- Email: [email protected]
Neurodevelopmental outcomes at 3 years old for infants with birth weights under 500 g
+
MODEL
Pediatrics and Neonatology (2017) xx, 1e7
Available online at www.sciencedirect.com
ScienceDirect journal homepage: http://www.pediatr-neonatol.com
Original Article
Neurodevelopmental outcomes at 3 years old for infants with birth weights under 500 g Syunsuke Nagara a,b, Masanori Kouwaki a,*, Takao Togawa a,c, Tokio Sugiura a,c, Mayumi Okada d, Norihisa Koyama a a
Department of Pediatrics, Toyohashi Municipal Hospital, Toyohashi, Aichi, Japan Department of Pediatrics, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Aichi, Japan c Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan d Department of Obstetrics and Gynecology, Toyohashi Municipal Hospital, Toyohashi, Aichi, Japan b
Received Feb 14, 2017; received in revised form Jun 5, 2017; accepted Sep 15, 2017
Available online - - -
Key Words extremely low birth weight infants; stillbirth; extreme prematurity; less than 500 g; survival rate
Background: Marked improvements have been achieved in the survival of extremely low birth weight infants, but survival rates and prognoses of extremely small infants with birth weights 500 g remain poor. The aim of this study was to clarify long-term outcomes for surviving infants with birth weights 500 g. Methods: The study population comprised fetuses of gestational age 22 weeks, expected live- or stillbirth weight 500 g, and birth date between 2003 and 2012. Developmental assessments were performed prospectively at 3 years old. Results: Data were obtained for 21 fetuses, including 10 live births and 11 stillbirths. Of the 10 live births, median gestational age was 25.2 weeks (range, 22.4e27.1 weeks), median birth weight was 426 g (range, 370e483 g), and two neonates died before discharge. One infant with severe asphyxia died within 12 h and another infant with Down syndrome died at 34 days. The survival rate was thus 80%. All surviving infants were small for gestational age. Seven of the 8 surviving infants (88%) weighed less than 2500 g at a corrected age of 40 weeks. Seven infants were available for developmental assessments at 3 years old. One infant could not be followed. Two of those seven infants (29%) showed normal development, three infants (42%) showed mild neurodevelopmental disability, and two infants (29%) showed severe neurodevelopmental disability. One infant had periventricular leukomalacia and cerebral palsy. Two of the seven infants (29%) had short stature (<3 SD) at 3 years old.
* Corresponding author. E-mail address: [email protected] (M. Kouwaki). https://doi.org/10.1016/j.pedneo.2017.09.005 1875-9572/Copyright ª 2017, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Nagara S, et al., Neurodevelopmental outcomes at 3 years old for infants with birth weights under 500 g, Pediatrics and Neonatology (2017), https://doi.org/10.1016/j.pedneo.2017.09.005
+
MODEL
2
S. Nagara et al Conclusion: Although the survival rate among live births was good (80%) in this study, neurodevelopmental outcomes remained poor in infants with birth weights 500 g. Further large studies are needed to assess long-term outcomes for extremely small infants. Copyright ª 2017, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).
1. Introduction With continuing advances in perinatal care, marked improvements in the survival of extremely low birth weight infants have been well documented.1,2 However, survival rates and prognoses of extremely small infants with birth weight less than 500 g are still poor. Many studies have defined live birth as requiring a birth weight 500 g, but increased reporting may account for the increased number of infants with birth weights 500 g.3 Although resuscitation of infants with birth weight 400 g was not recommended by the American College of Cardiology/American Heart Association 2005 guidelines,4 this criterion was discarded in 2015. Although the criteria defining human viability vary between countries, this has recently changed. Neonatal mortality rates are higher in infants with lower birth weights and greater degree of prematurity.2,3 Consequently, extending the gestational period and increasing the birth weight is recommended. However, intrauterine growth restriction represents an important risk factor for sudden stillbirth,5 and inadequate fetal growth may occasionally increase the risk of stillbirth even if the gestational period is extended. In cases with live- or stillbirth weight 500 g, no consensus has been reached and data are lacking on whether early delivery to preempt intrauterine hypoxia is preferable to delaying delivery to obtain maturity and growth even in view of the risk of stillbirth. Moreover, few studies have examined the long-term prognosis in infants with birth weights less than 500 g.6,7 Our strategy with regard to the timing of delivery for pregnancies with live- or stillbirth weight 500 g is to deliver cases where continued pregnancy would compromise maternal health or where non-reassuring fetal status (NRFS) is identified. Apart from the above-mentioned situations, we opt for expectant management rather than early delivery until 26 weeks of gestation, in anticipation of fetal growth. Beyond 26 weeks of gestation, we consider delivery if fetal growth has ceased. To evaluate our policy, the clinical characteristics of alive and stillborn or dead infants with body weights less than 500 g were compared retrospectively. In addition, to clarify the long-term outcomes of surviving infants with birth weights less than 500 g, developmental assessments were performed prospectively at a corrected age of 18 months old and at 3 years old.
