Antenatal corticosteroid exposure : studies on neonatal and long term outcome

Background: Preterm delivery affects six to twelve per cent of all pregnant women each year. Treatment with antenatal corticosteroids (ACS) has contributed greatly to improve outcome after preterm birth. It is administered to women at risk for preterm delivery to reduce the risk of respiratory distress syndrome (RDS) and death of her preterm infant. The protective effect of ACS declines after 7-10 days. Considering that up to 50% of women remain undelivered 7-10 days after ACS administration, and in view of the neonatal benefits, repeat courses of ACS could be considered. However, unresolved concerns about safety still make such treatment regime controversial. Furthermore, it is not clear whether ACS is effective also in extremely preterm gestations. Objective: The overall objective with this thesis was to investigate the impact of repeat courses of ACS in exposed subjects, both on infant size at birth, and on longer term outcomes (study I-III). Another objective was to explore the association between timing of ACS administration and survival in extremely preterm infants (study IV). Methods: All studies in the thesis are cohort studies. In study I-III we used a cohort of about 100 children exposed to various courses of ACS in utero. We evaluated them regarding infant anthropometry at birth (study I), and risk factors for cardiovascular disease (study II) and neuropsychological function (study III) at follow up in adolescence/young adulthood. In study IV we evaluated a national population-based cohort of extremely preterm infants (EXPRESS – Extremely Preterm Infant in Sweden Study) regarding ACS administration-tobirth interval and survival. Results: We found a dose-dependent association between number of ACS-courses and restricted body size at birth (study I). There was no clear correlation between repeat courses of ACS in fetal life and cardiometabolic risk factors at 14-26 years of age (study II). In addition, there was no indication that repeat ACS exposure had an adverse impact on cognitive function or psychological health at follow-up in adolescents and young adults (study III). In study IV we found a significant reduction in mortality among extremely preterm infants after any ACS, with an optimal administration-to-birth interval of 1-7 days. Conclusions: Although exposure to repeat courses of ACS in utero were found to be related to gradually reduced body size at birth (indicating fetal growth restriction), it seems less likely from our findings that there are clinically important and long-standing adverse effects on cardiovascular and neuropsychological health. Another conclusion from this thesis is that ACS effectively reduces the mortality risk in extremely preterm infants and that timing of antenatal corticosteroids is important also in women delivering extremely preterm. LIST OF SCIENTIFIC PAPERS I. NORBERG H, Stålnacke J, Diaz Heijtz R, Smedler AC, Nyman M, Forssberg H, Norman M. Antenatal corticosteroids for preterm birth: dose-dependent reduction in birthweight, length and head circumference. Acta Paediatrica. 2011 Mar;100(3):364-9 II. NORBERG H, Stålnacke J, Nordenström A, Norman M. Repeat antenatal steroid exposure and later blood pressure, arterial stiffness, and metabolic profile. The Journal of Pediatrics. 2013 Sep;163(3):711-6. III. Stålnacke J, Diaz Heijtz R, NORBERG H, Norman M, Smedler AC, Forssberg H. Cognitive outcome in adolescents and young adults after repeat courses of antenatal corticosteroids. The Journal of Pediatrics. 2013 Aug;163(2):441-6. IV. NORBERG H, Kowalski J, Maršál K, Norman M. Timing of antenatal corticosteroid administration and survival in extremely preterm infants: a national population-based cohort study. BJOG: An International Journal of Obstetrics & Gynaecology. 2017 Mar 15. doi: 10.1111/1471-0528.14545. [Epub ahead of print]