Advances in Obstetrics and Gynecology Shalini Rajaram, Neerja Goel, Surveen Ghumman, KC Singh
INDEX
×
Chapter Notes

Save Clear

Current Concepts in Antenatal CorticosteroidsCHAPTER 1

P Arya,
TN Leung
Preterm birth remains the most important cause of perinatal mortality and morbidity in modern obstetrics. The more preterm the baby at birth, the greater are the risks, especially when delivery occurs before 32 to 34 weeks of gestation.1 One established obstetric intervention for improving neonatal outcome in women at high risk of preterm delivery is the antenatal administration of corticosteroids.2–4 Transplacental passage of corticosteroids induces alveolar surfactant secretion and enhances response to postnatal surfactant treatment, which ultimately results in improvement in lung compliance and respiratory function.5 However, there are still several incompletely addressed issues, which include the choice of corticosteroids, its use in preterm pre-labor rupture of membranes and multiple pregnancies, the appropriateness of repeated courses, and the effectiveness of combined use of antenatal corticosteroids and thyrotrophin-releasing hormone. The aims of this review are to provide an update of the benefits and safety of administration of antenatal corticosteroids as well as to address the less well-defined issues concerning its use. Much emphasis would be given on the discussion regarding pros and cons of repeated courses of antenatal corticosteroids.
 
 
Single Course of Antenatal Corticosteroids
 
Benefits and Safety
The beneficial effect of antenatal corticosteroids in human was first reported in a randomized-controlled trial by Liggins and Howie in 1972, which showed a significant reduction in the incidence of respiratory distress syndrome (RDS) and intraventricular hemorrhage (IVH) in preterm babies following one course of antenatal betamethasone.6 The recent Cochrane meta-analysis published in the year 2004 further 2confirmed that babies delivered after a single course of antenatal corticosteroids had a significant reduction in the incidence of RDS (odds ratio OR 0.53; 95% confidence interval CI 0.44–0.63), IVH (OR 0.29; 95% CI 0.14–0.61), and neonatal mortality (OR 0.60; 95% CI 0.48–0.75).7 Its use was also associated with a lower requirement for postnatal surfactant (OR 0.41; 95% CI 0.18–0.89)8 and a lower cost of neonatal care.9 The effect of treatment is optimal if the baby is delivered more than 24 hours and less than 7 days after the first dose.7 The number required to treat to prevent one case of RDS was estimated to be 13 (95% CI 10–18).10
Side effects due to a single course of corticosteroids are rare.7 There was no increased risk of either maternal or fetal infection. Long-term follow-up studies also did not demonstrate any adverse effect up to 22 years’ age.11, 12 There was no difference in growth and neurological or cognitive development of the survivors between the corticosteroids and placebo groups.11, 12
 
Gestation of Its Use
The initial study by Liggins and Howie which included subjects between 24 and 36 week of gestation for treatment showed that the effect of antenatal corticosteroids was more apparent below 32 weeks of gestation.6 From Crowley's meta-analysis, a significant reduction in RDS was shown in preterm babies born before 34 weeks of gestation (OR 0.36;95% CI 0.27–0.48).7 A trend towards benefit was noted for those born after 34 weeks but this did not reach statistical significance (OR 0.65; 95% CI 0.33–1.29).
As the incidence of RDS decreases with gestational age, it is not surprising that the beneficial effects of antenatal corticosteroids have become less apparent after 34 weeks of gestation. Indeed, based on 4 trials that presented results by each of the gestational age strata, the number required to prevent one case of RDS was 4, 15 and 145 at <31 weeks, 31 to 34 weeks, and > 34 weeks respectively.10 The benefits for its use after 34 weeks, if any, might be balanced out by any potential side effects. Thus, most international authorities, including the National Institutes of Health of the United States of America, the American College of Obstetricians and Gynecologists and the Royal College of Obstetricians and Gynaecologists recommended its use in pregnant women at risk of preterm delivery before 34 weeks.2–4 However, in countries where neonatal intensive care facilities are less developed or surfactant therapy is less readily available, it is reasonable to consider antenatal corticosteroids even between 34 and 36 weeks of gestation.
 
