Equitable Design

Background

Preterm birth has been attributed to 28% of neonatal deaths worldwide. Antenatal corticosteroids (ACS) administered to women with high risk of pre-term birth has been known to reduce neonatal mortality in high-resource settings. However, ACS are not routinely used in low-resource settings.

The "Antenatal Corticosteroids Trial" was initiated to address this problem. The trial was an 18-month two-arm parallel cluster randomized trial designed to assess the feasibility, effectiveness, and safety of an intervention package versus a control group to increase the use of ACS in low- and middle-income countries (LMICs). The study which was funded by the National institute of Child Health and Human Development (NICHD) under the National Institutes of Health (NIH), USA and was conducted at seven study sites - one site each in Argentina, Zambia, Guatemala, Pakistan, Kenya, and two sites in India.

The details of the trial, methods and results have been described elsewhere. Briefly, the intervention arm included health-provider training to identify women who are at risk of preterm birth and provision of a kit to facilitate appropriate use of antenatal corticosteroids. The control arm was standard care in those communities. In both study arms, health providers were trained in the basics of care for low birth weight babies.

To reduce bias, the primary outcome data which was 28-day neonatal mortality among infants less than the 5th percentile for birthweight, were collected independently by the maternal and newborn health (MNH) registry staff. Secondary outcomes were the level of use of antenatal corticosteroids and suspected maternal infection. The MNH routinely collects data consists of outcome data for all pregnant women residing within the study clusters.

The intervention showed an increase of ACS use to 45% in women delivering infants less than the 5th percentile for birthweight, compared with about 10% in women in the control group. The intervention resulted in an increase in neonatal deaths (3.5 per 1000 livebirths) and an increase in perinatal deaths (5.1 per 1000 births) in the population. In addition, the intervention was also associated with a 3.6% absolute increase in suspected infection among mothers of less-than-5th -percentile infants and a significant 0.8% increase among all women.

Analyses showed that ACS contributed to the overall increase in neonatal deaths. One explanation was that the screening approach used to determine risk of preterm birth was not very specific. That could have led to potentially harmful use of ACS for infants not delivered preterm. However, researchers could not make a definitive statement about the impact of the intervention on stillbirth rates in smaller and earlier gestational age fetuses due to the poor gestational age dating available to those participating in the trial.

In summary, the Antenatal Corticosteroids Trial presented negative results. The intervention employed in the trial did not reduce neonatal mortality in less-than- 5th-percentile infants. In addition, the intervention increased deaths in the overall population and increased the risk of maternal infectious deaths.

Selected ethical concerns and suggestions for ways forward

Since Antenatal Corticosteroids Trial presented negative results, a keen interest was generated among the different funding agencies and researchers. The NIH policy expects researchers of primary study who are funded by the NIH to share their individual level de-identified data through the NIH data sharing repositories that make the data accessible for reuse around the world.

Researchers encountered the following ethical issues related to data sharing after the completion of the trial:

1. The Antenatal Corticosteroids Trial was completed in March 2014. According to the NIH data sharing policy, researchers need to share the trial data after the primary publication for further secondary analyses. In this case, it was difficult to abide by this policy since the outcomes of the Antenatal Corticosteroids Trial were captured in the MNH registry which remains an ongoing study. The MNH registry started in 2008 by NICHD Global Network and since then it has been continued as a population based registry to document maternal and newborn mortality as well as their trends over time. Should data be available for only completed studies or even ongoing studies as well?

After discussion among the primary researchers and the funding agencies, it was decided that the researchers would release the raw data of MNH study (which captures the outcomes of Antenatal Corticosteroids Trial) for the completed period from 2010 to 2013 in NICHD Data and Specimen Hub (NDASH). Since the MNH registry is an ongoing study, the decision of releasing the data of further years will be taken by the primary researchers after periodically conducting the primary trend analysis.

2. Concern was raised on the consent taken which was only for the primary analysis. Since the primary researchers did not plan for sharing of data for secondary analyses during the protocol development, there was no mention in the consent form for secondary analyses of the data. There was no consensus on whether a reconsent was needed during secondary analyses.

3. The primary researchers also had apprehension on the wrong interpretation of the data from the researchers during any secondary analyses. The primary researchers decided that they should be involved in the designing of future secondary analyses to prevent any misinterpretation of the data.