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

We aimed to present the active management and outcomes of infants born at 22 weeks of gestation. 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. The survival rate was 82.8% (24/29). Tracheal intubation was performed in all patients, and surfactant was administered 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%) patients, respectively. No patient required a tracheostomy or ventriculoperitoneal shunt. The overall survival rate and survival rate without morbidities were high among infants born at 22 weeks of gestation.


INTRODUCTION
Decision-making on resuscitation in the delivery room in neonates born between 22 and 24 weeks of gestation is complex and varies according to institutions [1,2].Despite advances in perinatal and neonatal medicine, these extremely premature neonates are termed "periviable" owing to the high risks of death and longterm morbidities.According to a systematic review and metaanalysis of proactive neonatal treatment at 22 weeks of gestation, the pooled prevalence of survival was 29.0% [95% confidence interval (CI), 17.2-41.6].The overall prevalence of survival without major morbidity, using a definition that includes any bronchopulmonary dysplasia (BPD), was 11.0% (95% CI, 8.0-14.3).The overall rate of survival without moderate or severe impairment was 37.0% (95% CI, 14.6-61.5)[3].Despite the few numbers of these infants, several statements and guidelines, which were largely consensus-based without clear data to guide the practice of evidence-based medicine, were formulated on the basis of the controversy regarding periviable neonate resuscitation.Most international guidelines on resuscitation decisions for extremely preterm infants state 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 [4].
The provision or withholding of neonatal resuscitation and intensive care among infants born at 22 weeks of gestation is highly controversial [5].Routine provision of active treatment is standard in some neonatal intensive care units (NICUs), whereas such care is deemed futile in others [6,7].Differences in the provision or withholding of active neonatal treatment have led to survival estimates ranging from 0% to >60% [7][8][9].In 1977, in Japan, the limit of viability changed from 28 to 24 weeks of gestation.In 1991, it was changed from 24 to 22 weeks of gestation by amendments to the Maternal Protection Act, which was subsequently 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 [10].
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 United States (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% [11].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 reported that the pooled prevalence of survival was 29.0% (95% CI, 17.2-41.6)[3].In contrast, in Japan, the database of the Neonatal Research Network Japan has performed a comparison between the outcomes of very preterm infants across countries and a nationwide cohort study from 2008 to 2012 and showed that the survival rate of infants born at 22 weeks of gestation was 46.1%, which was much higher than that in other countries [12].
This study aimed to report a Japanese single-center experience of periviable neonates born at 22 weeks of gestation, particularly focusing on active management and relatively favorable outcomes.

MATERIALS/PARTICIPANTS AND METHODS 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 actively resuscitated and admitted to the NICU of Saitama Medical Center, Saitama Medical University, Saitama, Japan from January 1, 2013, to December 31, 2020.We performed a cesarean section at 22 weeks of gestation for both maternal and fetal indications following informed consent obtained by obstetricians and did not limit the resuscitation of neonates born at 22 weeks of gestation based on gestational age or birth weight.Active resuscitation, including umbilical cord milking (UCM), continuous positive airway pressure, endotracheal intubation, and surfactant replacement therapy, was provided to all live-born infants.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).Gestational age was determined by the best obstetrical estimate recorded in the maternal medical record, based on early prenatal ultrasound or the last menstrual period, in that order.During the study period, neonates born at 22 weeks of gestation were routinely resuscitated.Neonates with major congenital anomalies, including any central nervous system, cardiac, gastrointestinal, genitourinary, chromosomal, pulmonary, or vascular and lymphatic 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 corticosteroids (ACSs) was defined as at least two doses of any ACSs administered before delivery during the present pregnancy to enhance fetal lung maturity.The intraventricular hemorrhage (IVH) grade was reported on the basis of the Papile classification system [13].Treated retinopathy of prematurity (ROP) was defined based on the need for ophthalmologic treatment, such as laser therapy and cryotherapy.Treated patent ductus arteriosus (PDA) was confirmed using echocardiography and determined on the basis of based on the need for medical treatment or surgical ligation.BPD was defined as the use of supplemental oxygen at 28 days of age and classified according to the 2001 and 2018 Eunice Kennedy Shriver National Institute of Child Health and Human Development definition at 36 weeks postmenstrual age [14,15].Treated necrotizing enterocolitis (NEC) or focal intestinal perforation was defined on the basis of 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 [16].Cerebral palsy was defined as a developmental disability affecting movement, posture, and coordination at 1.5 years of age at any level of severity, as reported by Bax [17].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 (DQ) score of <70, which was equivalent to a Bayley III Cognitive Scale score of <85, represented significantly delayed performance [16].Neurodevelopmental impairment (NDI) is a composite score based on cognition, neurological assessment, and the presence of visual and/or hearing impairment (Supplementary Table) [18].NDI was classified as mild if cognitive scores showed a DQ between 70 and 84; vision or hearing loss without aid or with good correction, or abnormal neurological tests in the absence of a neurological syndrome.NDI was scored as moderate if cognitive DQ scores were between 55 and 69 if had limited vision or hearing and had been using aids or with unilateral cerebral palsy.NDI was scored as severe if cognitive DQ scores were below 55, or blindness, deafness, or bilateral cerebral palsy was present.NDI was determined for examinations at 1.5 years of age.

