A multi-faceted intervention including antenatal corticosteroids to reduce neonatal mortality associated with preterm birth: a case study from the Guatemalan Western Highlands
© Garces et al. 2016
Received: 10 December 2015
Accepted: 5 May 2016
Published: 24 May 2016
The Global Network for Women’s and Children’s Health Research undertook a cluster-randomized trial to assess the impact of a multi-faceted intervention to identify women at high-risk of preterm birth at all levels of care, to administer corticosteroids to women and refer for facility delivery compared with standard care. Of the seven sites that participated in the ACT trial, only two sites had statistically significant reductions in the neonatal mortality among the target group of <5th percentile infants, and of the two, Guatemala’s improvement in neonatal mortality was by far the largest.
We used data available from the ACT trial as well as pretrial data in an attempt to understand why neonatal mortality may have decreased in the intervention clusters in <5th percentile infants in Chimaltenango, Guatemala. The intervention and control clusters were compared in regards to ACS use, the various types of medical care, outcomes in facility and community births and among births in various birth weight categories.
Neonatal mortality decreased to a greater extent in the intervention compared to the control clusters in the <5th percentile infants in Guatemala during the ACT Trial. ACS use for the <5th percentile infants in the intervention clusters was 49.1 % compared to 13.8 % in the control clusters. Many measures of the quality of obstetric and neonatal care improved to a greater extent in the intervention compared to the control clusters during the trial. Births in facilities and births weighing 1500 to 2500 g had the greatest reduction in neonatal mortality.
The combination of improved care and greater ACS use may potentially account for the observed difference in neonatal mortality between the intervention and control clusters.
In high-resource countries, antenatal corticosteroids (ACS) given to the mother in the week prior to a preterm birth <34 weeks is associated with a reduction in respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis and neonatal death [1–3]. Because few studies have evaluated the effectiveness of ACS in low-middle income countries (LMIC), from 2012 to 2014, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)’s Global Network for Women and Children’s Health Research conducted the Antenatal Corticosteroids Trial (ACT). This trial was carried out in Chimaltenango, Guatemala and 6 other sites in LMIC (Argentina, Kenya, Zambia, Pakistan and India [2 sites]). ACT was a cluster randomized trial which tested whether an intervention including birth attendant training and the provision of kits with ACS increased the use of ACS, and if use increased, whether the intervention was effective in reducing neonatal mortality and was safe . Overall, the intervention substantially increased the use of ACS in the intervention clusters, but was not effective in reducing neonatal mortality in the targeted infants and was associated with a small but significant increase in overall neonatal mortality. However, two of the 7 sites had lower neonatal mortality in the targeted less than 5th percentile infants in the intervention compared to the control clusters and of these two, the reduction in Guatemala was the greatest .
In Guatemala, the ACT study took place in the Chimaltenango region, an area in the Western highlands populated predominantly by indigenous peoples . In that region, the infant mortality is generally higher than in other areas of Guatemala and has been associated with a high percentage of home births cared for by traditional birth attendants (TBAs) [7, 8]. For home births, pregnant women at risk for preterm birth rarely receive ACS. While ACS use is recommended by the Guatemala Ministry of Health (MOH), there are no data on the rate of use within hospitals.
In recent years, the Chimaltenango district hospital (Hospital Nacional de Chimaltenango), which serves as a referral hospital, has undergone extensive improvements. As a national law to improve maternal and neonatal care was implemented, there was a concerted effort by the MOH to improve the quality of care in the community health services and at this district hospital. The hospital, which in 2010 had five obstetricians and five pediatricians, as of 2015 had 11 obstetricians and 11 pediatricians on staff. There are residency programs in both obstetrics and gynecology and pediatrics, with 12 residents in each program. There is a newborn care nursery with intensive care and a referral system with ambulances available for transport from other lower level health services in the district. In addition, substantial effort has been directed to ensure that TBAs identify and make early referrals of pregnancies and deliveries, when needed, and to improve the overall collaboration between community level and institutional health personnel .
Since 2010, in the Chimaltenango district, births inside a facility increased from one third to one half of the total and were accompanied by measurable improvements in the quality of care . With these changes, there have been substantial improvements in both the neonatal mortality and stillbirth rates in the Chimaltenango area. It is in this setting that the ACT study took place from September 2012 to March 2014. The goal of this case study was to explore the potential reasons for the lower rate of neonatal mortality in the <5th percentile infants in the intervention clusters compared to the control clusters in the Chimaltenango region of Guatemala during the ACT trial period.
