Chemistry:Antenatal steroid

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Antenatal steroid
Other namesAntenatal corticosteroids
SpecialtyOB/GYN

Antenatal steroids, also known as antenatal corticosteroids, are medications administered to pregnant women expecting a preterm birth. When administered, these steroids accelerate the maturation of the fetus' lungs, which reduces the likelihood of infant respiratory distress syndrome and infant mortality.[1] The effectiveness of this corticosteroid treatment on humans was first demonstrated in 1972 by Sir Graham Liggins and Ross Howie, during a randomized control trial using betamethasone.[2]

Uses

Preterm birth

Antenatal steroids have been shown to reduce the occurrence and mortality of infant respiratory distress syndrome, a life-threatening condition caused by underdeveloped lungs.[3]

Current evidence suggests that giving antenatal corticosteroids reduces risk of late miscarriages and baby deaths. The baby is also less likely to develop respiratory distress syndrome or die during or after birth.[1] They are also less likely to have intraventricular hemorrhage (bleeding of the brain),[4][5] necrotizing enterocolitis (problems with the bowels), or systemic infections (infections affecting the whole body) in the first two days of life.[1]

Steroids do not appear to increase the number of women who develop infection of the fetal membranes (chorioamnionitis) or of the womb (endometritis).[1]

There is robust evidence that a single course of antenatal corticosteroids (i.e., 24 mg of betamethasone or dexamethasone), when there is a risk of preterm birth (at less than 34 weeks of gestation), reduces the risk of child death, regardless of resource level.[1][6]

Multiple gestation

Further research must be conducted to adequately determine outcomes of antenatal steroid administration for multiple pregnancies.[1] However, certain national clinical practice guidelines recommend the usage of steroids for preterm birth regardless of multiple gestation.[7]

Preterm premature rupture of membranes

Antenatal steroids have also been shown to have definite beneficial effect in treating the condition of preterm premature rupture of membranes (PPROM).[8] Similar to its effects on preterm birth, research evidence suggests that the administration of antenatal steroids to patients with PPROM reduces risks of neonatal mortality, intraventricular hemorrhage and respiratory distress syndrome.[9]

Adverse effects

Preliminary research has suggested that the use of antenatal corticosteroids may have adverse long-term effects.[10] In animals, antenatal corticosteroid use has been associated with adverse effects on the cardiometabolic system and inhibited growth of the brain, as well as worsened memory and learning difficulties.[10] While it is not yet certain if human fetuses would experience these same effects, some literature has found that human preterm fetuses treated with antenatal corticosteroids may be at greater risk of developing mental and behavioural disorders during childhood,[11] as these drugs are able to enter the fetus' brain and could affect neurodevelopment.[10] In both humans and animals, research has suggested that repeated doses of antenatal corticosteroids could lead to an increased risk of vision and hearing issues in the long-term.[12][13][14]

Contraindications

Contraindications to the administration of antenatal corticosteroids include:[15]

  • Systemic maternal infection
  • Maternal chorioamnionitis

Drugs

Corticosteroids encourage the development of the lungs in a premature fetus before birth,[16] and are administered when the premature fetus is expected to be delivered within 24 to 48 hours. The period of optimal benefit begins 24 hours after administration and lasts 7 days.[17][18] In some parts of the world, antenatal steroids are used at up to 36 weeks of pregnancy.[19] The time between administration of steroids and delivery may alter the effectiveness of the steroids.[20]

National Guidelines Published in English on Antenatal Steroid Administration for Preterm Birth
Country Organization (Year of Publication) Gestational Age Recommendations Other Inclusion Criteria Betamethasone or Dexamethasone
Australia & New Zealand Australian & New Zealand Neonatal Network (2018)[21] < 34 weeks and 6 days Preterm birth anticipated in 1 – 8 days Not specified
Antenatal Corticosteroids Clinical Practice Guidelines

Panel (2015)[22]

