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

doi:10.21203/rs.3.rs-2601057/v1

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

https://doi.org/10.21203/rs.3.rs-2601057/v1

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published 01 Jul, 2023

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OBJECTIVE: We aimed to present the active management and outcomes of infants born at 22 weeks of gestation.
STUDY DESIGN: This retrospective observational study presented the resuscitation methods, management during hospitalization, and outcomes of 29 infants born at 22 weeks of gestation who were actively resuscitated and admitted to our center during 2013–2020.

RESULTS: The survival rate was 82.8% (24/29). Tracheal intubation was performed in all patients, and surfactant was given for 27 (93.1%). Conventional mechanical ventilation was introduced in 27 (93.1%), and this was changed to high-frequency oscillatory ventilation in more than half by day 4. Surgical treatments of patent ductus arteriosus, necrotizing enterocolitis, and retinopathy of prematurity were required in 4 (13.7%), 3 (10.3%), and 15 (51.7%), respectively. No patient required a tracheostomy or ventriculoperitoneal shunt.

CONCLUSIONS:Among infants born at 22 weeks of gestation, the overall survival rate and survival rate without morbidities were relatively high.

Health sciences/Medical research/Outcomes research

Health sciences/Health care/Paediatrics

Decision-making on resuscitation in the delivery room in neonates born between 22 and 24 weeks of gestation is complex and varied by institutions (1, 2). Despite advances in perinatal and neonatal medicine, these extremely premature neonates are termed “periviable” due to the high risks for death and long-term morbidities. Despite the few numbers of these infants, many statements and guidelines were formulated based on the controversy about the resuscitation of periviable neonates. Most international guidelines on resuscitation decisions for extremely preterm infants mention providing comfort care only at 22 weeks of gestation followed by active care at 25 weeks. The American Academy of Pediatrics recommends that decision-making on resuscitation for infants born between 22 and 24 weeks of gestation is to be individualized and family-centered, based on maternal beliefs and parental values (3).

The provision or withholding of neonatal resuscitation and intensive care among infants born at 22 weeks of gestation is highly controversial (4). Routine provision of active treatment is standard in some neonatal intensive care units (NICUs), whereas such care is deemed futile in others (5, 6). Differences in the provision or withholding of active neonatal treatment have led to survival estimates ranging from 0% to > 60% (6, 7, 8). In Japan, the limit of viability changed from 28 to 24 weeks of gestation in 1977. It was changed from 24 to 22 weeks of gestation in 1991 by amendments to the Maternal Protection Act, which was then referred to as the Eugenic Protection Act. A national survey conducted in Japan in 2012 reported that active resuscitation of neonates born at 22 weeks of gestation was performed in 81% of NICUs; of these, 42% of NICUs resuscitated them, regardless of parents’ wishes (9).

In neonates born at 22 weeks of gestation in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network in the US from 2006 to 2011, the overall rate of survival was 5.1% (interquartile range (IQR), 0–10.6) (2). Similarly, from 2004 to 2007, the 1-year survival of infants born alive at 22 weeks of gestation in Sweden was 9.8% (10). A systematic review and meta-analysis of 31 studies that included 2,226 infants born at 22 weeks of gestation and provided active neonatal treatment revealed that the pooled prevalence of survival was 29.0% (95% confidence interval, 17.2–41.6) (11). In contrast, in Japan, the database of the neonatal research network Japan has compared the outcomes of very preterm infants across countries and a nationwide cohort study from 2008 to 2012 showed that the survival rate of infants born at 22 weeks of gestation was 46.1%, much higher than that in other countries (12).

In this study, we report a Japanese single-center experience of periviable neonates born at 22 weeks of gestation, especially focusing on active management and relatively favorable outcomes.

Study Design and Study Participants

This single-center retrospective cohort study reviewed resuscitation methods, post-hospitalization management, and outcomes of neonates born between 22 weeks 0 days and 22 weeks 6 days of gestation who were admitted to NICU at Saitama Medical Center, Saitama Medical University, Saitama, Japan from January 1, 2013, to December 31, 2020. Data were collected from electronic medical records. The Ethics Committee of Saitama Medical Center, Saitama Medical University approved this study with a waiver of informed consent (approval number, 2022 − 105). We do not limit resuscitation of neonates born at 22 weeks of gestation based on gestational age or birth weight. Gestational age was assessed by the best obstetrical estimate recorded in the maternal medical record. During the study period, neonates born at 22 weeks of gestation were resuscitated routinely. Neonates with major congenital anomalies were excluded from this study.

