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Brief Summary
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Background and Rationale
Antenatal steroid has become the standard of care both in developed and
developing countries as a tool to improve the outcome of preterm newborns.
World Health Organization (WHO) has recommended antenatal steroid in women at
risk of preterm birth from 24 weeks to 34 weeks of gestation1.
Following the publication of Antenatal Late Preterm Steroid trial (ALPS)
antenatal steroid has found its application in women at risk of giving birth
between 34 -36 6/7 weeks in developed countries as well2.
However, the use of antenatal steroid for women at risk of late preterm
delivery is still not universal in low to middle income countries. The concern
arises because of the lack of evidence on long term neurodevelopmental outcome
on steroid exposed late preterm infants1. Moreover, several
randomized controlled trials and cohort studies have shown the risk of neonatal
hypoglycemia in steroid exposed late preterm infants 2,3. However,
most of these studies are from high resource settings with only a few focusing
on late preterm infants from low resource settings, like India. Mothers and
infants of developing countries are quite different from that of a developed
country with higher rate of maternal infection, suboptimal antenatal care, and
more intrauterine growth restrictions. In addition, the percentage of eligible
mothers receiving complete course of antenatal steroid is also poor in low to
middle income countries, mostly because of the late presentation at the
hospital and poor referral system. So, the inference drawn on the neonatal
populations of a developed country might not be applicable to the developing
countries. In view of the above, WHO and Government of India still recommend
against the use of antenatal steroid beyond 34 weeks gestation 1,4.
Whereas, American College of Obstetricians and Gynaecolgists (ACOG) and Society
for Maternal-Fetal Medicine (SMFM) recommend that clinicians can consider
antenatal steroid in women at risk of delivery between 34- 36 6/7
weeks 5,6.
The major concern for antenatal steroid use in women at risk of late
preterm delivery has been the increased risk of neonatal hypoglycemia and its
impact on neurodevelopmental outcome. Although American Academy of Pediatrics
(AAP) recommends routine monitoring of blood glucose in late preterm infants,
irrespective of the exposure to antenatal steroid, it is less likely to be
followed in a low resource setting due to lack of resources and manpower 7 .However,
no study from developing countries is yet to address this issue specifically.
Moreover, studies from developed countries use betamethasone as the steroid of
choice, whereas in India dexamethasone is recommended because of wider
availability, low cost and better temperature stability 4. With this
information in background, we would like to conduct a prospective cohort study in
the setting of a developing country to determine the incidence and severity of
hypoglycemia in late preterm infants exposed to antenatal dexamethasone
compared to those who do not.
Review of Literature:
In the landmark ALPS trial in 2016, Gyamfi- Bannerman .et al
demonstrated lower incidence of severe respiratory complications, surfactant
use, transient tachypnea of the newborn (TTNB) and bronchopulmonary dysplasia
(BPD) in late preterm infants exposed to betamethasone. However, neonatal
hypoglycemia was more frequent in the steroid group (24% vs 15%, Relative
risk1.60,95% CI 1.37-1.87) 2. Although there was no data regarding
the trend of blood glucose level over time, there was no reported adverse
events related to hypoglycemia. The authors concluded that the event was self –
limiting and recommended to monitor the
blood glucose levels of late preterm infants. This study was followed by
several cohort studies to explore the association between neonatal hypoglycemia
and antenatal steroid. Kristina E et al
in a prospective cohort study from USA concluded that the risk of neonatal
hypoglycemia was twofold higher with late preterm steroids (24.2% vs
12.5%,p-0.006) with a lower mean blood glucose level in the steroid group(
56.3± 27.3 vs 62±23.6,p-0.04) 8. In another retrospective cohort
study from the USA, K .R. Uquillas et al. found that late preterm infants born
to women given steroid were 2.25 times more likely to develop
hypoglycemia(47.3% vs 29.3% , adjusted OR-2.25, p-0.01) and 4.71 times more likely to be admitted to NICU
solely for hypoglycemia 3. However, there is lack of evidence regarding
the effect of antenatal steroid in late preterm infants from resource limited
setting. Antenatal corticosteroid trial (ACT) conducted in six low to middle
income (LMIC) countries showed the unusual findings of increased perinatal
mortality in the intervention group along with increased maternal infection 9.
This population based study from LMIC clearly showed that the result of a study
from a developed country can’t be generalized to the population of a developing
country. Currently WHO ACTION II trial is recruiting women at risk of late
preterm delivery in low resource countries to compare the effect of
dexamethasone to placebo on neonatal mortality, stillbirth, severe respiratory
distress, neonatal morbidities (including hypoglycemia) and maternal bacterial
infection. However, the result of ACTION I trial showed a lack of effect on the
overall incidence of hypoglycemia( 24.2% vs
27%, RR-0.91, 95% CI:0.80-1.04)and reduced risk of early hypoglycemia
(7.5% vs 10.3%,RR-0.73,95%CI:0.56-0.95) with the use of dexamethasone in
preterm newborns of 26 weeks – 33 6/7 weeks gestation 10.
Only one randomized controlled trial from India in 2018 neither shown any
benefit regarding respiratory morbidity nor any harm with respect to
hypoglycemia in late preterm infants exposed to dexamethasone 11.