≤ 34 weeks and 6 days Preterm birth anticipated in ≥7 days Either Betamethasone or Dexamethasone
Society of Obstetric Medicine of Australia and New Zealand (2014)[23] < 34 weeks - Not specified
Canada Society of Obstetricians & Gynaecologists of Canada (2018)[24] 24 – 34 weeks and 6 days Preterm birth anticipated in ≥7 days Either Betamethasone or Dexamethasone
United Kingdom Royal College of Obstetricians and Gynaecologists (2015)[25] 24 – 33 weeks and 6 days Anticipated preterm birth Not specified
United States of America The American College of Obstetricians and Gynecologists (2020)[7] 24 – 33 weeks and 6 days Preterm birth anticipated within 7 days Betamethasone
International World Health Organization (2015)[26] 24 – 34 weeks Gestational age can be accurately assessed, preterm birth anticipated within 7 days, lack of maternal infection Either Betamethasone or Dexamethasone

Choice of steroid

Common corticosteroids include dexamethasone and betamethasone. Dexamethasone is often recommend over the latter due to its increased efficacy and safety, wide availability, and low cost,[27] while betamethasone is better at preventing the softening of the brain in premature fetuses.[28] Both drugs share certain commonalities, including the ability to traverse the placenta, as well as a very similar molecular structure. In fact, the two steroids are identical save for a single additional methyl group on betamethasone.[29] Although betamethasone has an increased half-life, there is no significant evidence indicating that one might be better than the other.[7] Literature on the subject is limited and inconsistent.[7] A Cochrane review (2022) found that it was unclear if there were significant differences,[30] while other studies determined that betamethasone results in improved longer term outcomes.[31]

Mechanism of action

In order to generate improved respiratory outcomes, antenatal steroids act on cells called type II pneumocytes which are located within the alveoli of infant lungs.[32] Glucocorticoids both increase rates of cell maturation, as well as increase the production of mRNA coding for proteins required for the synthesis of surfactant.[32] Surfactant is a phospholipid-rich substance secreted by the lungs in order to increase elasticity and decrease surface tension, consequently generating more efficient rates of ventilation.[33] Additionally, surfactant lines the insides of alveoli in the lungs and as a result, prevents alveoli from collapsing during exhalation.[34] Since infants born preterm often have immature or incompletely developed lungs, the surfactant coating of the alveoli is similarly insufficient, resulting in poor respiratory outcomes or the development of respiratory distress syndrome.[35] The administration of antenatal corticosteroids increases production of surfactant (decreasing the need to use surfactant after birth), and therefore result in better health outcomes for preterm infants.[1]

History

In 1969, Graham Liggins, a medical research scientist, began investigating the effects of dexamethasone administration on the timing of labor in pregnant sheep.[36] Liggins conducted this experiment in the hopes of proving his hypothesis that the fetus, and not the mother, is responsible for inducing labour.[37] Liggins found that dexamethasone caused pregnant sheep to deliver their fetuses prematurely, however, despite the fact that the lamb fetus was extremely premature, it was delivered alive.[37]

With the help of his colleague, pediatrician Ross Howie, Liggins conducted a similar experiment with 282 human women, all of whom were projected to have a preterm delivery.[38] This preliminary trial showed that the administration of corticosteroids, specifically betamethasone, resulted in immediate improvements that were statistically significant, such as:[38]

  • Lowered neonatal mortality rate
  • Reduced incidence of respiratory distress syndrome, but only in fetuses who had
    1. Undergone less than 32 weeks of gestation, and;
    2. Were treated for a minimum 24 hours before they were delivered
  • Reduced incidence of intraventricular cerebral hemorrhage

