Effect of steroid in expecting mothers delivering prematurely on the blood glucose levels of the newborn baby-A study from a developing country

Completed

• Conditions: Newborn affected by other maternalmedication,

• Registration Number: CTRI/2021/05/033444
• Lead Sponsor: Institute of Post Graduate Medical Education and Research Department of Neonatology

Brief Summary

**Background and Rationale**

Antenatal steroid has become the standard of care both in developed anddeveloping countries as a tool to improve the outcome of preterm newborns.World Health Organization (WHO) has recommended antenatal steroid in women atrisk 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 birthbetween 34 -36 6/7 weeks in developed countries as well2.However, the use of antenatal steroid for women at risk of late pretermdelivery is still not universal in low to middle income countries. The concernarises because of the lack of evidence on long term neurodevelopmental outcomeon steroid exposed late preterm infants1. Moreover, severalrandomized controlled trials and cohort studies have shown the risk of neonatalhypoglycemia in steroid exposed late preterm infants 2,3. However,most of these studies are from high resource settings with only a few focusingon late preterm infants from low resource settings, like India. Mothers andinfants of developing countries are quite different from that of a developedcountry with higher rate of maternal infection, suboptimal antenatal care, andmore intrauterine growth restrictions. In addition, the percentage of eligiblemothers receiving complete course of antenatal steroid is also poor in low tomiddle income countries, mostly because of the late presentation at thehospital and poor referral system. So, the inference drawn on the neonatalpopulations of a developed country might not be applicable to the developingcountries. In view of the above, WHO and Government of India still recommendagainst the use of antenatal steroid beyond 34 weeks gestation 1,4.Whereas, American College of Obstetricians and Gynaecolgists (ACOG) and Societyfor Maternal-Fetal Medicine (SMFM) recommend that clinicians can considerantenatal steroid in women at risk of delivery between 34- 36 6/7weeks 5,6.

The major concern for antenatal steroid use in women at risk of latepreterm delivery has been the increased risk of neonatal hypoglycemia and itsimpact 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 befollowed 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 ofchoice, whereas in India dexamethasone is recommended because of wideravailability, low cost and better temperature stability 4. With thisinformation in background, we would like to conduct a prospective cohort study inthe setting of a developing country to determine the incidence and severity ofhypoglycemia in late preterm infants exposed to antenatal dexamethasonecompared to those who do not.

**Review of Literature**:

In the landmark ALPS trial in 2016, Gyamfi- Bannerman .et aldemonstrated lower incidence of severe respiratory complications, surfactantuse, transient tachypnea of the newborn (TTNB) and bronchopulmonary dysplasia(BPD) in late preterm infants exposed to betamethasone. However, neonatalhypoglycemia was more frequent in the steroid group (24% vs 15%, Relativerisk1.60,95% CI 1.37-1.87) 2. Although there was no data regardingthe trend of blood glucose level over time, there was no reported adverseevents related to hypoglycemia. The authors concluded that the event was self –limiting and  recommended to monitor theblood glucose levels of late preterm infants. This study was followed byseveral cohort studies to explore the association between neonatal hypoglycemiaand antenatal steroid.  Kristina E et alin a prospective cohort study from USA concluded that the risk of neonatalhypoglycemia was twofold higher with late preterm steroids (24.2% vs12.5%,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 cohortstudy from the USA, K .R. Uquillas et al. found that late preterm infants bornto women given steroid were 2.25 times more likely to develophypoglycemia(47.3% vs 29.3% , adjusted OR-2.25, p-0.01) and  4.71 times more likely to be admitted to NICUsolely for hypoglycemia 3. However, there is lack of evidence regardingthe effect of antenatal steroid in late preterm infants from resource limitedsetting. Antenatal corticosteroid trial (ACT) conducted in six low to middleincome (LMIC) countries showed the unusual findings of increased perinatalmortality in the intervention group along with increased maternal infection 9.This population based study from LMIC clearly showed that the result of a studyfrom a developed country can’t be generalized to the population of a developingcountry. Currently WHO ACTION II trial is recruiting women at risk of latepreterm delivery in low resource countries to compare the effect ofdexamethasone to placebo on neonatal mortality, stillbirth, severe respiratorydistress, neonatal morbidities (including hypoglycemia) and maternal bacterialinfection. However, the result of ACTION I trial showed a lack of effect on theoverall 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 inpreterm newborns of 26 weeks – 33 6/7 weeks gestation 10.Only one randomized controlled trial from India in 2018 neither shown anybenefit regarding respiratory morbidity nor any harm with respect tohypoglycemia in late preterm infants exposed to dexamethasone 11.Physiologically, there are two major mechanisms implicated in neonatalhypoglycemia due to antenatal steroid exposure. The first one is steroidinduced maternal hyperglycemia leading to fetal and neonatal hyperinsulinemia andhypoglycemia. The second mechanism is mediated by fetal adrenal suppression 12.However, none of them has been proved conclusively. Overall, although there isevidence of hypoglycemia in late preterm infants due to maternal steroidexposure, there is lack of studies from low resource settings.

**Research Question**:

Is the risk of neonatal hypoglycemia in the first 72 h of life ininfants increased due to exposure to antenatal dexamethasone compared to thosewho do not?