Physiologically, there are two major mechanisms implicated in neonatal
hypoglycemia due to antenatal steroid exposure. The first one is steroid
induced maternal hyperglycemia leading to fetal and neonatal hyperinsulinemia and
hypoglycemia. The second mechanism is mediated by fetal adrenal suppression 12.
However, none of them has been proved conclusively. Overall, although there is
evidence of hypoglycemia in late preterm infants due to maternal steroid
exposure, there is lack of studies from low resource settings.
Research Question:
Is the risk of neonatal hypoglycemia in the first 72 h of life in
infants increased due to exposure to antenatal dexamethasone compared to those
who do not? Study Procedure: Eligible women after admission will be approached
for consent. Gestational age at enrollment will be ascertained from the first
trimester dating scan which will be crosschecked with the gestational age
calculated from the date of last menstrual period given by the mother. If the
discrepancy is found to be more than ± 7 days, then the gestational age
calculated from the dating scan will be considered. Decision to administer
antenatal steroid will be left to the concerned obstetricians. Accordingly the
mother will be placed either in the “exposed†or “unexposed†group. Use of
tocolytics and antibiotics will also be left on the treating obstetricians. After
delivery the baby will be managed as per unit protocol. Baby will be kept with the
mother after birth unless there is any indication of admission in the neonatal
unit. Babies admitted to the neonatal unit will be managed as per standard
protocol depending on the diagnosis. Every attempt will be made to start
enteral feeding as soon as possible (within 1h of birth) unless there is any
contraindication, such as presence of shock, absent or reversed end diastolic
flow in the umbilical artery doppler in babies of gestation < 35 weeks.
Babies kept with mother will be encouraged to breast feed and babies admitted
in the neonatal unit will be given either expressed breast milk or formula
depending on the availability. Those babies not tolerating full enteral feed or
contraindications to feed will be given intravenous dextrose to maintain normoglycemia
and hemodynamic stability. Feed volume will be gradually increased depending on
the feed tolerance and clinical condition of the baby. Capillary blood glucose
(CBG) of the late preterm infants will be monitored at predefined 2h, 6h ,12h,
24h ,48h and 72h of life routinely with a point of care glucometer and reagent
strips (glucose oxidase method).The glucometer will be calibrated frequently as
per manufacturer’s instruction. Any value of < 40 mg/dL will be confirmed on
whole blood by sending it immediately to the laboratory in an oxalate vial.
Babies with whole blood glucose level of <40 mg/dL will be considered to
suffer from neonatal hypoglycemia. However, treatment will be initiated depending
on the CBG value. Any baby with symptoms compatible with hypoglycemia (apnea,
lethargy, jitterniess, seizure) will be checked for hypoglycemia apart from
routine monitoring. Infants with symptomatic hypoglycemia will be started on
glucose infusion, beginning at 6 mg/kg/min, progressively increasing to 12
mg/kg/min, with the target glucose level of >50 mg/dL. Babies with
asymptomatic hypoglycemia with glucose level of <20 mg/dL will be treated
similarly, whereas babies with glucose level between 20-40 mg/dL will be given
first a trial of oral feed. If the next blood glucose after 1h remain above
>40 mg/dL baby will be observed with frequent oral feeds. Alternatively, if
the next blood glucose remain <40 mg/dL, the baby will be treated in the same
way as symptomatic hypoglycemia. In any case , CBG will be monitored every 6h
till the resolution of hypoglycemia followed by less frequent monitoring( 8
hourly to 12 hourly ) until the baby is taking full enteral feed and
maintaining CBG. Any CBG of <40 mg/dL will be confirmed with the whole blood
glucose value. One investigator from the Gynaecology & Obstetrics
department will be responsible for steroid administration and he/she will not
take any further part in data collection.
Maternal and neonatal details and clinical outcomes will be assessed by
separate investigators unaware of the exposure status of the mother. Finally
data will be analyzed by a separate investigator who will also be unaware of
the original group allocation.
Confounding factors: Known confounding variables, such as gestational age,
birth weight, intrauterine growth restriction, diabetes in mother, intake of
drugs which are known to affect neonatal blood glucose levels (e.g- Labetolol,
Oral hypoglycemic agents in mother ), and maternal intrapartum glycemic status will
be matched between the exposed and unexposed group and analyzed accordingly. Statistical analysis: Continuous variables will be displayed as mean
±standard deviation (SD) for normally distributed data and as median (range)
for skewed data. Categorical variables will be presented as frequencies and
percentages. Relative risk (RR) of neonatal hypoglycemia will be calculated
between the exposed and unexposed group and adjusted for confounding variables.
RR of other neonatal outcome will also be calculated .The Student’s t test will
be used for quantitative variables with a normal distribution and the
Mann-Whitney U test for variables with a skewed distribution. The Chi-square
test or Fisher’s Exact Test will be used for analyzing qualitative variables.
All study outcomes will be analyzed using SPSS (version 23; IBM corporation,
Armonk, NY, USA). The 95% confidence interval (CI) of salient statistical
measures shall be estimated and a p value
of <0.05 will be considered significant.
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