These findings were first reported in the article A Controlled Trial of Antepartum Glucocorticoid Treatment for Prevention of the Respiratory Distress Syndrome in Premature Infants, published in the journal Pediatrics in 1972.[38] Liggins and Howie's research proved that antenatal corticosteroids were able to decrease respiratory complications and infant mortality by inducing cellular differentiation, and thus maturation, in the lungs.[37][38] However, these results were not incorporated into clinical practice in the United States until over two decades later.[37]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth". The Cochrane Database of Systematic Reviews 12 (2): CD004454. December 2020. December 25, 2020. doi:10.1002/14651858.CD004454.pub4. PMID 33368142. 
  2. ↑ "A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants". Pediatrics 50 (4): 515–525. October 1972. doi:10.1542/peds.50.4.515. PMID 4561295. 
  3. ↑ "Antenatal steroids in preterm labour for the prevention of neonatal deaths due to complications of preterm birth". International Journal of Epidemiology 39 (Supplement 1): i122–i133. April 2010. doi:10.1093/ije/dyq029. PMID 20348115. 
  4. ↑ "Antenatal corticosteroids prior to 24 weeks' gestation and neonatal outcome of extremely low birth weight infants". American Journal of Perinatology 27 (1): 61–66. January 2010. doi:10.1055/s-0029-1223269. PMID 19544249. 
  5. ↑ "Antenatal steroids, delivery mode, and intraventricular hemorrhage in preterm infants". American Journal of Obstetrics and Gynecology 172 (3): 795–800. March 1995. doi:10.1016/0002-9378(95)90001-2. PMID 7892866. 
  6. ↑ "Antenatal Dexamethasone for Early Preterm Birth in Low-Resource Countries". The New England Journal of Medicine 383 (26): 2514–2525. December 2020. doi:10.1056/NEJMoa2022398. PMID 33095526. 
  7. ↑ 7.0 7.1 7.2 7.3 "Antenatal Corticosteroid Therapy for Fetal Maturation" (in en). https://www.acog.org/en/Clinical/Clinical%20Guidance/Committee%20Opinion/Articles/2017/08/Antenatal%20Corticosteroid%20Therapy%20for%20Fetal%20Maturation. 
  8. ↑ "Antenatal corticosteroids after preterm premature rupture of membranes". Clinical Obstetrics and Gynecology 54 (2): 337–343. June 2011. doi:10.1097/GRF.0b013e318217d85b. PMID 21508704. 
  9. ↑ "Do antenatal corticosteroids help in the setting of preterm rupture of membranes?". American Journal of Obstetrics and Gynecology 184 (2): 131–139. January 2001. doi:10.1067/mob.2001.108331. PMID 11174492. 
  10. ↑ 10.0 10.1 10.2 "A Growing Dilemma: Antenatal Corticosteroids and Long-Term Consequences". American Journal of Perinatology 39 (6): s–0040–1718573. October 2020. doi:10.1055/s-0040-1718573. PMID 33053595. 
  11. ↑ "Evaluation of Long-term Outcomes Associated With Preterm Exposure to Antenatal Corticosteroids: A Systematic Review and Meta-analysis". JAMA Pediatrics 176 (6): e220483. April 2022. doi:10.1001/jamapediatrics.2022.0483. PMID 35404395. 
  12. ↑ "Retinal maturation is delayed by repeated, but not single, maternal injections of betamethasone in sheep". Eye 14 (1): 93–98. February 2000. doi:10.1038/eye.2000.20. PMID 10755109. 
  13. ↑ "Repeated antenatal corticosteroid treatments adversely affect neural transmission time and auditory thresholds in laboratory rats". Neurotoxicology and Teratology 34 (1): 196–205. 2012-01-01. doi:10.1016/j.ntt.2011.09.004. PMID 21963399. 
  14. ↑ "Association between gestational age at birth, antenatal corticosteroids, and outcomes at 5 years: multiple courses of antenatal corticosteroids for preterm birth study at 5 years of age (MACS-5)". BMC Pregnancy and Childbirth 14 (1): 272. August 2014. doi:10.1186/1471-2393-14-272. PMID 25123162. 
  15. ↑ "Guideline for the use of antenatal corticosteroids for fetal maturation". Journal of Perinatal Medicine 36 (3): 191–196. 2008-01-01. doi:10.1515/JPM.2008.032. PMID 18576926. 
  16. ↑ "Surfactant-replacement therapy for respiratory distress in the preterm and term neonate". Pediatrics 121 (2): 419–432. February 2008. doi:10.1542/peds.2007-3283. PMID 18245434. 
  17. ↑ Recommendations for Use of Antenatal Corticosteroids. http://www.perinatology.com/protocols/Steroids.htm. Retrieved 6 January 2014. 
