preterm labour remaining pregnant 14 days later.100,101 This has raised the question whether or not to repeat the ACS course to women who remains undelivered 7 days after the initial course. In Danderyd hospital, Stockholm, Sweden, and many other settings, it was routine during the 1980´s and 90´s to repeat the ACS course weekly to undelivered women with threatening preterm delivery until delivery occurred or until pregnancy reached 34 weeks. In some settings a rescue course of ACS is used, meaning administering a second course to patients whose pregnancies continue more than a week or 2 beyond their original course and in whom delivery has again become likely. 102 Studies have shown that repeat courses of ACS add positive effects on neonatal outcome compared to a single course. The latest Cochrane review from 2015 found that repeat courses of ACS to pregnant women still undelivered 7 days after an initial course was associated with 17% reduction in RDS and 16% reduction in serious infant outcome and the absolute benefit of repeat doses was similar to that of an initial course (numbers needed to treat to prevent respiratory distress syndrome: single course 12; repeat courses 17).103 The suggested beneficial effects from repeat courses of ACS must however be put in relation to the concerns of potential negative effects from excess glucocorticoid exposure on fetal 19 growth and development, as well as long-term health. The rationale for these concerns mainly rises from results from experimental animal studies, showing that repeat courses of ACS could have negative effects on a variety of functions including fetal growth104, brain development81, behaviour105, vascular function106, fat/glucose metabolism107,108 and HPAfunction104. In human studies however, the effects from repeat courses of ACS appears to be less harmful: 1.2.5.1 Effects on fetal growth after repeat courses of ACS Some studies in humans have shown a reduction in fetal growth after repeat courses of ACS109-112 whereas others have not113,114. Reductions in both birth weight, birth length and head circumference at birth have been reported. However, the observed reductions in some measures of growth seems to be transient with the observed differences in birth size no longer significant at hospital discharge112 or at later follow-up of the child87,115. Furthermore, many of the studies where a difference in birth size has been observed have not adjusted for gestational age, making the results difficult to interpret.103 Several mechanisms have been suggested to contribute to the glucocorticoid-induced retardation of fetal growth. These include altered placental function and nutrient transfer,116 decreased DNA synthesis and cell division,117 reduced fetal tissue water content118 and increased protein catabolism.119 It is likely that altered expression and action of insulin-like growth factors (IGF) underlie many of these changes. 120 1.2.5.2 Long term outcome after repeat courses of ACS The largest randomized controlled studies investigating the effects of repeat courses of ACS have reported outcomes in early childhood (2-8 years) and the results are reassuring.87- 89,115,121,122 As shown in table 1, there is no increased risk for any of the reported outcomes following repeat courses of ACS. However, one large American RCT reported higher rates of CP in the repeat group (five of six cases), although not statistically significant (p=0.12).115 In addition, the Australasian RCT reported that more individuals in the repeat group were assessed for attention problems than in the single course group at the 2-year follow-up.87 At the follow-up at 6-8 years of age there were however no reported differences in neurodevelopmental outcome (table 1). 121 Follow-ups into adolescence and adulthood are however lacking and there is a concern that possible negative effects of excessive glucocorticoid exposure could be revealed later in life. The latest Cochrane review states that there is a need for follow-up studies into adulthood after repeat courses of ACS.12 20 Table 1. Outcomes after repeat courses of ACS reported in randomized controlled trials. Red text indicates adverse outcomes, arrows indicate direction of an effect after repeat ACS courses versus a single course. Author/group Neonatal outcome Outcome at follow-up Asztalos et al/ MACS (Multiple Courses of Antenatal Corticosteroids Study) • Mortality, severe RDS, IVH 3-4, PVL, BPD, NEC è • Birth weight, birth length, head circumference ê 2 years • Death, neurologic impairment è 5 years • Death, survival with neurodevelopmental disability è Crowther et al/ ACTORDS (The Australasian Collaborative Trial of Repeat Doses of Corticosteroids) • RDS, severe lung disease, oxygen therapy, mechanical ventilation ê • Birth weight, head circumference ê - no difference at discharge from hospital 2 years • Body size, blood pressure, respiratory morbidity, behavior score, survival free of major morbidity è • Assessed for attention problems é 6-8 years • Body size, fat mass, blood pressure, spirometry, insuline sensitivity, estimated GFR, neurodevelopment, cognitive function, behaviour, healthrelated quality of life, use of health services è Wapner et al • Surfactant administration, mechanical ventilation, CPAP ê (≥4 courses) • Birth weight ê (≥4 courses) • Small for gestational age é •