In this study, we found that the outborn group included more cases at small risk of EPT and had a significantly higher frequency of severe IVH, NEC or FIP, and cognitive impairment. We could not find studies about the long-term outcomes of outborn EPT infants, although there were some reports on short-term outcomes. To the best of our knowledge, this is the first large cohort study to explore short- and long-term outcomes of EPT inborn and outborn infants. Higher rates of mortality and morbidity for outborn infants have been reported (1–3).
Significant differences were observed between the inborn and outborn groups in demographic and clinical factors. The outborn group may include more cases at smaller risk of EPT when compared with the inborn group, since the inborn group had significantly higher rates of twin birth, PIH, pathologic chorioamnionitis, PROM, SGA, and lower birth weight. If only background factors are considered, a good outcome for outborn infants can be expected, with the exceptions of ACS treatment and higher rate of a low Apgar score at 5 minutes. We found no difference in mortality risk between outborn and inborn infants. However, a significant difference in severe IVH and NEC or FIP was found, even after adjusting for perinatal risk factors. Nevertheless, the rates of all these morbidities remain low compared with other studies (7). There were no significant differences in long-term outcomes between the two groups, except for the rate of cognitive impairment. The high rate of cognitive impairment may be due to the high rate of severe IVH and NEC or FIP seen in the short-term outcomes.
Our data did not include stillbirths and deaths in the delivery room at birth hospitals other than the participating tertiary centers. Data about resuscitation of outborn livebirths were only available for those referred to tertiary centers and not for outborn infants who died at the birth hospital without being referred. Thus, it was not possible to obtain information on decision-making or other aspects of care for outborn livebirths that were not referred to tertiary centers. Insufficient time to administer ACS, suboptimal resuscitation at birth, and lack of medical equipment and staff expertise have been identified as risk factors contributing to mortality in EPT infants (16). Previous studies emphasize the value of high-volume level III NICU care in minimizing neonatal mortality and morbidity among VLBW infants (1718).
Unfortunately, there is no nationwide standard for the transportation of EPT infants (including use of transport incubators and presence of a neonatologist and neonatal nursing staff) in Japan at present. Improvements in the regional perinatal system, such as optimized transportation to tertiary centers, can improve the outcomes of EPT infants, as several factors at birth or during transport play a role in the health risks of outborn EPT infants (219). The risk of severe IVH and NEC or FIP in outborn infants may reflect the influence of inappropriate circumstances such as insufficient resuscitation at the time of birth and unstable environment such as hypo- or hyperthermia in an ambulance during the transportation period. The association between admission temperature and mortality and morbidity in EPT infants has been reported (19). It seems unlikely that there will be a dramatic improvement in this situation in the future, as small regional birth centers and level I maternity care hospitals handle approximately 50% of deliveries in Japan. In other words, EPT outborn births will continue to occur for a long period in Japan. Part of the solution to improve neonatal retrieval services of the births in birth centers and level I maternity care hospitals could be to increase efforts to transport the pregnancies at risk of EPT in utero. Retrieval services means not only emergency transport services but also for subspecialized neonatologists to be present at births of the EPT infants in nontertiary hospitals to resuscitate and to stabilize the infants whenever possible. The regional maternal and neonatal transport system has been improving gradually, but the neonatal retrieval services for the regional perinatal system have remained largely unimproved in the past 20 years. Improved quality of resuscitation was reported when dedicated neonatal retrieval teams resuscitated outborn infants in the delivery room (16). Retrieval services may make it possible to provide outborn infants with intensive care or interventions such as intubation, surfactant administration, cardiorespiratory monitoring, ventilation support, and accurate drug administration at the birth hospital and during transport, thus increasing the possibility that outborn infants will receive intensive care approximately equal to that of a level III NICU at birth centers or level I maternity care hospitals. It was reported that the mortality before NICU admission for EPT outborn infants was significantly higher when compared with that for inborn infants (20). We may need to equip the regional perinatal system to send the neonatal retrieval team to birth hospitals in case of emergency as much as possible; however, there are several issues to address, such as securing neonatologists, sharing information between the birth hospital and tertiary center, and arranging the ambulance for exclusive use for newborn babies. Naturally, obstetricians at birth hospitals should acquire enough knowledge and skills to resuscitate EPT infants and to stabilize their general condition until the arrival of the retrieval team or transport to a tertiary hospital.