  18. ↑ "Medscape Obstetrics". http://www.medscape.com/viewarticle/408941_9. (Subscription content?)
  19. ↑ "UK National Health Service". http://www.nelm.nhs.uk/en/NeLM-Area/News/2011---April/132/Antenatal-corticosteroids-at-34-36-weeks-gestation-do-not-appear-to-reduce-incidence-of-respiratory-disorders-in-late-preterm-infants. 
  20. ↑ "Decreased respiratory compliance in infants less than or equal to 32 weeks' gestation, delivered more than 7 days after antenatal steroid therapy". Pediatrics 121 (5): e1032–e1038. May 2008. doi:10.1542/peds.2007-2608. PMID 18450845. 
  21. ↑ Chow, SSW, Creighton, P, Chambers, GM, Lui, K. 2020. "Report of the Australian and New Zealand Neonatal Network" 2018. Sydney: ANZNN.
  22. ↑ "Antenatal corticosteroids given to women prior to birth to improve fetal, infant, child and adult health: Clinical Practice Guidelines" (PDF). Antenatal Corticosteroid Clinical Practice Guidelines Panel. 2015. Liggins Institute, The University of Auckland, Auckland. New Zealand.
  23. ↑ "Guideline for the Management of Hypertensive Disorders of Pregnancy" (PDF). Society of Obstetric Medicine of Australia and New Zealand. 2014.
  24. ↑ "No. 364-Antenatal Corticosteroid Therapy for Improving Neonatal Outcomes". Journal of Obstetrics and Gynaecology Canada 40 (9): 1219–1239. September 2018. doi:10.1016/j.jogc.2018.04.018. PMID 30268316. 
  25. ↑ "Preterm labour and birth" (PDF). National Institute for Health and Care Excellence. 2015.
  26. ↑ "WHO | WHO recommendations on interventions to improve preterm birth outcomes". http://www.who.int/reproductivehealth/publications/maternal_perinatal_health/preterm-birth-guideline/en/. 
  27. ↑ "Dexamethasone versus betamethasone as an antenatal corticosteroid (ACS)". UN Commission / Born Too Soon Care Antenatal Corticosteroids Working Group. August 20, 2013. http://www.healthynewbornnetwork.org/sites/default/files/resources/ACS%20Beta%20vs%20Dexa%20130820.pdf. Retrieved 6 January 2014. 
  28. ↑ "Antenatal Steroid Video". http://www.ovguide.com/antenatal-steroid-9202a8c04000641f8000000000862be6. 
  29. ↑ "Periventricular leukomalacia--prospects for prevention". The New England Journal of Medicine 341 (16): 1229–1231. October 1999. doi:10.1056/NEJM199910143411611. PMID 10519903. 
  30. ↑ Williams, Myfanwy J.; Ramson, Jenny A.; Brownfoot, Fiona C. (2022-08-09). "Different corticosteroids and regimens for accelerating fetal lung maturation for babies at risk of preterm birth". The Cochrane Database of Systematic Reviews 2022 (8): CD006764. doi:10.1002/14651858.CD006764.pub4. ISSN 1469-493X. PMID 35943347. 
  31. ↑ "Neurodevelopmental outcomes of extremely low birth weight infants exposed prenatally to dexamethasone versus betamethasone". Pediatrics 121 (2): 289–296. February 2008. doi:10.1542/peds.2007-1103. PMID 18245420. 
  32. ↑ 32.0 32.1 "Effects of antenatal and postnatal corticosteroids on the preterm lung". Archives of Disease in Childhood. Fetal and Neonatal Edition 77 (2): F147–F150. September 1997. doi:10.1136/fn.77.2.f147. PMID 9377142. 
  33. ↑ "Fetal lung development and the influence of glucocorticoids on pulmonary surfactant". Journal of Steroid Biochemistry 8 (5): 463–470. May 1977. doi:10.1016/0022-4731(77)90248-5. PMID 579641. 
  34. ↑ McMaster Children's Hospital (July 2018). "How surfactant helps your baby's lungs". https://www.hamiltonhealthsciences.ca/wp-content/uploads/2019/08/Surfactant-lw.pdf. 
  35. ↑ "Pulmonary surfactant in newborn infants and children" (in en). Breathe 9 (6): 476–488. 2013-12-01. doi:10.1183/20734735.006513. ISSN 1810-6838. https://breathe.ersjournals.com/content/9/6/476. 
  36. ↑ "Premature delivery of foetal lambs infused with glucocorticoids" (in en-US). The Journal of Endocrinology 45 (4): 515–523. December 1969. doi:10.1677/joe.0.0450515. PMID 5366112. 
  37. ↑ 37.0 37.1 37.2 37.3 "Beyond antenatal corticosteroids: what did mont liggins teach us?". Reviews in Obstetrics & Gynecology 3 (3): 79–80. 2010. PMID 21364857. 
  38. ↑ 38.0 38.1 38.2 38.3 "A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants". Pediatrics 50 (4): 515–525. October 1972. doi:10.1542/peds.50.4.515. PMID 4561295. 

Further reading



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