Management And Outcomes

Prenatal care was defined as at least one visit before admission for the delivery. A complete course of antenatal steroids was defined as at least two doses of any corticosteroids administered before delivery during the present pregnancy to enhance fetal lung maturity. Intraventricular hemorrhage (IVH) grade was reported based on the Papile classification system (13). Treated retinopathy of prematurity (ROP) was defined based on the need for ophthalmologic treatment. Treated patent ductus arteriosus (PDA) was confirmed by echocardiography and determined based on the need for medical treatment or surgical ligation. Bronchopulmonary dysplasia (BPD) was defined as the use of supplemental oxygen at 28 days of age and classified according to the 2001 Eunice Kennedy Shriver National Institute of Child Health and Human Development definition at 36 weeks postmenstrual age (14). Treated necrotizing enterocolitis (NEC) or focal intestinal perforation was defined based on the need for peritoneal drainage or surgery.

Long-term neurodevelopmental outcomes in an infant aged 1.5 years included cerebral palsy and visual, hearing, and cognitive impairments as indicated by developmental testing according to the Kyoto Scale of Psychological Development (15). Cerebral palsy was defined as a developmental disability that affects movement, posture, and coordination at 1.5 years of age at any level of severity, as reported by Bax (16). Visual impairment was defined as blindness with no functional vision in one or both eyes. Hearing impairment was considered present when amplification was required. A total developmental quotient score < 70, equivalent to a Bayley III Cognitive Scale score < 85, represented significantly delayed performance (15).

Statistical Analyses

Statistical analyses were conducted using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan) (17). Demographic, treatment, and outcome data were reported using median and IQR for the continuous data and the frequency and percentage 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.

This study included 29 neonates born at 22 weeks of gestation at our center during the study period. All infants were actively resuscitated and admitted alive to the NICU (Supplemental Figure).

Demographic characteristics of neonates born at 22 weeks of gestation are presented in Table 1. Antenatal steroid therapy was received in 6 infants (20.7%). Receipt of prenatal care was universal (100% with ≥ 1 prenatal clinic visit before the hospital admission for delivery). Cesarean delivery was performed at 22 weeks of gestation in 23 cases (79.3%).

Table 1

Demographic data
Factors		Infants delivered at 22 weeks (n = 29)
Female		15 (051.7)
Gestational age, wk		22.4 (22.2–22.6)
Birth weight, g		512 (463–580)
Birth weight z-score		-0.12 (-0.67–0.78)
Birth head circumference, cm		20.0 (19.5–20.5)
Birth head circumference z-score		-0.05 (-0.56–0.45)
Maternal age, y		35 (31–38)
Assisted pregnancy		05 (017.2)
Gravidity		02 (01–03)
Premature rupture of membranes		10 (034.5)
24 h to 7 d		03 (010.3)
> 7 d		00 (000.0)
Singleton gestation		29 (100.0)
Cesarean delivery		23 (079.3)
Any prenatal care*		29 (100.0)
Partial course of antenatal steroids		04 (013.8)
Complete course of antenatal steroids		06 (020.7)
Apgar score, median
At 1 min		3 (2–4)
At 5 min		6 (4–7)
At 10 min		7 (6–8)
Data are presented as number (%) or median (IQR).
*At least one prenatal visit before admission for the delivery.

In-hospital Morbidities And Mortality

In-hospital outcomes are presented in Table 2. Neonates born at 22 weeks of gestation had severe IVH (≥ Grade III or IV) at the rate of 13.8% (4/29), ROP requiring treatment at 51.7% (15/29), PDA requiring surgical ligation at 13.7% (4/29), severe BPD at 6.8% (2/29), and NEC or focal intestinal perforation with surgery at 10.3% (3/29). No neonate needed tracheostomy, whereas 6 (20.6%) used home oxygen therapy. Neonates born at 22 weeks of gestation and admitted to the NICU had a survival rate of 82.8% (24/29). Five infants died from sepsis during the NICU stay (Supplemental Figure).