Choice of Corticosteroids
Both betamethasone and dexamethasone are recommended. The regimens are either two doses of betamethasone 12 mg intramuscularly 324 hours apart or four doses of dexamethasone 6 mg intramuscularly 12 hours apart.3, 13 Compared with placebo, both regimens are associated with a similar reduction in incidence of RDS.7
It has been shown that administration of betamethasone was associated with a significant reduction in fetal movement and fetal heart-rate variability and the use of betamethasone may interfere with the CTG interpretation.14 Another retrospective analysis showed that the antenatal administration of betamethasone to women between 24–31 weeks was associated with reduced incidence of periventricular leukomalacia.15 Dexamethasone, however, was associated with a higher risk of periventricular leukomalacia, compared with no treatment, but this has not reached statistical significance (adjusted OR 1.5; 95% CI 0.8–2.9).15 It is uncertain whether these different outcomes are related to the corticosteroids themselves or the preservatives used in the commercially available preparations.15 Periventricular leukomalacia is a major risk factor for cerebral palsy and mental retardation. It is because of these findings that the Royal College of Obstetricians and Gynae-cologists now recommends betamethasone to be the steroid of choice.4 However, there are several limitations of the paper by Baud et al.15 First, it was an uncontrolled retrospective review. The betamethasone, dexamethasone, and the no-treatment groups all had different neonatal characteristics. Second, the data was obtained in three centers in France and one center had a particular low incidence of use of dexamethasone. It was in this center that an unusually high incidence of periventricular leukomalacia in the dexamethasone group was found. All these might present biases and confounding factors for the results. While it seems reasonable to use betamethasone as the first choice as it is the most extensively studied one in the clinical trials, there is lack of good evidence to condemn dexamethasone as an alternative.
 
Preterm Prelabor Rupture of Membranes
A debate exists whether antenatal corticosteroids is beneficial in the presence of preterm prelabor rupture of membranes (PPROM).16 More recent data from a meta-analysis of 15 controlled trials has demonstrated significant reduction in RDS, IVH and necrotizing enterocolitis by a single course of antenatal corticosteroids in women who had rupture of membranes at trial entry.17 This effect was consistent regardless of whether rupture of membranes was before trial entry or before labor (PPROM). The benefits were non-significant for rupture of membranes > 48 hours but only 2 trials were eligible for inclusion for this analysis and it is uncertain whether the lack of significant effect was related to the small sample size. Chorioamnionitis is always a concern following rupture of membranes. However, there was no increase in risk of both 4maternal and neonatal infection with the use of steroids in the presence of rupture of membranes. Therefore, it appears that rupture of membranes poses no contraindication for the use of antenatal corticosteroids.
 
Multiple Pregnancies
It is controversial whether the benefits of antenatal corticosteroids seen in singleton pregnancy can be extrapolated to multiple pregnancies. The recent meta-analysis showed a trend towards reduction in RDS but this did not reach statistical significance (OR 0.72; 95% CI 0.31–1.68).7 This might be related to the small sample size because only 2 trials with total of 140 babies were eligible for the analysis. As preterm twins or triplets are far less common compared to singletons, randomized placebo-controlled trial of adequate size is difficult to run. Until further evidence is available, it is the opinion of the authors that multiple pregnancies should be treated in the same way of singleton pregnancies for the potential benefit of antenatal corticosteroids.
 
