EBNEO Commentary: Management and outcomes of periviable neonates born at 22 weeks of gestation: a single-center experience in Japan

February 24, 2024

Manuscript citation

Motojima Y, Nishimura E, Kabe K, Namba F. Management and outcomes of periviable neonates born at 22 weeks of gestation: a single-center experience in Japan. J Perinatol 2023; 43(11):1385-1391. PMID: 37393397

Reviewed by

Reviewed by:
Vonita Chawla MD
Assistant Professor
Department of Pediatrics – Division of Neonatology
University of Arkansas for Medical Sciences / Arkansas Children’s Hospital

Corresponding author
Vonita Chawla MD
chawlavonita@uams.edu
Phone: 501-364-1028
Address: #1 Children’s Way, Slot 512-5, Little Rock, AR 72202, United States

Type of Investigation

Observational study

Question

In neonates born between gestational age (GA) of 22 weeks and 0 days and 22 weeks and 6 days, at a single tertiary center in Japan, between the years 2013 and 2020, what are the resuscitation methods, post-hospitalization management and outcomes including survival, morbidity, and neurodevelopmental impairment. This is not a comparative study.

Methods

      • Design

Single-center retrospective cohort study of neonates born between 22 weeks and 0 days and 22 weeks and 6 days GA from January 1, 2013, to December 31, 2020

      • Allocation

Not applicable as active resuscitation was provided to all live-born infants

      • Blinding

Not applicable for this retrospective, observational study

      • Follow-up period

–    For respiratory, circulatory and nutrition management, neuroprotective care, infection protection and control – from birth to post menstrual age (PMA) of 40 weeks

–    For neurodevelopmental outcomes – chronologic age of 1.5 years

      • Setting

Single tertiary neonatal intensive care unity (NICU) in Saitama, Japan

      • Patients
        • Inclusion criteria

All neonates born between 22 weeks and 0 days and 22 weeks and 6 days of gestation who were actively resuscitated and admitted to the NICU between January 1, 2013, to December 31, 2020

        • Exclusion criteria

Neonates with major congenital anomalies, including any central nervous system, cardiac, gastrointestinal, genitourinary, chromosomal, pulmonary, or vascular and lymphatic anomalies

      • Interventions/Exposure
        • Resuscitation (umbilical cord management, respiratory support), procedures (intubation, arterial and venous catheters), and drugs administered (surfactant, antibiotics, antifungals, sedatives, blood products, indomethacin and insulin) on admission to the NICU
        • During hospitalization – respiratory (respiratory support), circulatory (vasopressor/inotrope/steroid use, fluid intake, thermoregulation, neonatologist-performed echocardiograms) and nutrition management (feeding methods, volume of enteral feeds, use of glycerin enema), neuroprotective care (sedative agents, use of head ultrasonography), infection prevention and control (use of antimicrobials and probiotics)
      • Outcomes

Primary and secondary outcomes are not specified. Short- and long-term outcomes studied include:

Survival rate, Intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), placement of Ommaya reservoir, ventriculoperitoneal (VP) shunt, retinopathy of prematurity (ROP) treatment, patent ductus arteriosus (PDA) treatment, bronchopulmonary dysplasia (BPD), tracheostomy placement, home oxygen therapy, necrotizing enterocolitis (NEC)/focal intestinal perforation, need for peritoneal drainage or surgery, discharge weight, discharge head circumference, cerebral palsy (CP), developmental quotient (postural-motor, cognitive-adaptive, language-social, visual and hearing impairment) and neurodevelopmental impairment (NDI) at 1.5 years of age

      • Analysis and sample size

Statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan). Demographic, treatment, and outcome data were reported using medians and IQRs for continuous data, and frequencies and percentages for categorical data. A box-and-whisker plot was used to assess the distribution of continuous data, and a bar graph was used to represent categorical data.

A sample size of 29 infants was used.

      • Patient follow up

Follow up visit was completed at 1.5 years of age for 18 of 23 patients that survived.

Main results

    • A total of 29 neonates were included, no patient was excluded based on the exclusion criteria.
    • No infant death happened in the delivery room.
    • Demographic information of the study population is listed below in Table 1.