Statistical analyses
Statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [19].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.

RESULTS
This study included 29 neonates born at 22 weeks of gestation at our center from January 1, 2013, to December 31, 2020.No neonates were excluded from this study due to major congenital anomalies.During this study period, no deaths or neonates born at 22 weeks of gestation were noted in the delivery room.All infants were actively resuscitated and admitted alive to the NICU (Supplementary Fig. delivery).Cesarean delivery was performed at 22 weeks of gestation in 23 cases (79.3%).

Clinical management
The resuscitation method and procedure and administered medications on admission to the NICU are shown in Table 2.
Phenobarbital was administered as a sedative agent in 15 cases (51.7%), and prophylactic indomethacin was administered to prevent IVH in 21 (72.4%).
Regarding respiratory management for neonates born at 22 weeks of gestation, 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.At 36 weeks postmenstrual age, three infants (12.5%) were still managed on an invasive mechanical ventilator.However, at 40 weeks postmenstrual age, all infants were weaned to no support or noninvasive respiratory support, including continuous positive airway pressure and low-or high-flow nasal cannula (Fig. 1A).Following surfactant replacement therapy administration in 93.1% of cases (27/29), 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 (Fig. 1B).

In-hospital morbidities and mortality
In-hospital outcomes are presented in Table 3 3.The overall rate of moderate or severe NDI was 38.9% (7/18).Cerebral palsy was observed in one infant (5.5%, 1/18).All infants had normal hearing, whereas four (22.2%) had blindness in one or both eyes.The DQ score was more than 70 in 10 cases (10/18, 55.6%), and more than 85 in 2 cases (2/18, 11.1%) using the Kyoto Scale of Psychological Development.