2. Methods 2.1. Study design and patient population The study population comprised fetuses with gestational age 22 weeks and lives- or stillbirth weight 500 g delivered between January 1, 2003 and December 31, 2012. Toyohashi Municipal Hospital is a single tertiary perinatal medical center as well as a specialized clinic for all highrisk pregnancies in the East Mikawa district, where the population is approximately 700,000. The average delivery rate is 900e1100 infants per year. About 20 extremely low birth weight infants are admitted to our hospital each year. Our strategy of acute period treatment for extremely low birth weight infants includes: the use of a bronchial tube of maximum possible size; artificial respiration by intermittent positive-pressure ventilation during the acute period; raising the target mean blood pressure to the number of weeks of gestation by means of catecholamines, hydrocortisone, and volume bolus; fentanyl sedation; administration of indomethacin at 12 h after birth to prevent patent ductus arteriosus; glucose and insulin therapy; minimal enteral nutrition at an extremely early period; administration of probiotics; and parenteral nutrition from an early stage. Table 1a and b show the patient characteristics for live births and stillbirths, respectively. The clinical characteristics of alive and stillborn or dead infants were compared retrospectively. Finally, to investigate long-term outcomes, developmental assessments were carried out prospectively at 3 years old. Development was assessed using the new Kyoto Scale of Psychological Development (KSPD) test, which yields scores for neurodevelopment. The new KSPD test is a Japanese standard developmental test.8 This individualized face-to-face test is administered by experienced psychologists to assess child development in the following three areas: posture and movement (fine and gross motor functions); cognitive and adaptation [non-verbal reasoning and visuospatial perceptions assessed using materials (e.g., blocks, miniature cars, and marbles)]; and language and society (interpersonal relationships, socialization, and verbal abilities).9 Developmental quotient (DQ) was determined using developmental age (as determined from the new KSPD test)/chronological age 100. We defined DQ 80 as normal, DQ 40 and < 80 as indicating mild
Please cite this article in press as: Nagara S, et al., Neurodevelopmental outcomes at 3 years old for infants with birth weights under 500 g, Pediatrics and Neonatology (2017), https://doi.org/10.1016/j.pedneo.2017.09.005
+
MODEL
Less than 500 grams Table 1a
3
Patient characteristics (live births).
Body weight, g Gestational age, weeks Sex SGA Maternal age, y Ethnicity Pregnancy Parity Multiple births Tocolysis Antenatal steroid NRFS Maternal or fetal complication
Case 1
Case 2
Case 3
Case 4
Case 5
Case 6
Case 7
Case 8
Case 9
Case 10
428 232/7
392 235/7
483 242/7
472 252/7
370 263/7
384 264/7
436 264/7
416 271/7
472 223/7
450 250/7
Female þ 26 Japanese ART MP DD twin þ e e e
Female þ 35 Brazilian SP PP Singleton e e e HELLP syndrome
Female þ 30 Japanese SP MP Singleton þ e e TTTS
Female þ 36 Japanese ART MP MD twin e e e PIH
Male þ 35 Japanese SP PP MD twin e þ þ PIH
Female þ 37 Brazilian SP PP Singleton e e þ e
Female þ 40 Japanese SP MP Singleton þ e þ Hypertension
Female þ 42 Japanese SP MP Singleton e e e PIH
Male þ 34 Brazilian SP MP Singleton e e e e
Male þ 32 Japanese SP PP Singleton e e þ e
ART Z assisted reproductive technology; DD twin Z dichorionic diamniotic twin; HELLP syndrome Z hemolysis, elevated liver enzymes, and low platelet syndrome; MD twin Z monochorionic diamniotic twin; MP Z multiparity; NRFS Z non-reassuring fetal status; PIH Z pregnancy-induced hypertension; PP Z primiparity; SGA Z small for gestational age; SP Z spontaneous pregnancy; TTTS Z twinetwin transfusion syndrome.
neurodevelopmental disability, and DQ < 40 as indicating severe neurodevelopmental disability.
deceleration, or prolonged deceleration with lack of variability.
