent trials -
•Reduction in RDS (RR 0.66, 95% CI 0.59-0.73, 21 studies, 4038
infants)
•Reduction in moderate to severe RDS (RR 0.55, 95% CI
0.43-0.71, 6 studies, 1686 infants)
•Statistically significant benefit - one and seven days after the first
treatment dose (RR 0.46; 95% CI 0.35-0.60, 9 trials, 1110
infants),
•But not < 24 hours or > 7 days after the first dose.
•The benefits of corticosteroids did not appear to be affected by
fetal gender or race

6. Reduction of IVH, NEC, NNM, infection
• Intraventricular hemorrhage (IVH) (RR 0.54, 95% CI 0.43-0.69;
13 studies, 2872 infants)
• Necrotizing enterocolitis (NEC) (RR 0.46, 95% CI 0.29-0.74; 8
studies, 1675 infants)
• Neonatal mortality (NNM) (RR 0.69, 95% CI 0.58-0.81; 18
studies, 3956 infants)
• Systemic infection in the first 48 hours of life (RR 0.56, 95% CI
0.38-0.85; 5 studies, 1319 infants)

7. DRUG AND INITIAL DOSE:
• Betamethasone two doses of 12 mg given intramuscularly 24
hours apart.
• Dexamethasone four doses of 6 mg given intramuscularly 12
hours apart.
- Less extensively metabolized by the placental enzyme 11 beta-
hydroxysteroid dehydrogenase type 2 than other steroids.
- 75 to 80 % of available corticosteroid receptors are occupied.
- Provide near-maximal induction of corticosteroid receptor-
mediated response in fetal target tissues.

8. Betamethasone — 1ml suspension used in clinical practice is actually a
combination
3 mg of betamethasone sodium phosphate and 3 mg of betamethasone
acetate.
Betamethasone sodium phosphate is soluble so it is rapidly absorbed,
Betamethasone acetate is only slightly soluble - sustained activity.
It is only available for intramuscular injection.
The biological half-life is 35 to 54 hours.
The onset and duration of action is affected by the vascularity at the
injection site.
Drug concentrations in cord blood are approximately 20 percent of maternal
levels one hour following maternal injection
In India only betamethasone sodium phosphate is only available as 6 mg /
ml

9. Dexamethasone —
Dexamethasone sodium phosphate
- Rapid onset and relatively short duration of action.
- The dosing frequency of dexamethasone is shorter than that of
betamethasone .
- Well absorbed from the gastrointestinal tract, evidence of safety
and efficacy for fetal maturation has not been established.

10. Comparative studies:
- The effects of betamethasone and dexamethasone have mostly been
studied in comparison with various controls
- Betamethasone was associated with a greater reduction in the risk of
adverse outcome than dexamethasone
- Betacode trial found no significant differences between the drugs in the
rate of RDS, need for vasopressor therapy, NEC, ROP, PDA, neonatal sepsis,
or Neonatal mortality.
- Betamethasone had a significantly higher rate of IVH (17 percent [17/100]
versus 6 percent [6/105],RR 2.97, 95% CI 1.22-7.24)
- Brain lesions (18 percent [18/100] versus 7 percent [7/105], RR 2.7,
95%CI 1.18-6.19).
- Dexamethasone was neurotoxic and associated with a greater risk of
adverse neurologic outcomes compared to use of betamethasone or no
steroid treatment

11. Hydrocortisone:
- Extensively metabolized by placental enzymes - little crosses
into the fetal compartment
- Beneficial fetal effects may not occur.
- Betamethasone and Dexamethasone are unavailable due to drug
shortages, hydrocortisone 500 mg intravenously every 12 hours for
four doses has been proposed as a last resort.
- Received high dose hydrocortisone for treatment of a medical
disorder
- Standard course of betamethasone or dexamethasone - for fetal
lung maturation is recommended.