DISCUSSION
Although more infants born at 22 weeks of gestation have been actively treated worldwide recently [20], few reports on specific management methods for periviable neonates were documented, indicating inadequate evidence for the optimal management of these neonates.In this retrospective observational study, we have reported a single-center experience on the 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 NDI 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 1 year, whereas 30% of those actively treated survived [20].Conversely, 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% [21].In infants born at 22 weeks of gestation in a Swedish center with a uniformly active approach to managing extremely preterm infants, survival was 52% [22].The survival rate of 82.8% (24/29) in our center was much higher than those in other developed countries.
In an observational study using datasets from the Neonatal Research Network Japan, ACS exposure improved the survival of extremely preterm infants born at <24 weeks of gestation, suggesting that ACS treatment should be considered for threatened preterm birth at 22-23 weeks of gestation [23].Furthermore, the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine have recently revised their recommendation regarding ACS administration at 22 weeks of gestation and stated that ACS may be considered at 22 weeks of gestation if neonatal resuscitation is planned and after appropriate counseling [24].In this study, the complete ACS course was administered to only 20.7% (6/29) of preterm infants born at 22 weeks of gestation.This low ACS treatment rate may be explained by the hesitancy of obstetricians to administer ACS to mothers who show signs of intrauterine infection, including chorioamnionitis, and the insufficient time to the delivery to complete ACS treatments.However, based on the reported evidence [23,25], we should discuss increasing the rate of ACS treatment at 22 weeks of gestation.
The controversy regarding umbilical cord management still exists.In our cohort, UCM was performed in all 23 infants born at 22 weeks of gestation except for the data missing cases.No delayed cord clamping (DCC) was performed.In the national survey conducted in 2022 on the management of infants born at 22 and 23 weeks of gestation, UCM was performed in 86% of NICUs in Japan (125/145), whereas DCC was performed in only 1% (1/145) (unpublished data).A systematic review and metaanalysis published in 2018 suggested that compared with DCC in preterm infants, UCM may lower the risk of IVH and improve certain neurodevelopmental outcomes [26].In contrast, a randomized controlled trial, which was conducted in four countries between 2017 and 2018, was terminated early owing to a safety signal comprising an imbalance in the number of severe IVH events by the UCM group [27].Moreover, a multicenter retrospective study of infants born at <29 weeks of gestation conducted in the US suggested that DCM was the preferred practice for placental transfusion, as UCM exposure was associated with an increase in the adverse outcome of severe IVH [28].However, in Japan, the trend of umbilical cord management has not been changing and UCM remains the preferred practice for preterm infants.To avoid pulmonary barotrauma caused by large fluctuations 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 CMV-induced lung pathology [29,30].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 (relative risk, 0.86; 95% CI 0.78-0.96;risk difference −0.05, 95% CI −0.08 to 0.02; required treatment treat for an additional beneficial outcome, 20; 95% CI, 12-50).However, the evidence was weakened by the inconsistency of this effect across trials [31].In most trials, the inclusion criterion of patients was infants born at more than 23 weeks of gestation or with a birth weight of over 500 g, indicating that 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 HFOV early after birth to prevent severe BPD in anticipation of the lung-protective effect of HFOV.The median age when converting from CMV to HFOV was 3 days of age (IQR 2-5).
Systemic hypotension is a common complication in preterm infants, particularly 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 for treating refractory hypotension in preterm infants without an increase in short-term adverse consequences, data on long-term safety or benefit are lacking.Therefore, steroids were not routinely recommended for treating hypotension in preterm infants [32].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.Subsequently, steroids were added to the inotropic therapy, if needed, in only five neonates during the first week following birth.
Phenobarbital is not routinely administered, however, its administration is individualized at the discretion of each physician to prevent IVH in extremely preterm neonates.In this cohort, phenobarbital was prophylactically administered to 26 cases (90%) following birth for IVH prevention.This high rate of phenobarbital use can be explained by the following reasons: 1) traditionally used as a sedative agent for newborns in our NICU and 2) concerns regarding opioid-induced bowel dysfunction due to fentanyl and morphine use.In contrast, in a Cochrane review published in 2013, Smit et al. concluded that the postnatal administration of phenobarbital cannot be recommended as prophylaxis for IVH prevention IVH prevention in preterm neonates and is associated with an increased need for mechanical ventilation [33].However, studies included in this review were published between 1981 and 2009, suggesting inadequate evidence regarding the use of phenobarbital for IVH prevention in periviable neonates born at 22 weeks of gestation.
Feeding intolerance is a common clinical problem among preterm infants.In a Cochrane review, Anabrees et al. assessed the effectiveness and safety of glycerin enemas for preventing or treating feeding intolerance in infants with very low birth weight.Their review showed that the 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 glycerin enema-induced adverse events, including NEC, ROP, BPD, PDA, and IVH were reported in included trials [34].Despite no evidence, we worry about the relationship between glycerin enema administration in the early days following birth and IVH.Therefore, in this study, all infants born at 22 weeks of gestation received glycerin enema after 4 days of age when we believed that risks of IVH were no longer observed.
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 a risk ratio of 0.54 (95% CI 0.45-0.65)with low certainty owing to the limitations in trial design and publication bias [35].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 NEC prevention at least once during their hospital days.
This study had some limitations.First, we described the experiences of a single perinatal center in a single country without comparison.Second, evaluating neurodevelopment and cognitive function in an infant aged 1.5 years is challenging and is therefore unreliable.
The main strength of this study is its uniqueness, as all periviable live-born 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.Further studies are needed to clarify optimal management for the care of these periviable newborns considering that we have been managing them without sufficient evidence.
Table 3. Short-and long-term outcomes.

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 (Supplementary Fig.).The follow-up visit was completed in 18 of 23 infants born at 22 weeks (78.3%).Results of neurodevelopmental testing and NDI classification at 1.5 years of corrected age are presented in Table

Fig. 1
Fig. 1 Respiratory and circulatory management.A Respiratory support.B Oxygenation index.C Arterial line placement.D Venous line placement.E Vasopressor.F Total fluid intake.G Incubator temperature.H Incubator humidity.I Number of neonatologist-performed ultrasounds.J Mean arterial blood pressure.A box-and-whisker plot was used to plot the distribution.CMV conventional mechanical ventilation, HFOV high-frequency oscillatory ventilation, CPAP continuous positive airway pressure, HFNC high flow nasal cannula, LFNC lowflow nasal cannula, UAC umbilical arterial catheter, PAC peripheral arterial catheter, UVC umbilical venous catheter, PICC peripherally inserted central venous catheter, PIV peripheral intravenous line, DOA dopamine, DOB dobutamine, N total number of cases, d day, w week, PMA postmenstrual age.

Fig. 2
Fig. 2 Nutritional support, neuroprotective care, and infection protection and control.A Feeding methods.B Total volume of enteral feeding.C Use of glycerin enema.D Body weight.E Use of sedative agents.F Use of antibiotics and antifungal agents.G Use of probiotics.NG nasogastric tube, OD oroduodenal tube, PB phenobarbital, DEX dexmedetomidine, FEN fentanyl, MDZ midazolam, N total number of cases, d day, w week, PMA postmenstrual age.

Table 1 .
). Demographic characteristics of neonates born at 22 weeks of gestation are presented in Table1.ACS therapy was administered in six infants (20.7%).Receipt of prenatal care was universal (100% with ≥1 prenatal clinic visit before the hospital admission for Demographic data. Data are presented as number (%) or median (IQR).a At least one prenatal visit before admission for the delivery.
Data are presented as number (%) or median (IQR).