2.2. Definitions
2.3. Statistical analysis
Gestational age was calculated from fertilization in the case of assisted reproductive technology or evaluated from crown-rump length using ultrasonography during early pregnancy in the case of spontaneous pregnancy. Infants with live- or stillbirth weight below the 10th percentile using Japanese charts were classified as small for gestational age (SGA). Chronic lung disease (CLD) was defined as a requirement for supplemental oxygen at the postmenstrual age of 36 weeks. Intraventricular hemorrhage (IVH) was diagnosed from cranial imaging via cranial ultrasound by day 28 after birth. Severe IVH was diagnosed as grade 3 or 4.10 A diagnosis of cystic periventricular leukomalacia (PVL) was made using either ultrasonography or magnetic resonance imaging of the head, performed at 2 weeks of age or later. Necrotizing enterocolitis was defined according to the classification of Bell et al.11 as stage II or higher. Late-onset circulatory dysfunction (LCD) was defined as the sudden development of hypotension (20% decrease in systolic or mean blood pressure) during the post-transitional period and/or oliguria (50% decrease in urine volume, passage of <1 mL/kg/h of urine over 8 h, or absence of urination for >4 h) after a period of stable respiration and circulation, without any obvious cause such as hemorrhage, sepsis, or symptomatic patent ductus arteriosus.12 Pregnancy-induced hypertension (PIH) was defined as hypertension with or without proteinuria occurring after 20 weeks of gestation. Severe PIH was defined as proteinuria >2.0 g/24 h. Twinetwin transfusion syndrome (TTTS) was defined according to the classification of Quintero et al.13 NRFS was defined as the lack of baseline variability in fetal heart rate, variable decelerations, late
Comparisons between groups were performed using the ManneWhitney non-parametric rank test or Fisher’s exact test, as appropriate. Values of P < 0.05 were considered statistically significant, and data are reported as median and range. Statistical analysis was performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, EZR is a modified version of R Commander designed to add statistical functions frequently used in biostatistics.14 This study was approved by the ethics committee of the research institute at Toyohashi Municipal Hospital and followed the ethical principles indicated in the Declaration of Helsinki.
3. Results Table 2 shows short-term outcomes for live births. Among 21 cases, 10 cases were live births with a median gestational age of 25.2 weeks (range, 22.4e27.1 weeks) and median birth weight of 426 g (range, 370e483 g). Among the 10 live births, eight neonates were discharged from hospital alive, while two neonates died before discharge. Nine of the 10 live births (90%) were delivered by cesarean section. The survival rate was 38% (8 of 21) for all cases, and 80% (8 of 10) for live births. Among the live births without chromosomal anomalies or severe asphyxia, the survival rate (at gestational age 23.3e27.2 weeks and live birth weight 370e483 g) was 100% (8 of 8). Seven of the
Please cite this article in press as: Nagara S, et al., Neurodevelopmental outcomes at 3 years old for infants with birth weights under 500 g, Pediatrics and Neonatology (2017), https://doi.org/10.1016/j.pedneo.2017.09.005
+
MODEL
ART Z assisted reproductive technology; DD twin Z dichorionic diamniotic twin; MD twin Z monochorionic diamniotic twin; MP Z multiparity; NRFS Z non-reassuring fetal status; PIH Z pregnancy-induced hypertension; PP Z primiparity; SGA Z small for gestational age; SP Z spontaneous pregnancy; TTTS Z twinetwin transfusion syndrome.