The NICHD Global Network undertook a cluster-randomized trial to assess the impact of a multi-faceted intervention to identify women at high-risk of preterm birth at all levels of care, to administer corticosteroids to women and refer for facility delivery compared with standard care. The methods for the ACT trial are described in detail elsewhere [4, 5], but briefly, at each site, intervention and control study clusters were included as part of a prospective Maternal Newborn Health Registry, in which study staff sought to identify all pregnant women and enroll them early in pregnancy and follow them through delivery [13, 14]. Clusters were geographically defined and generally included 300–500 pregnant women who delivered each year. Following randomization, the trial staff aimed to train all birth attendants within the intervention clusters on identifying signs of preterm birth, determining which mothers were within the gestational age range to be eligible for ACS, and transferring these mothers to a hospital to receive ACS.
In Guatemala, the trial occurred in 10 clusters in the Chimaltenango Province, located 60 km from Guatemala City, the capital of Guatemala. The MOH is the most common provider of health care in the region and physicians and nurses provide care through a network of ten health centers and 35 health posts. There is one single referral hospital for the region. In this intervention, preterm birth was identified at the community level and/or inside health services and women were referred to the Chimaltenango hospital for delivery and care.
The outcome data were collected independently by trained Registry Administrators in a prospective Maternal and Newborn Health (MNH) registry [13, 14]. The primary outcome of the ACT trial was 28-day neonatal mortality among <5th percentile birth weight infants (proxy for preterm birth due to poor gestational age dating). The <5th percentile was based on the pre-trial rates and the site-specific cut-off for Guatemala was 2,267 g. ACS administration and suspected maternal infection were secondary outcomes of the ACT trial. To define maternal infection, we collected data on clinical symptoms and process measures for a composite outcome of suspected infection (but did not have confirmed maternal infection).
We also explored the relationship between ACT treatment group and measures of delivery care, facility characteristics, and neonatal infection. Facilities were characterized as having cesarean section capabilities if two or more women received a cesarean section at the facility during the ACT trial period. Similarly, facility neonatal care capabilities including bag and mask, and oxygen or mechanical ventilation were determined in the same manner. For newborn infection, we used the Word Health Organization (WHO) Young Infants Clinical Signs Study criteria [15, 16] to define possible severe bacterial infection (PSBI). PSBI was defined as an infant with any of the following: breathing difficulty, feeding problems (i.e., stopped suckling or feeding), high fever (>38 °C), hypothermia (<35 °C), convulsions, and bleeding or pus-like discharge from umbilicus. Finally, we calculated 28-neonatal mortality rates stratified by delivery location and birth weight category.
The ACT trial was powered to detect a 30 % reduction in 28-day neonatal mortality among <5th percentile birth weight infants but the trial was not designed to conduct country-specific analyses. A total of 10 defined geographic clusters in Guatemala were randomized within five randomization strata. Because one control cluster was dropped early in the trial due to security reasons which prevented study activities, we excluded both intervention and control data from that stratum. The trial period included births between September 2012 and March 2014 and used data for births occurring in 2010 as pretrial data.
Generalized linear models were used to evaluate the relationship between ACT treatment group and 28-day neonatal mortality and PSBI, and to develop point and interval estimates of relative risk (RR) associated with these risk factors. Additionally, we used a generalized linear model with an identity link to test whether the change in prevalence of specific prenatal and delivery characteristics from the pretrial to the trial periods differed by treatment group. For all models, generalized estimating equations were used to account for the correlation of outcomes within cluster to develop appropriate confidence intervals. Analyses were adjusted for randomization strata. Descriptive statistics (frequencies, percentages and rates per 1,000 live births) are provided for treatments, morbidities, and 28-day neonatal mortality. Analyses were performed by RTI International with SAS versions 9.3 and 9.4 (SAS Institute, Cary, NC, USA).
The trial was reviewed and approved by the ethics committees at each site, the World Health Organization and the NICHD. An independent data monitoring committee appointed by NICHD reviewed the progress of the trial, as specified in the protocol. All women provided informed consent prior to enrollment.