Repeated Courses of Corticosteroids
While the value of a single course of antenatal corticosteroids is well established, much uncertainty exists whether repeated courses of corticosteroids should be administered to those mothers who remain at risk for preterm delivery more than 7 days after the initial course.2, 18, 19 Since the meta-analysis failed to demonstrate a significant reduction in incidence of RDS after 7 days it was concluded that maximum neonatal benefits of corticosteroids appear to wane after that period.7, 20 Therefore, it evolved a practice of prescribing repeated courses to high-risk women on a weekly basis until 34 weeks of gestation. Indeed, previous surveys in Australia and U.K. showed that this was a common practice among many obstetricians.21, 22
 
Animal Studies
Data from animal models have suggested dose dependent improvement in lung function with repeated courses of antenatal corticosteroids.23 However, this benefit was at the expense of fetal growth.23–25 Three courses of antenatal steroids given one week apart has been shown to reduce birth weight in sheep by 20 to 25 percent.26 Other concerns raised from animal studies regarding repeated courses include delayed myelination in ovine brain27 and delayed retinal maturation in lambs.28 The meta-analysis of 19 randomized controlled trials in animals demonstrated beneficial effects in terms of lung function with repeated courses of antenatal corticosteroids but that also posed adverse effects on brain function and fetal growth.295
 
Case-controlled or Cohort Studies
Data of repeated courses of antenatal corticosteroids on human are less clear-cut. To date, only one large randomized control trial was published.30 Results from other retrospective case controlled or prospective cohort studies were conflicting.31 Two studies demonstrated an association of reduced incidence of RDS with repeated courses of antenatal corticosteroids.32, 33 However, in a post-hoc analysis of 710 neonates delivered at 25 to 32 weeks of gestation, those who received ≥ 3 courses of antenatal corticosteroids was shown to have a significantly higher incidence of ‘early severe lung disease’ (10.6% versus 3.5%) and neonatal mortality (9.2% versus 4.8%), compared with those who received 1 to 2 courses.34 Association between repeated courses of antenatal corticosteroids and adverse neonatal outcomes, including early-onset neonatal sepsis, chorioamnionitis, endometritis, and neonatal death has also been reported by others.35, 36
Maternal and neonatal morbidity after repeated courses of antenatal corticosteroids are also major concern. Repeated courses of corti-costeroids were shown to result in more significant suppression of the maternal hypothalamic-pituitary-adrenal (HPA) axis compared with a single course.37, 38 Whether this suppression is of clinical significance remains to be determined, as Addisonian crisis was not observed among the studied subjects. A significant reduction in head circumference and birthweight ratio, defined as the ratio of the baby's birth weight to the median birth weight for that specified gestational age, have been reported in neonates exposed to repeated courses of antenatal corticosteroids.39, 40 In one long-term follow-up study on 541 very preterm infants up to 6 years of age, increasing number of courses of antenatal corticosteroids were associated with a reduction in the rate of cerebral palsy but exposure to ≥ 3 courses was also associated with an increased risk of aggressive and hyperkinetic behavior.41 Another study assessed the psychological development at 21.5 months of 429 very low birth weight infants.42 When statistically adjusted for the gestational age and antenatal risk factors, the use of multiple courses of antenatal corticosteroids was independently associated with a delay in psychomotor development compared with those exposed to a single course or no treatment.42 These findings suggest that accumulated doses may have adverse influence on the developing brain.
The main limitation of these non-randomized studies was the potential selection bias. Women who received repeated courses of antenatal corticosteroids were likely to have different clinical characteristics and pathologies from those who received a single course. The single-course group was more likely to consist of subjects with 6preterm rupture of membranes and preterm labour whereas the multiple-course group was more likely to involve pregnancies with multiple gestations, pre-eclampsia and intrauterine growth restriction. Those in the multiple-course group would tend to present earlier and the early insults might predispose to undesirable neonatal outcomes.
 