Female þ 34 Japanese ART MP Singleton e e e PIH Male þ 28 Japanese SP MP Singleton e e e e Female þ 27 Japanese SP PP Singleton e e e e Unknown þ 33 Japanese SP PP Singleton e e e Primary aldosteronism Male e 26 Japanese ART MP DD twin þ e þ e Female e 34 Japanese ART PP MD twin e e e TTTS Male e 38 Japanese SP PP Singleton e e e Fetal hydrops Female e 32 Chinese SP MP Singleton e e e Excessive torsion of umbilical cord Male þ 42 Japanese SP MP Singleton e e e e
Male e 28 Japanese SP MP Singleton e e e Chronic glomerulo-nephritis
Female e 34 Japanese ART PP MD twin e e e TTTS
260 252/7 320 240/7 320 240/7 500 232/7 500 232/7 500 232/7 380 223/7
Body weight, g Gestational age, weeks Sex SGA Maternal age, y Race Pregnancy Parity Multiple birth Tocolysis Antenatal steroid NRFS Maternal or fetal complication
280 222/7
500 224/7
450 232/7
Case 20 Case 19 Case 18 Case 17 Case 16 Case 15 Case 14 Case 13 Case 12 Case 11
Patient characteristics (stillbirths). Table 1b
400 253/7
S. Nagara et al
Case 21
4
eight surviving infants (88%) weighed less than 2500 g at a corrected age of 40 weeks. Table 3 shows a comparison between alive infants and stillbirths or deaths. Body weight, maternal age, race, pregnancy, parity, multiple births, tocolysis, antenatal steroid, and NRFS did not differ significantly between groups. Among the factors correlating strongly with live infants as compared to stillbirths or deaths, gestational age and SGA differed significantly. Median gestational age for alive infants was 25.9 weeks (range, 23.3e27.1 weeks) and all surviving infants were SGA. On the other hand, median gestational age was 23.3 weeks (range, 22.2e25.4 weeks) for stillbirth or death. No significant difference was found in sex, but seven of the eight surviving infants were female. Multivariate logistic regression analysis was conducted, using the backward stepwise elimination method. Gestational age, SGA, sex, and maternal age, as the only dependent variables showing values of P < 0.2 on univariate analysis, were included in the multiple logistic models. Gestational age was associated with an increased risk of death (odds ratio, 0.361; 95% confidence interval: 0.151e0.864; P Z 0.022). Mortality risk increased 2.8-fold per 1-week decrease in gestational age. Table 4 shows long-term outcomes at a corrected age of 18 months and at 3 years of age for surviving infants. Two of seven infants (29%) showed normal DQ, three infants (42%) showed mild neurodevelopmental disability, and two infants (29%) showed severe neurodevelopmental disability at 3 years. One infant (Case 3) had periventricular leukomalacia and cerebral palsy. Case 8 showed low DQ in language and society at a corrected age of 18 months. She was diagnosed with autism spectrum disorder according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition by a psychiatrist. Language development subsequently improved, and she showed normal DQ at 3 years old. Two infants (Cases 1 and 6) had dysopia, and one infant (Case 7) had hypacusia. One patient (Case 2) returned to Brazil and long-term outcomes were unable to be determined. Two of the seven infants (29%) had short stature at 3 years old (<3 SD).
4. Discussion Treatment strategy, including decisions on the timing of delivery for fetuses with expected live- or stillbirth weight 500 g, was determined based on the experience of the physician in charge, because these types of cases are uncommon, and reports on survival rates and long-term prognosis remain limited. In the present study, survival rate was 80% among live births with birth weights less than 500 g. Upon reaching 3 years old, two of the seven infants (29%) showed normal development, three infants (42%) showed mild neurodevelopmental disability, and two infants (29%) showed severe neurodevelopmental disability. Although the relationship between neurological outcomes at a corrected age of 18 months and at 3 years old showed a substantial correlation, it may be different, and long-term follow-up is needed. Rieger-Fackeldey et al.7 found that 26% of infants with birth weight 500 g who reached 5 years old had developed normally, and 58% showed mild disability. On the other hand, Keir et al.6 reported that 11%
Please cite this article in press as: Nagara S, et al., Neurodevelopmental outcomes at 3 years old for infants with birth weights under 500 g, Pediatrics and Neonatology (2017), https://doi.org/10.1016/j.pedneo.2017.09.005
+
MODEL
PDA with ligation, Cow’s milk allergy, CLD, ROP LCD, ROP NEC, CLD, ROP LCD PDA with ligation, LCD, Sepsis, PVL, ROP, Cataract LCD, CLD, ROP Severe IVH, CLD, ROP
CLD Z chronic lung disease; CS Z cesarean section; IVH Z intraventricular hemorrhage; LCD Z late-onset circulatory dysfunction; NEC Z necrotizing enterocolitis; PDA Z patent ductus arteriosus; PVL Z periventricular leukomalacia.