Relative risk and 95 % confidence intervals for neonatal mortality by site for <5th percentile births and all births
<5th %ile births RR (95 % CI)
All births RR (95 % CI)
1.43 (0.90, 2.28)
1.77 (1.42, 2.20)
1.30 (0.94, 1.81)
1.47 (1.02, 2.12)
0.96 (0.75, 1.22)
1.13 (0.99, 1.27)
0.94 (0.72, 1.23)
1.36 (1.09, 1.71)
0.89 (0.80, 0.99)
0.93 (0.82, 1.07)
1.60 (0.99, 2.58)
1.06 (0.54, 2.09)
0.74 (0.68, 0.81)
0.88 (0.73, 1.06)
Pretrial and trial data by group and period
Trial period, N (Rate/1000)
RR (95 % CI), p-value
<5th percentile live births (% of live births)
Neonatal death 28 daysa
0.88 (0.73, 1.06), p = 0.1875
0.74 (0.68, 0.81), p = <.0001
We also compared the <5th percentile neonatal mortality in the intervention and control clusters in the period before the trial to the results during the trial. In the control clusters the neonatal mortality in the <5th percentile infants increased from 219/1000 live births to 235/1000 live births, while in the intervention clusters the neonatal mortality in the <5th percentile infants fell from 286/1000 to 183/1000. Therefore, neonatal mortality in the <5th percentile infants decreased substantially from the pretrial period to the trial period in the intervention clusters, but actually increased slightly in the control clusters. And importantly, the significant difference in neonatal mortality in the <5th percentile infants between the intervention and control clusters during the trial was not due to a lower neonatal mortality in the intervention clusters prior to the trial.
The use of ACS in the intervention and control clusters in the overall population and in the <5th percentile births during the ACT trial was compared. In the intervention clusters, the overall use of ACS was 10.2 % compared to 1.0 % in the control clusters. For the <5th percentile infants, in the intervention clusters, 49.1 % received ACS compared to 13.8 % in the control clusters, nearly a four-fold increase (data not shown).
Maternal characteristics by intervention and control group
Maternal age, N (%)
Maternal education, N (%)
No formal education
Parity, N (%)
2 or more
Prenatal and delivery characteristics by group and period
Crude Estimate of Change in Prevalence as a Percentagea
Crude Estimate of Difference in Change in Prevalencea
Adjusted Estimate of Difference in Change in Prevalence (95 % CI), p-valueb
At least one antenatal care visit, (%)
−1.72 (−4.00, 0.55),
p = 0.1379
Prenatal vitamins/iron, (%)
6.46 (2.02, 10.89),
p = 0.0043
Birth attendant, (%)
7.56 (−3.09, 18.20),
p = 0.1643
Delivery mode, (%)
−2.21 (−8.17, 3.76),
p = 0.4689
BA used new gloves, (%)
−0.53 (−2.02, 0.97),
p = 0.4894
Delivery location characteristics by group and period
Pre trial period
Crude Estimate of Change in Prevalencea
Crude Estimate of Difference in Change in Prevalenceb
Adjusted Estimate of Difference in Change in Prevalence (95 % CI), p-valuec
Delivery location, (%)
Birth at facility level (hospital or clinic), (%)
7.70 (−2.61, 18.01), p = 0.1434
Birth at facility with C-section or any neonatal care capabilitiesd, (%)
7.36 (−3.39, 18.12), p = 0.1797
Birth at facility that has C-section capabilities, (%)
Birth at facility that has bag and mask capabilities, (%)
Birth at facility that has oxygen or mechanical ventilation capabilities, (%)
We also evaluated the capability of the facilities used for deliveries in the intervention and control clusters in the pretrial and trial periods (Table 5). Births in a facility of any kind increased substantially in both the intervention and control clusters, but to a greater extent in the intervention clusters (adjusted difference in change in prevalence of delivery in facility 7.70, 95 % CI −2.61, 18.01, p = 0.1434). When the capability of the facilities was evaluated, there were again substantial improvements from the pretrial to the trial period in births at facilities with cesarean section capabilities, bag and mask capabilities for neonatal resuscitation and oxygen. When the percent of births in facilities with any of those capabilities was evaluated, there was a substantial increase in these characteristics from the pretrial to the trial period, but the increases were greater in the intervention compared to the control clusters but the difference was not statistically significant (adjusted difference in change in prevalence 7.36, 95 % CI −3.39, 18.12, p = 0.1797).