Randomized-controlled Trials
Only 4 randomized placebo-controlled trials have so far been reported in the English literature, comparing the efficacy of single versus repeated courses of antenatal corticosteroids.30, 43–45 The first one was reported by Guinn et al in 2001.30 Five hundred and two pregnant women at high risk of preterm delivery were recruited between 24 and 32 weeks of gestation. Participants who did not deliver one week after the initial course treatment were randomly assigned to receive either weekly corticosteroids or placebo. The primary outcome measure was the composite neonatal morbidity, which was defined as the presence of one of the following complications, including severe RDS, chronic lung disease, severe IVH, periventricular leukomalacia, proven sepsis, necrotizing entercolitis, or perinatal death. The result showed that the use of repeated weekly courses was not associated with significant reduction in the incidence of composite neonatal morbidity (relative risk RR 0.80; 95% CI 0.59–1.10).30 However, repeated courses significantly reduced the rate of severe RDS (RR 0.63; 95% CI 0.44–0.91), although there was no concomitant improvement in neonatal survival, chronic lung disease or duration of hospitalization. Paradoxically, there was a trend towards an increased risk of severe IVH in the repeated-course group but this effect was not statistical significant.30 Repeated courses did not affect the incidences of puerperal sepsis or neonatal infection, birth weight, and head circumference.30
This trial30 was frequently quoted as evidence against the use of repeated courses of antenatal corticosteroids because it was the first and the largest randomized-controlled trial published so far. However, it is important to realise that it might still be underpowered to demonstrate any potential benefits46, 47 because only 52.3 and 47.1 percent of subjects in the treatment and placebo groups respectively delivered before 34 weeks of gestation. Those who delivered beyond 34 weeks, which constituted nearly 50 percent of subjects in each group, were less likely to benefit from the antenatal steroid therapy as the background risk of neonatal complications was low anyway. Hence, a much larger sample size would be required to demonstrate a significant effect. Indeed, the risk of composite neonatal morbidity was significantly reduced in the weekly course group among those who were delivered before 28 weeks (RR 0.80; 95% CI 0.65–0.98).307
One other published randomized-controlled trial was a pilot study with inclusion of only 12 subjects.43 The sample size is too small to draw any meaningful conclusion. The trial by McEvoy et al consisted of 37 subjects and it targeted at comparing the neonatal pulmonary mechanics between the multiple-course group and the single-course group who were delivered more than 7 days after steroids.45 No significant difference was found in both the neonatal functional residual capacity and respiratory compliance between groups.45 The most recently published trial by Lee et al44 was a secondary analysis of subjects with PPROM in the original cohort by Guinn et al.30 It was shown that while there was no significant difference in the composite morbidity between groups, chorioamnionitis was significantly more common (49.4% versus 31.7%) in the repeated-steroid group.44
Several other large randomized-controlled studies on the efficacy of single versus multiple courses of antenatal corticosteroids are known to be in progress and one such study aims to recruit 4000 subjects and this sample size will be big enough to assess the primary outcomes of the mortality rate in the first year of life and mental impairment at 2 years of age.47 Another one (ACTORDS) conducted in Australia and New Zealand have already finished recruitment at present. Hopefully, the effectiveness and risks of multiple courses of antenatal cortico-steroids could be adequately addressed by these much larger studies in the near future. Before the availability of conclusive evidence on its benefit, the routine use of repeated courses of antenatal corticosteroids should not be encouraged.
 
Role of Thyrotropin-releasing Hormone
Data from animal studies have demonstrated an increase in lung fluid phospholipids and lung distensibility when thyroid hormones were used in combination with corticosteroids.48 Thyroid hormones given to the mother antenatally do not reach the fetus due to metabolism by the placenta. However, by giving thyrotropin-releasing hormone (TRH) to the mother antenatally will result in elevation of thyroid stimulating hormone and thyroid hormones in the fetal circulation.49 This has generated an interest of prescribing antenatal TRH in combination with corticosteroids for women at high risk of preterm birth as it may further reduce the incidence of respiratory morbidity in premature infants. However, a recent systemic review involving 13 trials did not show a reduction in the incidence of RDS, chronic oxygen dependence or any of the neonatal or childhood outcomes with the addition of TRH to the antenatal corticosteroid treatment.50 Further, the use of antenatal TRH was associated with an increased risk of requiring mechanical 8ventilation (RR 1.16; 95% CI 1.03 to 1.29) and a low Apgar score at five minutes (RR 1.48; 95% CI 1.14 to 1.92). Maternal side-effects were more frequent in the TRH treated women, with an increased risk of nausea, vomiting, light headedness, urgency of micturition and facial flushing. There was also a significant increase in maternal blood pressure in women given antenatal TRH.50 The current evidence has convincingly disproved the value of antenatal TRH and its use for women at high risk of preterm birth is not recommended.
 