Table 1

Factors Number (%) or median (IQR)
Infants delivered at 22 weeks 29 (100%)
Female 15 (51.7%)
GA, wk 22.4 (22.2-22.6)
Birth weight, grams 512 (463-580)
Birth weight z-score –0.12 (–0.67-0.78)
Birth head circumference, cm 20 (19.5-20.5)
Birth head circumference z-score –0.05 (–0.56-0.45)
Maternal age, years 35 (31-38)
Assisted pregnancy 5 (17.2)
Gravidity 2 (1-3)
Premature rupture of membranes (PROM)

–       24 hours to 7 days

–       >7 days

  

10 (34.5)

3 (10.3)

0 (0)
Singleton gestation 29 (100)
Cesarean delivery 23 (79.3)
Any prenatal care 29 (100)
Partial course of antenatal steroids 4 (13.8)
Complete course of antenatal steroids 6 (20.7)
Apgar score, median

–       At 1 minutes

–       At 5 minutes

–       At 10 minutes

  

3 (2-4)

6 (4-7)

7 (6-8)
    • Data on resuscitation methods, procedures and drugs used at the time of NICU admission are listed below in Table 2.

Table 2

Factors Number (%) or median (IQR)
Umbilical cord management

–       Delayed cord clamping (DCC)

–       Umbilical cord milking (UCM)

–       Unknown

  

0 (0)

23 (79.3)

6 (20.7)
Intubation in the delivery room 29 (100)
Time to intubation after delivery, minutes 3.25 (3-6)
Tracheal tube size

–       2.0 mm

–       2.5 mm

  

13 (44.8)

16 (55.2)
Surfactant replacement therapy 27 (93.1)
Venous line

–       Umbilical venous catheter (UVC)

–       Peripherally inserted central catheter (PICC)

  

24 (82.8)

 

5 (17.2)
Arterial line

–       Umbilical arterial catheter (UAC)

–       Peripheral arterial line (PAL)

  

27 (93.1)

 

2 (6.9)
Respiratory support

–       Conventional mechanical ventilation (CMV)

–       High-frequency oscillatory ventilation (HFOV)

  

27 (93.1)

 

2 (6.9)
Antibiotics/Antifungal agents

–       Ampicillin

–       Gentamicin

–       Fluconazole

  

29 (100)

29 (100)

28 (96.6)
Sedative agents

–       Phenobarbital

  

15 (51.7)
Globulin 23 (79.3)
Prophylactic indomethacin for IVH prevention 21 (72.4)
Insulin for nonoliguric hyperkalemia 16 (55.1)

 

  • Respiratory management:
    • HFOV use increased from 6.9% on day 0 to 78.6% on day 7.
    • Invasive mechanical ventilation at 36 weeks PMA, was needed for 3 (12.5%) infants. At 40 weeks PMA, all infants were on non-invasive respiratory support.
    • After surfactant administration in 27 (93.1%) neonates, the median Oxygenation index decreased from 12.4 (IQR 6.3-30.1) on day 0 to 7.2 (IQR 5.2-10.1) on day 1.
  • Cardiovascular management:
    • Umbilical arterial and venous line use reduced to 7.7% and 11.5% in week 2.
    • Dopamine, dobutamine or steroids were started in 26 neonates (92.9%) on day 1 and continued for 1 month in 29.2% of the neonates.
    • Median starting doses of dopamine and dobutamine on day 0 were 3.1 (IQR, 0-3.95) and 2.7 (IQR, 0-3.95) µg/kg/min respectively.
    • In the first 3 days of life, more than a median of one echocardiography per day was performed by a neonatologist.
    • On day 0, the median mean arterial blood pressure (MAP) was 21 mm Hg (IQR 20-26). On day 1, 2,and 3 the median MAP was 28 (IQR 25-31), 29 (IQR 27-32) and 30.5 (IQR 27.7-33) mm Hg, respectively.
  • Fluid and nutrition management:
    • Median total fluid intake started at 50.4 ml/kg/day (IQR 31.7-60.5) on day 0 and increased to 6 ml/kg/day (IQR 105.6-140.5) on day 7.
    • At birth, the median temperature and humidity of the incubator were 39° Celsius (IQR 38-39) and 92.5% (IQR 90-95), respectively.
    • On day 1, enteral feeding was started for all neonates at 0.5 ml every 3 hours using a nasogastric tube.
    • Median enteral feed volume was 16.3 ml/kg/day (IQR 8.7-33.0) in week 1 and reached 100 ml/kg/day in week 4 (IQR 89.9-133.8).
    • Oroduodenal tube use increased from day 4 and reached 50% (12/24) by week 4.
    • Glycerin enema was performed ≥ 3 times/day in all neonates on day 5 and continued until 32 weeks PMA.
    • Bottle feeding was established in 8.3% (2/24) and 47.8% (11/23) infants at 36 and 40 weeks PMA, respectively.
    • Median body weight at 40 weeks PMA was 2048 g (IQR 1704-2274).
  • In 89.3% (25/28) of neonates, phenobarbital was used for sedation from day 1 to 3.
  • Head ultrasound (US) was performed by neonatologists at a median of 2 (IQR 1-2), 3 (IQR 2-3) and 2 (IQR 1-2) times on days 1, 2 and 3 respectively.
  • Antibiotics and antifungals were continued until day 5 in 96.4% (27/28) of infants.
  • Probiotics were given to 93.1% (27/29) of infants.
  • Data on short- and long-term outcomes is listed below in Table 3.