Table 2

Short- and long-term outcomes
Short-term outcomes		Infants delivered at 22 weeks (n = 29)
Intraventricular hemorrhage
Grade 0		11 (37.9)
Grade I		07 (24.1)
Grade II		07 (24.1)
Grade III		01 (03.4)
Grade IV		03 (10.3)
Periventricular leukomalacia		00 (00.0)
Ommaya reservoir		00 (00.0)
Ventriculoperitoneal shunt		00 (00.0)
Retinopathy of prematurity
Treatment		15 (51.7)
Patent ductus arteriosus
Medical treatment		16 (55.1)
Surgical ligation		04 (13.7)
Bronchopulmonary dysplasia
Mild		19 (65.5)
Moderate		03 (10.3)
Severe		02 (06.8)
Tracheostomy		00 (00.0)
Home oxygen therapy		06 (20.6)
Necrotizing enterocolitis/ Focal intestinal perforation
Peritoneal drainage		00 (00.0)
Surgery		03 (10.3)
Discharge weight, g		3,010 (2,409–3,343)
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 (0.02–0.50)
Long-term outcomes		Infants delivered at 22 weeks (n = 18)
Cerebral palsy		01 (05.5)
Developmental quotient
> 85		02 (11.1)
70–84		08 (44.4)
55–69		06 (33.3)
< 55		02 (11.1)
Visual impairment		04 (22.2)
Hearing impairment		00 (00.0)
Neurodevelopmental impairment
No/mild		11 (61.1)
Moderate		05 (27.8)
Severe		02 (11.1)
Data are presented as number (%) or median (IQR).

Neurodevelopmental Outcomes At 1.5 Years

Of the 29 infants included in this study, one was transferred to another hospital before being discharged and 23 survived to 1.5 years and were eligible for neurodevelopmental follow-up (Supplemental Figure). The follow-up visit was completed in 18 of 23 infants born at 22 weeks (78.3%). Results of neurodevelopmental testing and classification of neurodevelopmental impairments at 1.5 years of corrected age are presented in Table 2. The overall rate of moderate or severe neurodevelopmental impairments was 38.9% (7/18). Cerebral palsy was observed in one (5.5%, 1/18). The hearing was normal in all infants, whereas four infants (22.2%) had blindness in one or both eyes. The developmental quotient score was more than 70 in 10 cases (10/18, 55.6%), and more than 85 in 2 cases (2/18, 11.1%) by the Kyoto Scale of Psychological Development.

Clinical Management

The resuscitation method and procedure and administered drug on admission to NICU are presented in Table 3. During resuscitation in the delivery room, umbilical cord milking was done on 23 infants (79.3%). All infants were intubated, while surfactant replacement therapy was given in 93.1% of infants (27/29) in the delivery room. Moreover, conventional mechanical ventilation (CMV) and high-frequency oscillation ventilation (HFOV) were started immediately on NICU admission in 27 (93.1%) and 2 (6.9%) neonates, respectively. Venous and arterial lines were inserted into all cases, mainly using umbilical venous and arterial catheters (24/29 (82.8%) and 27/29 (93.1%), respectively). After venous line insertion, antibiotics were started in all cases, and antifungal agents accompanied them in 28 neonates (96.6%). Phenobarbital was given as a sedative agent in 15 cases (51.7%), and prophylactic indomethacin was administered to prevent IVH in 21 (72.4%).

Table 3

Resuscitation in the delivery room, procedure and administered drug on admission to NICU
Factors		Infants delivered at 22 weeks (n = 29)
Umbilical cord management
Delayed umbilical cord clamping		00 (000.0)
Umbilical cord milking		23 (079.3)
Unknown		06 (020.7)
Intubation in the delivery room		29 (100.0)
Time to intubation after delivery, min		3.25 (3–6)
Tracheal tube size
2.0 mm		13 (044.8)
2.5 mm		16 (055.2)
Surfactant replacement therapy		27 (093.1)
Venous line
Umbilical venous catheter		24 (082.8)
Peripherally inserted central catheter		05 (017.2)
Arterial line
Umbilical arterial catheter		27 (093.1)
Peripheral arterial line		02 (006.9)
Respiratory support
Conventional mechanical ventilation		27 (093.1)
High-frequency oscillatory ventilation		02 (006.9)
Antibiotics/ Antifungal agents
Ampicillin		29 (100.0)
Gentamicin		29 (100.0)
Fluconazole		28 (096.6)
Sedative agents
Phenobarbital		15 (051.7)
Blood products
Globulin		23 (079.3)
Prophylactic indomethacin for intraventricular hemorrhage prevention		21 (072.4)
Insulin for non-oliguric hyperkalaemia		16 (055.1)
Data are presented as number (%) or median (IQR).