Conclusion
The discovery of the benefit of antenatal corticosteroids in preterm infants almost 30 years ago has been confirmed by various randomised controlled trials and meta-analysis. Its safety has also been well documented by long-term follow-up studies. It is now an established intervention for women at high risk of preterm birth below 34 weeks of gestation. Clinicians should be familiar with the recommended regimes. Preterm pre-labor rupture of membranes in the absence of chorio-amnionitis is not a contraindication for its use, and neither are multiple pregnancies. The issue of repeated courses of antenatal corticosteroids remains unresolved. It is uncertain whether the effects of repeated courses of antenatal corticosteroids seen in animal studies, namely lung maturation, growth inhibition and impairment with brain myelination, also holds true in human. However, before conclusive evidence on its benefit is available, repeated courses of antenatal corticosteroids should not be a routine practice. The controversy with antenatal TRH has been resolved by the recent meta-analysis and its use for prevention of neonatal morbidity from preterm birth is not supported.
References
  1. Kipikasa J, Bolognese RJ.Obstetric management of prematurity. In: Martin RJ, ed. Neonatal-Perinatal Medicine. Mosby,  St. Louis:  1997.
  1. National Institute of Health. Antenatal corticosteroids revisited: repeat courses. NIH Consens Statement 2000;17:1–18.
  1. American College of Obstetricians and Gynecologists. Committee opinion: antenatal corticosteroid therapy for fetal maturation. Obstet Gynecol 2002;99: 871–3.
  1. Royal College of Obstetricians and Gynaecologists. Antenatal corticosteroids to prevent respiratory distress syndrome. RCOG Guideline No 7 London, UK, 2004.
  1. Ballard PL, Ballard RA. Scientific basis and therapeutic regimens for use of antenatal glucocorticoids. Am J Obstet Gynecol 1995;173:254–62.
  1. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972;50:515–25. 9
  1. Crowley P. Prophylactic corticosteroids for preterm birth (Cochrane review). The Cochrane Library, Issue 3: Chichester, John Wiley and Sons, Ltd,  UK: 2004.
  1. Kari MA, Hallman M, Eronen M, et al. Prenatal dexamethasone in conjunction with rescue therapy of human surfactant—a randomized placebo controlled multicenter study. Pediatrics 1994;93:730–6.
  1. Morales WJ, Diebel ND, Lazar AJ, Zadrozny D. The effect of antenatal dexamethasone administration on the prevention of respiratory distress syndrome in preterm gestations with premature rupture of membranes. Am J Obstet Gynecol 1986;154:591–5.
  1. Sinclair JC. Meta-analysis of randomized controlled trials of antenatal corticosteroid for the prevention of respiratory distress syndrome: discussion. Am J Obstet Gynecol 1995;173:335–44.
  1. Smolders-de Haa. H, Neuvel J, Schmand B, Treffers PE, Koppe JG, Hoeks J. Physical development and medical history of children who were treated antenatally with corticosteroids to prevent respiratory distress syndrome: a 10- to 12-year follow-up. Pediatrics 1990;86:65–70.
  1. Dessens AB, Haas HS, Koppe JG. Twenty-year follow-up of antenatal corticosteroid treatment. Pediatrics 2000;105E77.
  1. National Institutes of Health. Effect of corticosteroids for fetal maturation on perinatal outcomes. NIH Consensus Development Panel on the Effect of Corticosteroids for Fetal Maturation on Perinatal Outcomes. Jama 1995;273: 413–8.