12. GESTATIONAL AGE AT ADMINISTRATION:
- ACS to pregnant woman at 23 to 34 weeks who are at increased
risk of preterm delivery within the next seven days.
- ACS < 26 weeks of gestation - 2011 prospective cohort study >
10,000 infants born at 22 to 25 weeks of gestation
• 23 weeks of gestation (83.4 versus 90.5 percent; AOR 0.58, 95%
CI 0.42-0.80)
• 24 weeks of gestation (68.4 versus 80.3 percent; AOR 0.62, 95%
CI 0.49-0.78)
• 25 weeks of gestation (52.7 versus 67.9 percent; AOR 0.61, 95%
CI 0.50-0.74)
• But not at 22 weeks of gestation (90.2 versus 93.1; AOR 0.80,
95% CI 0.29-2.21)

13. After 34 weeks:
- 34 weeks of gestation is unclear since the baseline risks of RDS,
IVH, and neonatal mortality is low at that time.
- ASTECS (Antenatal Steroids for Term Caesarean Section) trial -
48 hours before planned cesarean delivery at ≥37 weeks of
gestation.
- The overall incidence of respiratory problems TTN and RDS was
lower in neonates who were treated antenatally (2.4 versus 5.1
percent; RR 0.46, 95% CI 0.23-0.93).
- ASTECS trial - 8 to 15 years after delivery reported antenatal
betamethasone administered at 37 to 38 weeks - no any adverse
outcomes

14. Potential fetal side effects:
- Associated with transient FHR and behavioral changes that typically
return to baseline by four to seven days after treatment.
Potential long-term side effects:
Infants:
Neonatal sepsis, SGA infant, HPA suppression, or air leak syndrome
Children and adults — Follow-up studies at ages 3 to 6, 12, 22, and
30 years
Term-born children at 6 to 11 years of age
Auckland Steroid Trial
British cohort

15. Maternal side effects:
Did not increase the risk of maternal death, chorioamnionitis, or
puerperal sepsis
Low mineralocorticoid activity- hypertension is not a
contraindication to therapy
Transient hyperglycemia
Total leukocyte count increases by about 30 percent within 24 hours
after betamethasone injection, and the lymphocyte count
significantly decreases

16. USE OF REPEATED COURSES OF THERAPY:
Risk of preterm birth ≥7 days after an initial course of therapy
For the neonate
• Reduced risk of RDS (RR 0.83, 95% CI 0.75-0.91, 8 trials, 3206 infants,
numbers needed to treat [NNT] 17, 95% CI 11-32)
• Reduced risk of composite serious infant outcomes (RR 0.84, 95% CI
0.75-0.94, 7 trials, 5094 infants, NNT 30, 95% CI 19-79)
Maternal Fetal Medicine Units network trial, 63 percent of patients received 4
or more courses of therapy.
This trial - small for gestational age (SGA) fetuses below the 10th percentile
and below the 5th percentile was significantly higher compared to the single
course group
- Increased incidence of cerebral palsy
- Decrease in fetal growth

17. Salvage (rescue) therapy:
Significant reduction in RDS (41.4 percent [67/162] with
betamethasone versus 61.6 percent [101/164] with placebo; OR 0.45,
95% CI 0.27-0.75).
• Clinically estimated to be at high risk of delivery within the next
seven days
• Initial course of antenatal corticosteroids at <28 weeks of gestation
• Prior exposure to antenatal corticosteroids at least two weeks
earlier

18. ALTERNATIVE DOSING REGIMENS:
Higher dose:
- No strong evidence - safety and efficacy of increasing the steroid dose,
accelerating the dosing interval, or using an intravenous or oral route of
administration.
- supraphysiological doses of glucocorticoids are known to induce suppression of
glucocorticoid receptor levels by a process known as homologous down-regulation.
Shorter dosing interval:
In a non-inferiority trial - efficacy of using a shorter dosing interval
- RDS with a 12-hour dosing interval was not statistically inferior to that with a
24-hour dosing interval RDS incidence 61/167 [36.5 percent] versus 28/75 [37.3
percent]

19. Intravenous administration:
Oral administration of dexamethasone:
- Significantly higher rates of IVH and sepsis

20. Preterm premature rupture of membranes:
- NIH consensus panel - the infection risk
- Pregnancies complicated by PPROM at less than 30 to 32 weeks of
gestation
- No clinical evidence of chorioamnionitis
Multiple gestation:
- NIH consensus statement - standard dosing schedule for both
singleton and multiple gestations

21. Hypertension:
Betamethasone has low mineralocorticoid activity
Diabetes:
- Hyperglycemia