Our study has some limitations. The first was the amount of missing data (53.2%) related to information on NDI at 3 years. We made a comparison for maternal and delivery characteristics between infants evaluated and not evaluated for NDI at 3 years. All ASD values to evaluate statistical difference were under 10%, and the low follow-up rate might not have a clinically important influence on short- and long-term outcomes between EPT infants who had data available for NDI and survivors who were lost to follow-up. The second was that we used the KSPD scale for evaluating developmental outcomes instead of the Bayley Scales of Infant Development III (Bayley III), which is widely used throughout the world. However, one study reported that the KSPD scale correlated well with Bayley III (15). Furthermore, our study design was a case-control comparison using the same developmental scale. Thus, we could not expect any discrepancy in our results. The third was that stillbirths and deaths of neonates who could not be transported to tertiary centers were not included in our data. These data may influence the result of our analysis for the short- and long-term outcomes to some extent. Recently, the unification of the nationwide neonatal and obstetrical data was discussed at the meeting of the Japan Society of Perinatal and Neonatal Medicine. We should acquire the information for outborn livebirths that were not referred to tertiary centers to more accurately determine the current provision of perinatal care.
Our study pointed out that there was a significantly higher frequency of severe IVH, NEC or FIP, and cognitive impairment in outborn infants compared with the inborn infants. Thus, outborn/inborn birth status may influence short- and long-term outcomes of EPT infants. For the improvement of the current perinatal care standard, we should obtain more precise data of outborn EPT infants, including livebirths that were not referred to tertiary centers. Based on this analysis, more effort is needed to improve our perinatal environment, such as developing a neonatal retrieval system for outborn EPT infants.
We thank all patients for their generous contributions. We also thank the data center at Tokyo Women’s Medical University (Tokyo, Japan) for providing organizational support to the Neonatal Research Network of Japan. List of participating units: Sapporo City Hospital, Asahikawa Kosei Hospital, Kushiro Red Cross Hospital, Obihiro Kosei Hospital, Tenshi Hospital, NTT East Sapporo Hospital, Nikko Kinen Hospital, Sapporo Prefecture Medical University, Asahikawa Medical University, Aomori Prefecture Central Hospital, Iwate Medical University, Iwate Prefecture Ohfunato Hospital, Prefecture Kuji Hospital, Iwate Prefecture Ninohe Hospital, Sendai Red Cross Hospital, Akita Red Cross Hospital, Akita University, Tsuruoka City Shonai Hospital, Yamagata, Yamagata Prefecture Central Hospital, Fukusima Prefecture Medical University, Takeda General Hospital, National Fukushima Hospital, Tsukuba University, Tsuchiura Kyodo Hospital, Ibaraki Children’s Hospital, Dokkyo Medical University, Jichi Medical University, Ashikaga Red Cross Hospital, Gunma Prefecture Children’s Hospital, Kiryu Kosei General Hospital, Gunma University, Saitama Prefecture Children’s Hospital, National Nishisaitama Central Hospital, Saitama Medical University Medical Center, Kawaguchi City Medical Center, Jichi Medical University Saitama Medical Center, Asahi Central Hospital, Chiba City Kaihin Hospital, Kameda General Hospital, Tokyo Women’s Medical University Yachiyo Medical Center, Juntendo University Urayasu Hospital, Tokyo Metropolitan Children’s Medical Center, Tokyo Women’s Medical University, Aiiku Hospital, Nihon University, National International Medical Center, Teikyo University, Showa University, Japan Red