Down syndrome Neonatal asphyxia
34 12 h 139 1476 164 1800 129 1950 107 1201 117 2344 156 2446 138 3430
110 1024
34 12 h 22 95 8 109 42 42 50
75
þ þ e e e þ þ þ þ
þ
Dead CS 4/7 Dead Vaginal 2/3 Alive CS 1/6 Alive CS 3/9 Alive CS 5/7 Alive CS 3/8 Alive CS 3/9 Alive CS 4/5 Alive CS 1/2 Alive CS 2/5
Case 2 Case 1
5
Alive or dead Delivery method Apgar score (1 min/5 min) Surfactant replacement Duration of ventilation, days Hospital stay, days Body weight at corrected age of 40 weeks Complications
Table 2
Short-term outcomes of live birth.
Case 3
Case 4
Case 5
Case 6
Case 7
Case 8
Case 9
Case 10
Less than 500 grams Table 3 death.
Comparison between alive and stillbirth or
Body weight, g Gestational age, weeks Male SGA Maternal age, y Japanese Spontaneous pregnancy Multiparity Singleton Tocolysis Antenatal steroid NRFS
Alive (n Z 8)
Stillbirth or death (n Z 13)
n (%) or median (range)
n (%) or median (range)
P value
422 (370e483) 450 (260e500) 0.47 25.9 (23.3e27.1) 23.3 (22.2e25.4) <0.05 1 (12.5) 8 (100) 35.5 (26e42) 6 (75.0) 6 (75.0)
7 (58.3) 6 (46.1) 33 (26e42) 11 (84.6) 9 (69.2)
0.15 <0.05 0.14 0.62 1
5 5 3 1
7 (53.8) 10 (76.9) 1 (7.7) 0 (0)
1 0.63 0.25 0.38
2 (15.3)
0.33
(62.5) (62.5) (37.5) (12.5)
3 (37.5)
NRFS Z non-reassuring fetal status; SGA Z small for gestational age.
of infants with a birth weight 500 g at a corrected age of 3 years displayed no developmental disability, while 89% had moderate or severe developmental disability. Table 5 shows a comparison of neurodevelopmental outcomes for infants with birth weights under 500 g. Such findings suggest that, in addition to strong growth restriction in utero, high rates of morbidity due to several complications after birth, artificial ventilation, and long hospital stay can affect neural development. Seven of the eight surviving infants (88%) showed extrauterine growth restriction at a corrected age of 40 weeks. However, two of the seven infants examined at 3 years old (14%) had short stature. Further nutritional improvement is needed to prevent extrauterine growth restriction and allow catch-up. In the present study, expectant management in anticipation of fetal growth and maturity resulted in stillbirth and death (13 of 21; 62%). Significant differences in gestational age and SGA were seen between alive infants and stillbirths or deaths. In our study, risk of mortality increased 2.8-fold per 1-week decrease in gestational age. Maturity is important for survival, but intrauterine growth restriction is an important risk factor for sudden stillbirth.5 A dilemma thus surrounds determination of the appropriate time of delivery, and Case 17 in the present study involved NRFS and stillbirth during tocolysis. We believe that these data can be used as a reference for the appropriate time of delivery. In retrospect, among cases of stillbirth in the present study, Case 21, a female at 25 weeks, may have survived if she had been promptly delivered without waiting for further fetal growth. However, more than half of the survivors in the present study exhibited poor neurological development. Therefore, in clinical practice, discussion about the timing of delivery among obstetricians, neonatologists, and parents is important. Furthermore, large studies are needed to determine the appropriate timing of delivery for infants weighing less than 500 g.
