Association of Antenatal Steroid Exposure with Survival Among Infants Receiving Postnatal Life Support at 22 to 25 Weeks’ Gestation

MANUSCRIPT CITATION 

Ehret DEY, Edwards EM, Greenberg LT, Bernstein IM, Buzas JS, Soll RF, Horbar JD. Association of Antenatal Steroid Exposure with Survival Among Infants Receiving Postnatal Life Support at 22 to 25 Weeks’ Gestation. JAMA Netw Open. 2018;1(6): e183235. doi:10.1001/jamanetworkopen.2018.3235. PMID:30646235 

REVIEWED BY

Ankita Shukla, MD
Assistant Professor of Pediatrics
Arkansas Children’s Hospital
University of Arkansas for Medical Sciences

Vikas Chowdhary, MD
Assistant Professor of Pediatrics
Arkansas Children’s Hospital
University of Arkansas for Medical Sciences

TYPE OF INVESTIGATION

Prevention, Treatment

QUESTION

(P) For infants born at the edge of viability (22-25 weeks of gestation) who received postnatal life support, (I) was the administration of antenatal steroids (C) compared to no antenatal steroids, (O) associated with higher rates of survival (O) until discharge.

METHODS

  • Design: Observational, retrospective, multi-center.
  • Allocation: Inapplicable
  • Blinding:
  • Follow-up period: Infants were followed until death, transfer or hospital discharge. Those transferred between hospitals were tracked until discharge for survival status.
  • Setting: 431 Level III and IV NICUs that are a part of the Vermont Oxford Network
  • Patients: Infants born between 22 0/7 -25 6/7 weeks’ gestational age, without a minimum birth weight.
    • Inclusion Criteria:  22 0/7-25 6/7 weeks’ gestational age, without a minimum birth weight, including those that died in the delivery room.
    • Exclusion Criteria:
      • Infants with recognized syndromes or major congenital malformations
      • Infants with missing data
      • Infants with implausible birth weights, defined as greater than 4 SD above the mean by week and sex.
  • Intervention: To estimate the proportion of infants that received antenatal steroids (ANS) at any time prior to delivery
  • Outcomes:
    • Primary outcome:  Survival to Hospital Discharge
    • Secondary outcomes:  Major morbidities in survivors: chronic lung disease (oxygen use at 36 weeks PMA or at discharge for infants 34 to 35 weeks PMA), severe intraventricular hemorrhage(Grade 3 and 4), cystic periventricular leukomalacia, necrotizing enterocolitis, culture-confirmed infection, severe retinopathy of prematurity (Stages 3 to 5). Also, composite outcome of survival at discharge without major morbidities
  • Analysis and sample size: Calculation of the overall rates of postnatal life support, with or without exposure to ANS, by gestation at birth. Risk ratios were calculated for survival and all secondary outcomes, comparing infants that received ANS vs those that did not, amongst infants that received postnatal life support. Data were collected for a total of 34, 472 eligible infants, of which 3540 (10.5%) did not receive postnatal life support and died. Analysis was based on receipt of ANS and gestational age subgroups were analyzed for the primary and secondary outcomes.  Sensitivity analyses for potential unmeasured confounders were performed.
  • Patient follow-up:  Of the enrolled infants, 29,932 (that received postnatal life support) were analyzed for difference in outcome based on antenatal steroid exposure.

MAIN RESULTS 

Of the infants that received life support postnatally, 51.9% were male infants, with a mean gestational age of 24.12 (0.86 SD) and mean birth weight of 668 g (140 g SD).

26, 090 (87.2%) were exposed to postnatal life support and ANS, and 3842 (12.8%) only received postnatal life support and were not exposed to any ANS.

Postnatal life support offered to eligible infants also differed by gestational age at birth: 30.8% at 22 weeks, 87.1% at 23 weeks, 98.4% at 24 weeks, and 99.6% at 25 weeks. The same trend continued in terms of the proportion exposed to ANS: 52.4% at 22 weeks, 82.7% at 23 weeks, 89.3% at 24 weeks, and 90.8% at 25 weeks.

PRIMARY OUTCOME 

For the primary outcome, at 22-25 weeks GA, 51.9% infants with postnatal life support survived in comparison to 72.3 % with both postnatal life support and ANS (aRR, 1.37; 95% CI, 1.32-1.42).