Cross Hospital, National Center for Child Health and Development, Tokyo Metropolitan Otsuka Hospital, Toho University, Tokyo Metropolitan Bokuto Hospital, Tokyo Jikei Medical University, Saint Luku Hospital, Juntendo University, Sanikukai Hospital, Katsushika Red Cross Hospital, Yokohama Rosai Hospital, Yokohama City University Medical Center, Marianna Medical University, Kanagawa Children’s Medical Center, Tokai University, Kitazato University, Odawara City Hospital, Nippon Medical School Musashi Kosugi Hospital, Saiseikai Eastern Yokohama Hospital, Yokohama Medical Center, Yamanashi Prefecture Central Hospital, Nagano Children’s Hospital, Shinshu University, Iida City Hospital, National Shinshu Ueda Medical Center, Saku General Hospital, Niigata University, Niigata Central Hospital, Niigata City Hospital, Nagaoka Red Cross Hospital, Koseiren Takaoka Hospital, Toyama Prefectural Central Hospital, Toyama University, Ishikawa Prefectural Central Hospital, Kanazawa, Medical University, Fukui Prefectural Hospital, Fukui University, Gifu Prefectural Medical Center, Takayama Red Cross Hospital, Seirei Hamamatsu Hospital, Shizuoka Saiseikai Hospital, Shizuoka Children’s Hospital, Hamamatsu Medical University, Yaizu City Hospital, Fujieda City Hospital, Nagoya Red Cross Daini Hospital, Nagoya University, Nagoya Red Cross Daiici Hospital, Anjokosei Hospital, Koritsu Tosei Hospital, Komaki City Hospital, Toyota Memorial Hospital, Okazaki City Hospital, Konankosei Hospital, National Mie Central Medical Center, Ise Red Cross Hospital, Yokkaichi City Hospital, Otsu Red Cross Hospital, Shiga Medical University, Nagahama Red Cross Hospital, Uji Tokushukai Hospital, Japan Baptist Hospital, Kyoto University, Kyoto Red Cross Daiichi Hospital, National Maizuru Medical Center, Fukuchiyama City Hospital, Kyoto Prefecture Medical University, Kyoto City Hospital, Yodogawa Christian Hospital, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka University, Takatsuki General Hospital, Kansai Medical University, Osaka City General Hospital, Osaka City Sumiyoshi Hospital, Aizenbashi Hospital, Toyonaka City Hospital, National Cerebral and Cardiovascular Center, Kitano Hospital, Saiseikai Suita Hospital, Chifune Hospital, Bell Land General Hospital, Rinku General Hospital, Yao City Hospital, Osaka City University, Kobe Children’s Hospital, Kobe University, Saiseikai Hyogo Hospital, Kobe City Medical Center Central Hospital, Hyogo Medical University, Himeji Red Cross Hospital, Toyooka General Hospital, Hyogo Prefectural Awaji Hospital, Nara Prefecture Medical University, Wakayama Prefecture Medical University, Tottori Prefectural Central Hospital, Tottori University, Shimane Prefectural Central Hospital, Matsue Red Cross Hospital, Kurashiki Central Hospital, Tsuyama Central Hospital, Kawasaki Medical University, National Okayama Medical Center, Okayama Red Cross Hospital, Hiroshima City Central Hospital, Hiroshima Prefectural Hospital, Tsuchiya General Hospital, National Kure Medical Center, Yamaguchi Prefecture Medical Center, Tokushima University, Kagawa University, Shikoku Medical Center for Children and Adults, Matsuyama Red Cross Hospital, Ehime Prefectural Central Hospital, Kochi Health Science Center, Saint Maria Hospital, National Kyushu Medical Center, Kurume University, Kitakyushu City Hospital, University of Occupational and Environmental Health Japan, Fukuoka University, Kyushu University, Iizuka Hospital, National Kokura Medical Center, National Saga Hospital, National Nagasaki Medical Center, Kumamoto City Hospital, Kumamoto University, Oita Prefectural Hospital, Almeida Memorial Hospital, Nakatsu City Hospital, Miyazaki University, Kagoshima City Hospital, Imakyure General Hospital, Okinara Prefectural Central Hospital, Naha City Hospital, and Okinawa Red Cross Hospital.