  1. Senat MV, Minoui S, Multon O, Fernandez H, Fryman R, Ville Y. Effect of dexamethasone and betamethasone on fetal heart rate variability in preterm labour: a randomised study. Br J Obstet Gynaecol 1998;105:749–55.
  1. Baud O, Foix-L’ Helias L, Kaminski M, et al. Antenatal glucocorticoids treatment and cystic perventricular leucomalacia in very premature infants. N Engl J Med 1999;341:1190–6.
  1. Imseis HM, Iams JD. Glucocorticoid use in patients with preterm premature rupture of the fetal membranes. Semin Perinatol 1996;20:439–50.
  1. Harding JE, Pang JM, Knight DB, Liggins GC. Do antenatal corticosteroids help in the setting of preterm rupture of membranes? Am J Obstet Gynecol 2001;184: 131–9.
  1. Spencer C, Neales K. Antenatal corticosteroids to prevent neonatal respiratory distress syndrome. We do not know whether repeated doses are better than a single dose. BMJ 2000;320:325–6.
  1. Smith GN, Kingdom JC, Penning DH, Matthews SG. Antenatal corticosteroids: is more better? Lancet 2000;355:251–2.
  1. McLaughlin KJ, Crowther CA, Walker N, Harding JE. Effects of a single course of corticosteroids given more than 7 days before birth: a systemic review. Aust N Z J Obstet Gynaecol 2003;43:101–6.
  1. Brocklehurst P, Gates S, McKenzie-McHarg K, Alfirevic Z, Chamberlain G. Are we prescribing multiple courses of antenatal corticosteroids? A survey of practice in the UK. Br J Obstet Gynaecol 1999;106:977–9.
  1. Quinlivan JA, Evans SF, Dunlop SA, Beazley LD, Newnham JP. Use of corticosteroids by Australian obstetricians—a survey of clinical practice. Aust N Z J Obstet Gynaecol 1998;38:1–7.
  1. Ikegami M, Jobe AH, Newnham J, Polk DH, Willet KE, Sly P. Repetitive prenatal glucocorticoids improve lung function and decrease growth in preterm lambs. Am J Respir Crit Care Med 1997;156:178–84. 10
  1. Jobe AH, Wada N, Berry LM, Ikegami M, Ervin MG. Single and repetitive maternal glucocorticoid exposures reduce fetal growth in sheep. Am J Obstet Gynecol 1998;178:880–5.
  1. Pratt L, Magness RR, Phernetton T, Hendricks SK, Abbott DH, Bird IM. Repeated use of betamethasone in rabbits: effects of treatment variation on adrenal suppression, pulmonary maturation, and pregnancy outcome. Am J Obstet Gynecol 1999;180:995–1005.
  1. Matthews SG. Antenatal glucocorticoids and programming of the developing CNS. Pediatr Res 2000;47:291–300.
  1. Dunlop SA, Archer MA, Quinlivan JA, Beazley LD, Newnham JP. Repeated prenatal corticosteroids delay myelination in the ovine central nervous system. J Matern Fetal Med 1997;6:309–13.
  1. Quinlivan JA, Beazley LD, Evans SF, Newnham JP, Dunlop SA. Retinal maturation is delayed by repeated, but not single, maternal injections of betamethasone in sheep. Eye 2000;14 (Pt 1):93–8.
  1. Aghajafari F, Murphy K, Matthews S, Ohlsson A, Amankwah K, Hannah M. Repeated doses of antenatal corticosteroids in animals: a systematic review. Am J Obstet Gynecol 2002;186:843–9.
  1. Guinn DA, Atkinson MW, Sullivan L, et al. Single vs weekly courses of antenatal corticosteroids for women at risk of preterm delivery: A randomized controlled trial. Jama 2001;286:1581–7.
  1. Leung TN, Lam PM, Ng PC, Lau TK. Repeated courses of antenatal corticosteroids: Is it justified? Acta Obstet Gynecol Scand 2003;82:589–96.
