The Antenatal Corticosteroids Trial (ACT)’s explanations for neonatal mortality - a secondary analysis

Fernando Althabe, Vanessa Thorsten, Karen Klein, Elizabeth M. McClure, Patricia L. Hibberd, Robert L. Goldenberg, Waldemar A. Carlo, Ana Garces, Archana Patel, Omrana Pasha, Elwyn Chomba, Nancy F. Krebs, Shivaprasad Goudar, Richard J. Derman, Fabian Esamai, Edward A. Liechty, Nellie I. Hansen, Sreelatha Meleth, Dennis D. Wallace, Marion Koso-Thomas, Alan H. Jobe, Pierre M. Buekens, José M. Belizán

The Antenatal Corticosteroid Trial assessed the feasibility, effectiveness, and safety of a multifaceted intervention to increase the use of antenatal corticosteroids (ACS) in mothers at risk of preterm birth at all levels of care in low and middle-income countries. The intervention effectively increased the use of ACS but was associated with an overall increase in neonatal deaths. We aimed to explore plausible pathways through which this intervention increased neonatal mortality. We conducted a series of secondary analyses to assess whether ACS or other components of the multifaceted intervention that might have affected the quality of care contributed to the increased mortality observed: 1) we compared the proportion of neonatal deaths receiving ACS between the intervention and control groups; 2) we compared the antenatal and delivery care process in all births between groups; 3) we compared the rates of possible severe bacterial infection between groups; and 4) we compared the frequency of factors related to ACS administration or maternal high risk conditions at administration between the babies who died and those who survived 28 days among all births in the intervention group identified as high risk for preterm birth and received ACS. The ACS exposure among the infants who died up to 28 days was 29 % in the intervention group compared to 6 % in controls. No substantial differences were observed in antenatal and delivery care process between groups. The risk of pSBI plus neonatal death was significantly increased in intervention clusters compared to controls (2.4 % vs. 2.0 %, adjusted RR 1.17, 95 % CI 1.04-1.30, p = 0.008], primarily for infants with birth weight at or above the 25(th) percentile. Regarding factors related to ACS administration, term infants who died were more likely to have mothers who received ACS within 7 days of delivery compared to those who survived 28 days (26.5 % vs 17.9 %, p = 0.014), and their mothers were more likely to have been identified as high risk for hypertension and less likely for signs of preterm labor. These results suggest that ACS more than other components of the intervention may have contributed to the overall increased neonatal mortality. ACS may have also been involved in the observed increased risk of neonatal infection and death. Further trials are urgently needed to clarify the effectiveness and safety of ACS on neonatal health in low resource settings.