**Study Procedure**: Eligible women after admission will be approachedfor consent. Gestational age at enrollment will be ascertained from the firsttrimester dating scan which will be crosschecked with the gestational agecalculated from the date of last menstrual period given by the mother. If thediscrepancy is found to be more than ± 7 days, then the gestational agecalculated from the dating scan will be considered. Decision to administerantenatal steroid will be left to the concerned obstetricians. Accordingly themother will be placed either in the “exposed†or “unexposed†group. Use oftocolytics and antibiotics will also be left on the treating obstetricians. Afterdelivery the baby will be managed as per unit protocol. Baby will be kept with themother after birth unless there is any indication of admission in the neonatalunit. Babies admitted to the neonatal unit will be managed as per standardprotocol depending on the diagnosis. Every attempt will be made to startenteral feeding as soon as possible (within 1h of birth) unless there is anycontraindication, such as presence of shock, absent or reversed end diastolicflow in the umbilical artery doppler in babies of gestation < 35 weeks.Babies kept with mother will be encouraged to breast feed and babies admittedin the neonatal unit will be given either expressed breast milk or formuladepending on the availability. Those babies not tolerating full enteral feed orcontraindications to feed will be given intravenous dextrose to maintain normoglycemiaand hemodynamic stability. Feed volume will be gradually increased depending onthe 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 reagentstrips (glucose oxidase method).The glucometer will be calibrated frequently asper manufacturer’s instruction. Any value of < 40 mg/dL will be confirmed onwhole 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 tosuffer from neonatal hypoglycemia. However, treatment will be initiated dependingon the CBG value. Any baby with symptoms compatible with hypoglycemia (apnea,lethargy, jitterniess, seizure) will be checked for hypoglycemia apart fromroutine monitoring. Infants with symptomatic hypoglycemia will be started onglucose infusion, beginning at 6 mg/kg/min, progressively increasing to 12mg/kg/min, with the target glucose level of >50 mg/dL. Babies withasymptomatic hypoglycemia with glucose level of <20 mg/dL will be treatedsimilarly, whereas babies with glucose level between 20-40 mg/dL will be givenfirst 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, ifthe next blood glucose remain <40 mg/dL, the baby will be treated in the sameway as symptomatic hypoglycemia. In any case , CBG will be monitored every 6htill the resolution of hypoglycemia followed by less frequent monitoring( 8hourly to 12 hourly ) until the baby is taking full enteral feed andmaintaining CBG. Any CBG of <40 mg/dL will be confirmed with the whole bloodglucose value. One investigator from the Gynaecology & Obstetricsdepartment will be responsible for steroid administration and he/she will nottake any further part in data collection. Maternal and neonatal details and clinical outcomes will be assessed byseparate investigators unaware of the exposure status of the mother. Finallydata will be analyzed by a separate investigator who will also be unaware ofthe original group allocation.

**Confounding factors:** Known confounding variables, such as gestational age,birth weight, intrauterine growth restriction, diabetes in mother, intake ofdrugs which are known to affect neonatal blood glucose levels (e.g- Labetolol,Oral hypoglycemic agents in mother ), and maternal intrapartum glycemic status willbe 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 andpercentages. Relative risk (RR) of neonatal hypoglycemia will be calculatedbetween the exposed and unexposed group and adjusted for confounding variables.RR of other neonatal outcome will also be calculated .The Student’s t test willbe used for quantitative variables with a normal distribution and theMann-Whitney U test for variables with a skewed distribution. The Chi-squaretest 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 statisticalmeasures shall be estimated and a *p* valueof <0.05 will be considered significant.

Detailed Description

Not available

Study Timeline

• Study Completion: 2021-03-11
• Last Update Posted: 2021-03-12
• Study Start: 2021-05-15

Recruitment & Eligibility

• Status: Completed
• Sex: Female
• Target Recruitment: 276

Inclusion Criteria

• 1.Women with singleton pregnancy presenting between 34 weeks -36 6/7 weeks of gestation who are likely to deliver within next 7 days.
• Indicators of delivery within next 7 days are the presence of true labor pain, antepartum hemorrhage, preterm premature rupture of membrane, severe pre-eclampsia and evidence of fetal distress.
• 2.Women with singleton pregnancy admitted between 34 weeks -36 6/7 weeks of gestation for scheduled caesarian section.

Exclusion Criteria

• 1.Presence of clinical chorioamnionitis 2.
• Presence of multiple pregnancy 3.
• If the woman had already received antenatal steroid before study enrollment 4.
• Absence of the first trimester dating scan or unsure about the date of last menstrual period 5.Presence of major congenital anomaly, chromosomal anomaly or surgical conditions either diagnosed antenatally or detected postnatally 6.Family history or presence of congenital hyperinsulinism , metabolic disorder, or Beckwith -Wiedemann syndrome in the newborn.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
1. Neonatal hypoglycemia which will be defined as a whole blood glucose level of 40 mg/dL2. For screening purpose initial blood glucose will be measured from capillary blood with a point of care glucometer. Any CBG value 40 mg/dL will be confirmed by whole blood glucose value.	1.At 2 hours of life | 2.At 6 hours of life | 3.At 12 hours of life | 4.At 24 hours of life | 5.At 48 hours of life | 6.At 72 hours of life

Secondary Outcome Measures

Name	Time	Method
1.Symptomatic hypoglycaemia	2.Duration of hypoglycemia

Trial Locations

Locations (1)

Institute of Post Graduate Medical Education and Research, Kolkata; 🇮🇳 Kolkata, WEST BENGAL, India

Institute of Post Graduate Medical Education and Research, Kolkata

🇮🇳Kolkata, WEST BENGAL, India

Somnath Pal

Principal investigator

9903457386

somnathpal1983@gmail.com