Mortality rates by delivery location and period
Live births, N
Neonatal deaths <28d, N (Rate/1000) in home birth
Neonatal deaths <28d, N (Rate/1000) in facility (clinic or hospital)
Neonatal deaths <28d, N (Rate/1000) in facility with C-section or any neonatal care capabilitiesb
Mortality rates by birth weight in intervention and control clusters during the trial period among live births
Live births, N
Mortality for births <1000 g
Births <1000 g, N
Neonatal deaths, N
Neonatal mortality < 28 days, n (rate/1000)
Mortality for births 1000–1499 g
Births 1000–1499 g, N
Neonatal deaths, N
Neonatal mortality < 28 days, n (rate/1000)
Mortality rates for births 1500–2499 g
Births 1500–2499 g, N
Neonatal deaths, N
Neonatal mortality < 28 days, n (rate/1000)
Mortality rates for births ≥ 2500 g
Births ≥ 2500 g, N
Neonatal deaths, N
Neonatal mortality < 28 days, n (rate/1000)
Indicators of infection in the intervention and control clusters during the trial period
RR (95 % CI), p-valuea
Suspected maternal infection
<5th percentile N,(%)
Possible severe bacterial infection (pSBI)
1.13 (0.88–1.45), p = 0.3371
<5th percentile N,(%)
1.06 (0.82–1.36), p = 0.6530
First, we emphasize that because this is a secondary analysis from a single site of a multisite trial, the results are exploratory in nature. We are presenting these data as a case study, to explore factors related to the mothers, the infants and the quality of care, including the use of ACS. This analysis is an attempt to understand the outcomes in Chimaltenango, Guatemala, which showed benefit in the intervention clusters in the targeted <5th birth weight percentile, differing from the overall findings of the ACT trial. The intervention aimed at improving identification of women likely to deliver preterm within 7 days and in the appropriate gestational age range and to facilitate appropriate use of antenatal corticosteroids for those women. The results showed a significant reduction in neonatal mortality in the <5th percentile infants in the Guatemala site.
During the trial, in the intervention clusters, irrespective of where delivery occurred (facility or home), the neonatal mortality rates were lower than deliveries in control clusters. However, the largest differences were observed in facility births. The reduction in neonatal mortality in the intervention clusters occurred in babies over 1500 g and was greatest and significant in the < 5th percentile infants.
We explored various factors that could explain these differences. The difference in neonatal mortality between the intervention and control clusters was not explained by differences in neonatal mortality in the pretrial period. We found no large differences in the populations of the intervention and control clusters; the proportion of births below the 5th percentile and the characteristics of mothers were similar overall in both groups during the trial.
During the ACT trial, the quantity of prenatal care did not appear to be different between intervention and control clusters, although the use of vitamins was increased in the intervention clusters. However, care at delivery appeared better in intervention clusters including delivery at a hospital or clinic, delivery by a physician and use of cesarean section, although the differences were not different statistically. ACS use in the intervention clusters was significantly higher than in the control clusters, 49.1 % compared to 13.8 %. Evidence of maternal or neonatal infection did not appear to be different between the two groups.
In conclusion, whether the improvement in care in the intervention clusters compared to the control clusters was due to the multipronged ACT intervention during the ACT Trial or occurred independently is unknown. In addition, the care available to pregnant women and newborns in the Chimaltenango hospital appears to be at a higher level than that available in many of the other trial sites and in some respects approaches that seen in high-income countries where most trials of ACS have shown benefits. If the Guatemalan results did not occur by chance, we suspect that the combination of improved care and greater ACS use may account for the observed difference in the <5th percentile neonatal mortality between the intervention and control clusters.
This study was funded by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant number U01 HD058322, U01 HD040477, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01 HD058326, and U01 HD040636). Support was also provided by the World Health Organization. Supplies were donated by Becton Dickson.
AG, EMM and RLG wrote the first drafts of the manuscript. AG, SP and LF implemented the trial and monitored with FA, KMH, NFK, VRT and EMM. LF, SP, KMH, NFK, VRT, DDW and FA reviewed and edited the manuscript. VRT and DDW performed statistical analyses. All authors reviewed and approved the manuscript.
The authors declare that they have no competing interests.
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