OPtimal TIming of antenatal COrticosteroid administration in pregnancies complicated by early-onset fetal growth REstriction: results of a large, multicenter cohort study (the OPTICORE study)

Background: Early-onset fetal growth restriction as consequence of placental insufficiency frequently requires iatrogenic, preterm birth. Administration of antenatal corticosteroids reduces risks of neonatal morbidity and mortality following preterm birth and is most beneficial if the neonate is delivered within two weeks following treatment. International guidelines on fetal growth restriction pregnancies do not provide directives regarding the timing of antenatal corticosteroids, resulting in practice variation.

Objective: (s): This study compared the two main timing strategies of antenatal corticosteroids administration in the Netherlands for early-onset fetal growth restriction pregnancies: administration when the umbilical artery shows a pulsatility index above the 95^th centile with (A) positive end-diastolic flow versus (B) absent or reversed end-diastolic velocity.

Study design: A multicenter, retrospective cohort study was performed in six tertiary hospitals in the Netherlands between 2012-2021. Three hospitals practiced timing strategy A and three strategy B. The primary outcome was defined as a composite of perinatal and in-hospital mortality. Secondary outcomes were in line with the core outcome set for fetal growth restriction (COSGROVE). Mixed effects analyses were performed adjusted for birthweight z-score and gestational age at birth to compare the two timing strategies.

Results: A total of 1,453 patients were included, of whom 871 and 582 were treated according to timing strategy A and B, respectively. Corticosteroids were administered at a mean gestational age of 28 weeks and 3 days (standard deviation 16.0 days) in timing strategy A and 28 weeks and 4 days (standard deviation 15.8 days) in timing strategy B. The median birthweights were 1050 (range 795, 1350) and 1060 (range 801, 1339) in timing strategy A and B, respectively. Although not statistically significant, rates of perinatal and in-hospital mortality were increased in timing strategy B infants (7.2% versus 9.8%; adjusted odds ratio 1.47; 95% confidence interval 0.97-2.22, reference A). 52.8% and 53.6% of patients in strategy A and B, respectively, delivered within the corticosteroids therapeutic window of 2 to 14 days (P-value 0.663), with a median time between corticosteroid administration and delivery of 6 days for strategy A and 6 days for strategy B. Timing strategy B was associated with more necrotizing enterocolitis (3.7% versus 7.6%; adjusted odds ratio 2.18; 95% confidence interval 1.29-3.69), but less respiratory distress syndrome (39.6% versus 34.5%; adjusted odds ratio 0.63; 95% confidence interval 0.45-0.88) and bronchopulmonary dysplasia (18.9% versus 17.4%; adjusted odds ratio 0.69; 95% confidence interval 0.50-0.96). Other outcomes were similar between groups.

Conclusion: Timing strategy B seemed to be associated with higher rates of the composite of perinatal and in-hospital mortality, which could not be explained by a difference in time intervals between corticosteroid administration and delivery. Importantly, most pregnant women delivered outside the presumed therapeutic corticosteroid window. Future research should focus on the improvement of the timing of antenatal corticosteroids in pregnancies complicated by early-onset fetal growth restriction and the identification of other differences in ante- and/or postnatal management to explain differences in outcomes, given the high risk for neonatal morbidity and mortality in this setting.