  1. Abbasi S, Hirsch D, Davis J, et al. Effect of single versus multiple courses of antenatal corticosteroids on maternal and neonatal outcome. Am J Obstet Gynecol 2000;182:1243–9.
  1. Elimian A, Verma U, Visintainer P, Tejani N. Effectiveness of multidose antenatal steroids. Obstet Gynecol 2000;95:34–6.
  1. Banks BA, Macones G, Cnaan A, Merrill JD, Ballard PL, Ballard RA. Multiple courses of antenatal corticosteroids are associated with early severe lung disease in preterm neonates. J Perinatol 2002;22:101–7.
  1. Jazayeri A, Gavrila D, Sincich T. Repeated antenatal corticosteroid treatments. Do they reduce neonatal morbidity? J Reprod Med 2001;46:788–90.
  1. Vermillion ST, Soper DE, Newman RB. Neonatal sepsis and death after multiple courses of antenatal betamethasone therapy. Am J Obstet Gynecol 2000;183: 810–4.
  1. McKenna DS, Wittber GM, Nagaraja HN, Samuels P. The effects of repeat doses of antenatal corticosteroids on maternal adrenal function. Am J Obstet Gynecol 2000;183:669–73.
  1. Helal KJ, Gordon MC, Lightner CR, Barth WH, Jr. Adrenal suppression induced by betamethasone in women at risk for premature delivery. Obstet Gynecol 2000;96:287–90.
  1. French NP, Hagan R, Evans SF, Godfrey M, Newnham JP. Repeated antenatal corticosteroids: size at birth and subsequent development. Am J Obstet Gynecol 1999;180:114–21.
  1. Lam PM, Yuen PM, Lau TK, Leung TN. Relationship between birthweight and repeated courses of antenatal corticosteroids. Aust N Z J Obstet Gynaecol 2001;41:281–4.
  1. French NP, Hagan R, Evan SF, Mullan A, Newnham JP. Repeated antenatal corticosteroids: effects on cerebral palsy and childhood behavior. Am J Obstet Gynecol 2004;190:588–95. 11
  1. Esplin E, Fausett MB, Smith S, et al. Multiple courses of antenatal steroids are associated with a delay in long-term psychomotor development in children with birth weights <= 1500 grams. Am J Obstet Gynecol 2000;182S24.
  1. Aghajafari F, Murphy K, Ohlsson A, Amankwah K, Matthews S, Hannah M. Multiple versus single courses of antenatal corticosteroids for preterm birth: a pilot study. JOGC 2002;24:321–9.
  1. Lee M, Davies J, Guinn D, et al. Single versus weekly courses of antenatal corticosteroids in preterm premature rupture of membranes. Obstet Gynecol 2004;103:274–81.
  1. McEvoy C, Bowling S, Williamson K, et al. The effect of a single remote course versus weekly courses of antenatal corticosteroids on functional residual capacity in preterm infants: a randomized trial. Pediatrics 2002;110:280–4.
  1. Jenkins TM, Wapner RJ, Thom EA, Das AF, Spong CY. Are weekly courses of antenatal steroids beneficial or dangerous? Jama 2002;287187–8; discussion 189–90.
  1. Murphy KE, Hannah M, Brocklehurst P. Are weekly courses of antenatal steroids beneficial or dangerous? Jama 2002;287 188; discussion 189–90.
  1. Schellenberg JC, Liggins GC, Manzai M, Kitterman JA, Lee CC. Synergistic hormonal effects on lung maturation in fetal sheep. J Appl Physiol 1988;65: 94–100.
  1. Roti E, Gnudi A, Braverman L, et al. Human cord blood concentrations of thyrotropin, thyroglobulin, and iodothyronines after maternal administration of thyrotropin-releasing hormone. J Clin Endocrinol Metab 1981;53:813–7.
  1. Crowther CA, Alfirevic Z, Haslam PR. Thyrotrophin-releasing hormone added to corticosteroids for women at risk of preterm birth for preventing neonatal respiratory disease (Cochrane review). The Cochrane Library, Issue 4: Chicester, John Wiley and Sons, Ltd,  UK: 2004.