1. Marlow N, Bennett C, Draper ES, et al. Perinatal outcomes for extremely preterm
babies in relation to place of birth in England: The EPICure 2 study. Arch Dis Child Fetal Neonatal Ed 2014; 99: F181–F188
2. Serenius F, Sjörs G, Blennow M, et al.; EXPRESS study group: EXPRESS study shows significant regional differences in 1-year outcome of extremely preterm
infants in Sweden. Acta Paediatr 2014; 103:27–37
3. Fellman V, Hellström-Westas L, Norman M, et al.; EXPRESS Group: One-year survival of extremely preterm
infants after active perinatal care in Sweden. JAMA 2009; 301:2225–2233
4. Iams JD, Romero R, Culhane JF, et al. Primary, secondary, and tertiary interventions to reduce the morbidity and mortality of preterm
birth. Lancet 2008; 371:164–175
5. Moore T, Hennessy EM, Myles J, Johnson SJ, et al. Neurological and developmental outcome in extremely preterm
children born in England in 1995 and 2006: The EPICure studies. BMJ 2012; 345:e7961
6. Serenius F, Källén K, Blennow M, et al.; EXPRESS Group: Neurodevelopmental outcome in extremely preterm
infants at 2.5 years after active perinatal care in Sweden. JAMA 2013; 309:1810–1820
7. Shah PS, Lui K, Sjörs G, et al.; International Network for Evaluating Outcomes (iNeo) of Neonates: Neonatal outcomes of very low birth weight and very preterm
neonates: An International Comparison. J Pediatr 2016; 177:144–152.e6
8. American Academy of Pediatrics: Committee on fetus and newborn: Level of neonatal care. Pediatrics 2004; 114:1341–1347
9. American College of Obstetrics and Gynecologists, Society for Maternal Fetal Medicine: Obstetric Care Consensus No. 2: Levels of maternal care. Obstet Gynecol 2015; 125:502–515
10. Katsuya K. Maternal and Child Health Statistics of Japan. 2016Tokyo, Japan, Mother`s and Children`s Health Organization.
11. Towers CV, Bonebrake R, Padilla G, et al. The effect of transport on the rate of severe intraventricular hemorrhage in very low birth weight infants. Obstet Gynecol 2000; 95:291–295
12. Hohlagschwandtner M, Husslein P, Klebermass K, et al. Perinatal mortality and morbidity. Comparison between maternal transport, neonatal transport and inpatient antenatal treatment. Arch Gynecol Obstet 2001; 265:113–118
13. Itabashi K, Miura F, Uehara R, et al. New Japanese neonatal anthropometric charts for gestational age at birth. Pediatr Int 2014; 56:702–708
14. Mishita J. Protocols for follow-up of high-risk infants. Perinat Med 2000; 30:1263–1272 (in Japanese)
15. Kono Y, Yonemoto N, Kusuda S, et al. Developmental assessment of VLBW infants at 18 months of age: A comparison study between KSPD and Bayley III. Brain Dev 2016; 38:377–385
16. Lui K, Abdel-Latif ME, Allgood CL, et al.; New South Wales and Australian Capital Territory Neonatal Intensive Care Unit Study Group: Improved outcomes of extremely premature outborn
infants: Effects of strategic changes in perinatal and retrieval services. Pediatrics 2006; 118:2076–2083
17. Binder S, Hill K, Meinzen-Derr J, et al. Increasing VLBW deliveries at subspecialty perinatal centers via perinatal outreach. Pediatrics 2011; 127:487–493
18. Phibbs CS, Baker LC, Caughey AB, et al. Level and volume of neonatal intensive care and mortality in very-low-birth-weight
infants. N Engl J Med 2007; 356:2165–2175
19. Laptook AR, Bell EF, Shankaran S, et al.; Generic and Moderate Preterm
Subcommittees of the NICHD Neonatal Research Network: Admission temperature and associated mortality and morbidity among moderately and extremely preterm
infants. J Pediatr 2018; 192:53–59.e2
20. Boland RA, Davis PG, Dawson JA, et al. Outcomes of infants born at 22–27 weeks’ gestation in Victoria according to outborn
birth status. Arch Dis Child Fetal Neonatal Ed 2017; 102:F153–F161
Keywords:Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.
inborn; outborn; perinatal system; preterm; retrieval system; very-low-birth-weight