Table 3

Outcomes Number (%) or median (IQR)
IVH

–       Grade 0

–       Grade I

–       Grade II

–       Grade III

–       Grade IV

  

11 (37.9)

7 (24.1)

7 (24.1)

1 (3.4)

3 (10.3)
PVL 0 (0)
Ommaya reservoir 0 (0)
VP shunt 0 (0)
ROP treatment 15 (51.7)
PDA

–       Medical treatment

–       Surgical ligation

  

16 (55.1)

4 (13.7)
BPD, National Institue of Health (NIH) 2001 definition

–       Mild

–       Moderate

–       Severe

  

 

14 (48.3)

1 (3.4)

9 (31)
BPD (NIH 2018 definition)

–       I

–       II

–       III

–       III (A)

–       Tracheostomy

–       Home oxygen therapy

  

7 (24.1)

7 (24.1)

3 (10.3)

0 (0)

0 (0)

6 (20.6)
NEC/Focal intestinal perforation

–       Peritoneal drainage

–       Surgery

  

0 (0.0)

3 (10.3)
Discharge weight, g 3010 (2409-3343)
Discharge weight z-score 0.17 (–0.36-0.47)
Discharge head circumference, cm 35 (33.1-37.5)
Discharge head circumference z-score 0.35 (0.02-0.5)
CP 1 (5.5)
DQ

–       Postural-Motor

>85

70-84

55-69

<55

–       Cognitive-Adaptive

>85

70-84

55-69

<55

–       Language-social

>85

70-84

55-69

<55

–       Total

>85

70-84

55-69

<55

–       Visual impairment

–       Hearing impairment

  

 

3 (16.7)

4 (22.2)

8 (44.4)

3 (16.7)

 

5 (27.8)

6 (33.3)

4 (22.2)

3 (16.7)

 

2 (11.1)

7 (38.9)

3 (16.7)

6 (33.3)

 

2 (11.1)

8 (44.4)

6 (33.3)

2 (11.1)

4 (22.2)

0 (0)
NDI

–       None/Mild

–       Moderate

–       Severe

  

11 (61.1)

5 (27.8)

2 (11.1)

 

  • 5 infants died due to sepsis.
  • 1 infant was transferred to another hospital.
  • 23 infants survived to 1.5 years corrected age.

Conclusion

The study showed favorable survival rates and management of periviable preterm neonates born at 22 weeks of gestation and actively resuscitated in a tertiary perinatal center.

 

Commentary

In 1991, an amendment to the Eugenic Protection Act lowered the limit of viability to 22 weeks of gestation, in Japan (1). Backed by a robust prenatal care program (2), the Japanese longitudinal experience in caring for neonates born at the cusp of viability has led to improved outcomes (3). Subsequently, active resuscitation is offered to most neonates born at 22 weeks GA, i.e.>80% of these neonates are intubated at birth, according to the year 2020 report of the Neonatal Research Network (NRN) Database, Japan (4) despite a lower rate of antenatal steroid use (~50%).