Regarding respiratory management for neonates born at 22 weeks gestational age, the mode of invasive respiratory support was changed from CMV to HFOV. The rate of infants using HFOV increased from 6.9% (2/29) on day 0 to 78.6% (22/28) on day 7. Three infants (12.5%) were still managed on an invasive mechanical ventilator at 36 weeks postmenstrual age. However, all infants were weaned to no support or non-invasive respiratory support, such as continuous positive airway pressure and low or high flow nasal cannula, by 40 weeks postmenstrual age (Fig. 1A). After surfactant replacement therapy was given in 93.1% of cases (27/29), the reduction of median oxygenation index was shown from 12.4 [IQR, 6.3–30.1] on day 0 to 7.2 [IQR, 5.2–10.1] on day 1 (Fig. 1B).

Circulatory management in the neonates of this study is presented in Fig. 1. Umbilical catheters for artery and venous were placed in 93.1% (27/29) and 82.8% (24/29). These umbilical lines were removed or replaced with peripheral lines by week 2, resulting in the decreased rates of use of umbilical lines to 7.7% (2/26) and 11.5% (3/26), respectively (Fig. 1C and 1D). After evaluating circulatory status using the vital signs and echocardiography, cardiovascular supports, including dopamine, dobutamine, and steroids, were started in 92.9% of infants (26/28) by day 1 and continued for one month in 29.2% of infants (7/24) (Fig. 1E). The median total water intake started at 50.4 ml/kg/day [IQR 31.7–60.5] on day 0 and increased to 120.6 ml/kg/day [IQR 105.6–140.5] on day 7 (Fig. 1F). The start setting of the incubator at birth was the median temperature of 39°C [IQR 38–39] and humidity of 92.5% [IQR 90–95] (Fig. 1G and 1H). On days 1, 2, and 3, an echocardiography was performed by neonatologists at a median of 2 [IQR 1–2], 3 [IQR, 2–3], and 2 [IQR 1–2] times, respectively (Fig. 1I). Mean arterial blood pressure was low on day 0 (21 [IQR 20–26]) but managed on days 1, 2, and 3 at the median of 28 [IQR 25–31], 29 [IQR 27–32], and 30.5 [IQR 27.7–33], respectively (Fig. 1J).

Enteral feeding started on day 1 through a nasogastric tube at a volume of 0.5 mL every 3 hours. Rates of the use of oroduodenal tubes gradually increased from day 4 and reached 50% (12/24) on week 4. Bottle feeding was established in 8.3% (2/24) and 47.8% (11/23) of infants at 36 and 40 weeks postmenstrual age, respectively (Fig. 2A). A median volume of enteral feeding on week 1 was 16.3 [IQR, 8.7–33.0] ml/kg/day and reach 100 ml/kg/day on week 4 (108.3 [IQR, 89.9–133.8] ml/kg/day) (Fig. 2B). On day 5, glycerin enema was performed three or more times daily in all neonates and continued until week 10 (32 weeks past menstrual age) (Fig. 2C). Median body weights of neonates measured at birth and 40 weeks postmenstrual age were 512 [IQR, 471–580] and 2,048 [IQR, 1,704–2274] g, respectively (Fig. 2D).

In 89.3% (25/28) of infants, phenobarbital was administered for sedation from Day 1 to Day 3 (Fig. 2E). On Days 1, 2, and 3, a head ultrasound was performed by neonatologists at a median of 2 [IQR, 1–2], 3 [IQR, 2–3], and 2 [IQR, 1–2] times, respectively accompanied by echocardiography (Fig. 1I). To protect and control infections, antibiotics or antifungal agents were started at birth in all neonates and were continued until day 5 in 96.4% (27/28). (Fig. 2F). Probiotics were used in 93.1% of infants (27/29) (Fig. 2G).

Although more infants born at 22 weeks of gestation have been actively treated worldwide recently (18), few reports on specific management methods for periviable neonates were documented, indicating inadequate evidence for optimal management of them. In this retrospective observational study, we have reported a single-center experience on outcomes and management of these periviable neonates. Of actively resuscitated infants, the survival rate was 82.8% (24/29), and the rate of no or mild neurodevelopmental impairments was 61.1% (11/18).

Bell et al. reviewed survival, in-hospital morbidities, care practices, and neurodevelopmental and functional outcomes at 22–26 months corrected age for extremely preterm neonates born in the US in 2013–2018. In this cohort, only 10.9% of neonates live-born at 22 weeks survived to discharge or one year, whereas 30% of those actively treated survived (18). On the other hand, in preterm neonates registered in the German Neonatal Network in 2011–2016, survival in neonates born at 22 weeks and receiving active care was 57% (19). The survival rate of 82.8% (24/29) in our center was much higher than in other developed countries.