Survival by Gestational ages:

GA Antenatal steroid exposure + Postnatal life support (%) Postnatal life support alone (%) Adjusted Risk ratios (aRR) 95% CI
22 38.5 17.7 2.11 1.68-2.65
23 55.4 35.6 1.54 1.40-1.70
24 71.3 59.6 1.18 1.12-1.25
25 83 75.7 1.11 1.07-1.14

SECONDARY OUTCOMES

Survival without major morbidities overall was also improved with administration of antenatal steroid at any time prior to delivery concurrently with life support vs no exposure [14.6% vs 9.1 %, aRR 1.67, 95 % CI 1.49-1.87]. Chronic lung disease was seen in 65% of surviving infants, and was unaffected by use of antenatal steroids. ANS exposure was however linked with improved survival without severe IVH (74% vs 86%; RR1.16, 95% CI 1.13-1.19) and periventricular leukomalacia (92% vs 95%; RR 1.03, 95% CI, 1.02-1.05).

Lowest gestational ages received the most benefit from ANS exposure, yet the rate of survival with major morbidities remained exceedingly high: 95.6% vs 99% at 22 weeks, 94.1% vs 97.2% at 23 weeks,88.6% vs 90.5% at 24 weeks and 77.8% vs 81.2% at 25 weeks

CONCLUSIONS

The authors conclude that the concordant receipt of ANS and postnatal life support was associated with significantly higher survival and survival without major morbidities at 22 through 25 weeks’ gestation compared with life support alone.  However, survival without major morbidity remained very low at 22 and 23 weeks.

COMMENTARY 

The definition for limits of viability has been steadily declining for the past decade with increased survival of infants born at lower gestational ages (1). ACOG and SMFM criteria for periviable birth includes infants delivered between 20 0/7 and 25 6/7 weeks of gestation. There are marked differences in reported survival from different centers and countries based on the perinatal care received, including counselling, antenatal steroids, magnesium sulfate use, approach to mode of delivery and resuscitation practices offered at delivery to lower gestational ages (2,3,4). Current ACOG guidelines recommend clinicians should evaluate aggressiveness of treatment provided to a 22-week gestation infant per family wishes but does not recommend antenatal steroid use (5). There is an urgent need for an accurate, objective and collaborative look at the short- and long-term outcomes of infants born at the edge of viability.

This article is a multicenter, observational cohort study evaluating the survival, and survival without major morbidities, in periviable infants that received postnatal life support with or without benefits of ANS exposure. Analysis was done for overall cohort as well as by gestational ages.

The study consistently showed that infants who received ANS prior to delivery at all gestational ages had higher survival and lower incidence of major morbidities among survivors. Although the difference in survival was most notable at the lowest gestational ages, the rate of survival without major morbidity remained extremely low. The study also reports that the percentage of infants offered postnatal life support was low for infants born at 22 weeks of gestation, possibly due to differential approaches among providers and lack of consensus.

A major strength of this study is its size, possible only with a major national database such as VON, lending strong credibility to the results. A major limitation of the study is its retrospective design, which prevents capture of certain variables. The authors also note that the decision-making burden which lies on the families during the perinatal period, as well as their possibly limited understanding of long-term outcomes, may lead to disparate care provided to some of these infants. Another potential bias could be that these data are collected from NICUs equipped to handle periviable births, which could lead to an overestimation of survival in infants that were outborn. Additionally, there are possible unmeasured confounders related to practices at larger centers with targeted treatment strategies for these particular GA’s leading to improved survival. This study does not look at long term neurodevelopmental outcomes or the economic burdens suffered by these families and by society, which is of paramount importance in such infants with very high risks of short and long-term consequences.

The study concludes that infants that receive ANS with postnatal life support have higher survival and a decrease in major morbidities.  However, survival without major morbidity remains low.  This study will add vital information to the standardization of the care of infants at the edge of viability.  Since clearly a randomized trial is unethical, large prospective cohort studies are needed to further guide practice.

REFERENCES

  1. Rysavy MA, Li L, Bell EF, Hintz S, Stoll B, Vohr BR et al for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Between-hospital variation in treatment and outcomes in extremely preterm infants. N Engl J Med 2015; 372: 1801-1811
  2. Raju TN, Mercer BM, Burchfield DJ, Joseph GF Jr. Periviable birth: executive summary of a joint workshop by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Academy of Pediatrics, and American College of Obstetricians and Gynecologists. Obstet Gynecol 2014; 123: 1083-1096
  3. Younge N., Goldstein RF, Bann CM, Hintz SR, Patel RM, Smith B et al: Survival and neurodevelopmental outcomes among periviable infants. N Eng J Med 2017; 376: 617-628
  4. Mori R, Kusuda S, Fujimura M, Neonatal Research Network Japan. Antenatal corticosteroids promote survival of extremely preterm infants born at 22 to 23 weeks of gestation. J Pediatr 2011; 159: 110-114
  5. El-Sayed YY, Borders A. ACOG Committee Opinion, Obstetrics and gynecology 2017; 130:e102-109

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