Please cite this article in press as: Nagara S, et al., Neurodevelopmental outcomes at 3 years old for infants with birth weights under 500 g, Pediatrics and Neonatology (2017), https://doi.org/10.1016/j.pedneo.2017.09.005
+
MODEL
6
S. Nagara et al Table 4
Long-term outcomes at 3 years.
Developmental quotient
Case 1
Case 2 Case 3
Case 4 Case 5 Case 6
Case 7
Case 8
Posture and movement
95 67 67 69 95 86 75 78 1 2.1 Dysopia
NA NA NA NA NA NA NA NA NA NA
71 84 78 93 95 87 78 91 0.7 1.1
54 56 53 50 53 47 53 50 3.3 3.6 Hypacusia
80 102 112 100 73 102 102 102 1.8 2.4 Autism spectrum disorder
18 mo 3y Cognitive and adaptation 18 mo 3y Language and society 18 mo 3y All areas 18 mo 3y Stature (SD) 3y Body weight (SD) 3y Complications
NA <40 NA <40 NA <40 NA <40 1.9 2.7 Cerebral palsy
41 35 54 43 40 30 50 41 3.4 3.6
94 103 81 31 94 42 85 39 0.9 2.4 Dysopia
A developmental quotient 80 was normal. NA Z not available; SD Z standard deviation; 18 mo Z at corrected age of 18 months; 3 y Z at 3 years old.
Table 5
Comparison of neurodevelopmental outcomes for infants with birth weights under 500 g.
Number of infants
Neurodevelopmental outcomes Normal
Mild
9 19 7
1 (11%) 5 (26%) 2 (29%)
0 (0%) 11 (58%) 3 (42%)
Hearing impairment
Evaluation age
Country
Reference
Moderate-severe
Visual impairment
8 (89%) 3 (16%) 2 (29%)
2 (22%) 8 (42%) 2 (28%)
1 (11%) 3 (16%) 1 (14%)
5 years 3 years 3 years
Australia Germany Japan
6 9 This study
Two factors limit the viability of infants: prematurity (gestational age of 22 or 23 weeks); and extremely low birth weight (birth weight 500 g). Stoll et al.15 and Ishii et al.1 found that infants born at 22 or 23 gestational weeks displayed a high risk of death and morbidity compared with infants born at 24e28 weeks. However, in our hospital, all six extremely low birth weight infants born at a gestational age of 22 weeks were discharged from hospital alive. We were thus able to report a satisfactory survival rate for infants born at 22 weeks.16 On the other hand, the 80% survival rate for live infants with birth weight 500 g in the present study and the 100% survival rate among live infants without congenital anomalies or severe asphyxia were higher than the survival rates described in previous reports, which ranged from 11% to 60%.6 Our strategy of acuteperiod treatment for extremely low birth weight infants is presumably conducted at many institutions throughout Japan, and determining how these treatment policies contribute to the high survival rate is difficult. However, differences in treatment policy may be related to differences in prognosis, and a comparative investigation of treatment policies in multiple institutions, including obstetric administration, may contribute to the improvement of prognoses for infants in the future. In 1991, because of rapid advances in neonatal intensive care, the limit of viability as defined in the Maternal Protection Law (formerly the Eugenic Protection Law) in Japan was revised from 24 to 22 completed weeks of gestation. Since then, Japanese clinicians have aimed at resuscitating infants at 22 weeks of gestation. However, responses differ among institutions in practice. In anticipation of pending delivery, we schedule antenatal visits as much as
possible. During these visits, the general prognosis of such cases in Japan is explained to the parents. A discussion is held with the parents on the status of the fetus to inform them about treatment decisions. In our hospital, we resuscitate babies born at gestational ages >22 weeks irrespective of birth weight. We believe that the active treatment of cases in which fetuses are close to viability thresholds leads to improvements in prognosis. The present study has some limitations. The sample size was small and the study was carried out in a single center over a long period. The results thus may not be representative of all hospitals in Japan and the possibility of selection bias exists because this hospital was chosen by mothers or referral patients. Nevertheless, the present data will provide useful information for obstetricians and neonatologists regarding the timing of delivery for babies with expected birth weights 500 g, because reports on neurodevelopmental outcomes based on gestational age and birth weight are few. Further large population-based studies are needed on the survival and neurodevelopmental outcomes of extremely small infants with birth weights less than 500 g.