 

In this study, Motojima et al describe the experience of a single Japanese tertiary center, in caring for periviable neonates born as early as 2013. In this cohort of 29 neonates, overall favorable outcomes are noted with more than 80% survival. Strikingly, only one neonate (5%) in this group developed CP long-term, and only 2 infants (11%) had severe NDI, with the overall greatest impairment seen in the language-social domain.

 

Key maternal/infant characteristics include universal prenatal care, a considerably higher median birth weight of 512 g (compared to median birth weight of 480 g reported by the National Institute of Child Health and Human Development NRN, 2013-2018) (5), use of C-section as the predominant mode of delivery and comparable rates (5) of antenatal steroid administration (34%), both of which are associated with increased survival in this population (6). Maternal illnesses and other prenatal exposures such as smoking and recreational drugs are not listed.

 

Cord milking is practiced commonly, which is currently not standard of care for infants <28 weeks GA, due to an increased risk of IVH (7). Interestingly, in this study, the incidence of severe IVH remained low. Other noteworthy management strategies include early enteral feeding (100% of infants fed by day of life (DOL) 1, despite 90% of these infants requiring some inotropic support), frequent use of neonatologist-performed echocardiograms to inform decisions regarding fluid management, PDA, selection/titration of inotropes/vasopressors, etc., and lung-protective approach to ventilation. All infants are on non-invasive respiratory support by 40 weeks PMA. Postnatal steroid use is not mentioned and a distinction between early vs. late onset sepsis is not made. Probiotics are used as early as DOL 0 in some neonates and phenobarbital is the primary sedative used in the first week of life.

 

Worldwide, several centers have well-established neonatal hemodynamics programs, however, this highly specialized area of neonatology is still evolving and many neonatal intensive care units rely on traditional clinical parameters. This may be one of many reasons for such wide variation in clinical practice and outcomes related to periviable neonates (8). Given the overall improved survival, the American College of Obstetricians and Gynecologists has provided updated recommendations to consider antenatal steroids for GA 22w 0d – 22w 6d (9).

 

Careful consideration should be given to individual patient factors including maternal comorbidities, presence of fetal/neonatal anomalies, inborn versus outborn neonates, resource availability, and most importantly, expectations of the families when choosing active resuscitation for these infants. 

References

  1. Nishida H, Ishizuka Y. Survival rate of extremely low birth weight infants and its effect on the amendment of the Eugenic Protection Act in Japan. Acta Paediatr Jpn 1992; 34(6):612-6. PMID: 1285508.

  2. Kusuda S, Hirano S, Nakamura T. Creating experiences from active treatment towards extremely preterm infants born at less than 25 weeks in Japan. Semin Perinatol 2022; 46(1):151537. PMID: 34862068.

  3. Miyazawa T, Arahori H, Ohnishi S, Shoji H, Matsumoto A, Wada YS, et al. Mortality and morbidity of extremely low birth weight infants in Japan, 2015. Pediatr Int 2023; 65(1):e15493. PMID: 36740921.

  4. Website for the Neonatal Research Network Database Japan: https://plaza.umin.ac.jp/nrndata/indexe.htm

  5. Bell EF, Hintz SR, Hansen NI, Bann CM, Wyckoff MH, DeMauro SB et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Mortality, In-Hospital Morbidity, Care Practices, and 2-Year Outcomes for Extremely Preterm Infants in the US, 2013-2018. JAMA 2022; 327(3):248-263. PMID: 35040888.

  6. Vidavalur R, Hussain Z, Hussain N. Association of Survival at 22 Weeks’ Gestation With Use of Antenatal Corticosteroids and Mode of Delivery in the United States. JAMA Pediatr 2023; 177(1):90-93. PMID: 36315137.

  7. Katheria A, Reister F, Essers J, Mendler M, Hummler H, Subramaniam A et al. Association of Umbilical Cord Milking vs Delayed Umbilical Cord Clamping With Death or Severe Intraventricular Hemorrhage Among Preterm Infants. JAMA. 2019; 322(19):1877-1886. PMID: 31742630.

  8. Silva ER, Shukla VV, Tindal R, Carlo WA, Travers CP. Association of Active Postnatal Care With Infant Survival Among Periviable Infants in the US. JAMA Netw Open 2023; 6(1):e2250593. PMID: 36656583

  9. Website for the American College of Obstetricians and Gynecologists: https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2021/09/use-of-antenatal-corticosteroids-at-22-weeks-of-gestation

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