To avoid pulmonary barotrauma caused by the large swings in pulmonary pressures during CMV, HFOV was used. In animal models, HFOV resulted in more uniform lung inflation, improved oxygenation, and reduced the severity of lung pathology produced by the CMV (20, 21). In a Cochrane systematic review published in 2015, Cools et al. concluded that the use of elective HFOV compared with CMV results in a slight reduction in the risk of BPD. Still, the evidence was weakened by the inconsistency of this effect across trials (22). In most trials, the inclusion criteria of patients were infants born at more than 23 weeks of gestation or with a birth weight of over 500 g, indicating this evidence does not apply to periviable infants born at 22 weeks of gestation. In our center, despite a lack of evidence, we convert the ventilator setting from CMV to HFO early after birth to prevent severe BPD in anticipation of the lung-protective effect of HFO. The median age when converting to HFO from CMV was three days of age [IQR 2–5].

Systemic hypotension is a common complication in preterm infants, especially in periviable infants born extremely prematurely. Corticosteroid treatment is used as an alternative or an adjunct to conventional volume expansion and inotropic therapy. In the Cochrane review published in 2011, Ibrahim et al. concluded that although steroids are effective in treating refractory hypotension in preterm infants without an increase in short-term adverse consequences, long-term safety or benefit data is lacking. Therefore, steroids were not recommended routinely for treating hypotension in preterm infants (23). Similarly, dopamine or dobutamine was initially used as an inotropic agent to stabilize the circulative status in 62% (18/29) of our cases at NICU admission. Then steroids were added to inotropic therapy, if needed, in only five neonates during the first week after birth.

Phenobarbital is not used routinely but is administered individually at the discretion of each physician to prevent IVH in extremely preterm neonates. In this cohort, phenobarbital was prophylactically given to 26 cases (90%) after birth for IVH prevention. In contrast, Smit et al. concluded in the Cochrane review published in 2013 that postnatal administration of phenobarbital cannot be recommended as prophylaxis to prevent IVH in preterm neonates and is associated with an increased need for mechanical ventilation (24). However, studies included in this review were published between 1981 and 2009, suggesting inadequate evidence concerning the use of phenobarbital for the prevention of IVH in periviable neonates born at 22 weeks of gestation.

Feeding intolerance is a common clinical problem among preterm infants. Anabrees et al. assessed the effectiveness and safety of glycerin enemas for preventing or treating feeding intolerance in very low birth weight infants in their Cochrane review. Their review showed that prophylactic administration of glycerin enema did not reduce the time required to achieve full enteral feeds, concluding that they did not support the routine use of prophylactic glycerin enemas in clinical practice. In contrast, no adverse events caused by glycerin enemas, such as NEC, ROP, BPD, PDA, and IVH were reported in included trials (25). Despite no evidence, we have been worrying about the relationship between glycerin enema administration early days after birth and IVH. Therefore, in this study, glycerin enema was given to all infants born at 22 weeks after four days of age when we thought there were no longer risks for IVH.

Dietary supplementation with probiotics to modulate the intestinal microbiome has been proposed as a strategy to reduce the risk of NEC. Meta-analyses by Sharif et al. showed that probiotics reduce the risk of NEC to risk ratio of 0.54 (95% CI 0.45–0.65) with low certainty because of the limitations in trial design and publication bias (26). In our NICU, dietary supplementation with probiotics has been routinely introduced to all extremely premature neonates. In our current cases, 93% (27/29) received probiotics treatment for the prevention of NEC at least once during their hospital days.

This study has some limitations. We described the experiences of a single perinatal center in a single country without comparison. The main benefit of this study is its uniqueness, as all periviable neonates born at 22 weeks of gestation were actively resuscitated and included in the analysis, despite the relatively small sample size.

In conclusion, this study demonstrated favorable survival rates and management of periviable preterm neonates born at 22 weeks of gestation and actively resuscitated in a tertiary perinatal center. Because we have been managing such tiny babies without evidence, further studies are needed to clarify optimal management for caring for these periviable newborns.

Conflict of Interest.

The authors declare no conflicts of interest.

Availability of Data and Materials.

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Acknowledgments.

No funding was received.

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There is NO conflict of interest to disclose.

sFigure.pdf
Supplemental Figure. Flowchart of infants included in the study. Twenty-nine infants born at 22 weeks of gestation and received active care were included.

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

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Management And Outcomes

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In-hospital Morbidities And Mortality

Neurodevelopmental Outcomes At 1.5 Years

Clinical Management

Discussion

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