Ethical approval All procedures performed in this paper are in accordance with the ethical standards of the institutional committee on human research.
Conflicts of interests The authors have no conflicts of interests to disclose.
Please cite this article in press as: Nagara S, et al., Neurodevelopmental outcomes at 3 years old for infants with birth weights under 500 g, Pediatrics and Neonatology (2017), https://doi.org/10.1016/j.pedneo.2017.09.005
+
MODEL
Less than 500 grams
Acknowledgements We are grateful to Dr. Tomohiro Iwasaki (Juntendo University Shizuoka Hospital) for his help.
References 1. Ishii N, Kono Y, Yonemoto N, Kusuda S, Fujimura M, Neonatal Research Network, Japan. Outcomes of infants born at 22 and 23 weeks’ gestation. Pediatrics 2013;132:62e71. 2. Itabashi K, Horiuchi T, Kusuda S, Kabe K, Itani Y, Nakamura T, et al. Mortality rates for extremely low birth weight infants born in Japan in 2005. Pediatrics 2009;123:445e50. 3. Lau C, Ambalavanan N, Chakraborty H, Wingate MS, Carlo WA. Extremely low birth weight and infant mortality rates in the United States. Pediatrics 2013;131:855e60. 4. ECC Committee, Subcommittees and Task Forces of the American Heart Association. 2005 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2005;112. IV1-203. 5. Frøen JF, Gardosi JO, Thurmann A, Francis A, StrayPedersen B. Restricted fetal growth in sudden intrauterine unexplained death. Acta Obstet Gynecol Scand 2004;83: 801e7. 6. Keir A, McPhee A, Wilkinson D. Beyond the borderline: outcomes for inborn infants born at 500 grams. J Paediatr Child Health 2014;50:146e52. 7. Rieger-Fackeldey E, Blank C, Dinger J, Steinmacher J, Bode H, Schulze A. Growth, neurological and cognitive development in infants with a birthweight <501 g at age 5 years. Acta Paediatr 2010;99:1350e5.
7 8. Uesugi M, Tokuhisa K, Shimada T. The reliability and validity of the alberta infant motor scale in Japan. J Phys Ther Sci 2008; 20:169e75. 9. Koyama T, Osada H, Tsujii H, Kurita H. Utility of the Kyoto scale of psychological development in cognitive assessment of children with pervasive developmental disorders. Psychiatry Clin Neurosci 2009;63:241e3. 10. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978;92:529e34. 11. Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 1978;187:1e7. 12. Koyama N, Kouwaki M, Tanaka T, Ohki S, Iwase K, Terasawa S, et al. Clinical features of late-onset circulatory dysfunction in premature infants. Res Rep Neonatol 2014;4:139e45. 13. Quintero RA, Morales WJ, Allen MH, Bornick PW, Johnson PK, Kruger M. Staging of twin-twin transfusion syndrome. J Perinatol 1999;19:550e5. 14. Kanda Y. Investigation of the freely available easy-to-use software ’EZR’ for medical statistics. Bone Marrow Transplant 2013;48:452e8. 15. Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC, et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 2010;126:443e56. 16. Sugiura T, Kouwaki M, Togawa Y, Sugimoto M, Togawa T, Koyama N. Neurodevelopmental outcomes at 18 months’ corrected age of infants born at 22 weeks of gestation. Neonatology 2011;100:228e32.
Please cite this article in press as: Nagara S, et al., Neurodevelopmental outcomes at 3 years old for infants with birth weights under 500 g, Pediatrics and Neonatology (2017), https://doi.org/10.1016/j.pedneo.2017.09.005
MODEL
Pediatrics and Neonatology (2017) xx, 1e7
Available online at www.sciencedirect.com
ScienceDirect journal homepage: http://www.pediatr-neonatol.com
Original Article
Neurodevelopmental outcomes at 3 years old for infants with birth weights under 500 g Syunsuke Nagara a,b, Masanori Kouwaki a,*, Takao Togawa a,c, Tokio Sugiura a,c, Mayumi Okada d, Norihisa Koyama a a
Department of Pediatrics, Toyohashi Municipal Hospital, Toyohashi, Aichi, Japan Department of Pediatrics, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Aichi, Japan c Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan d Department of Obstetrics and Gynecology, Toyohashi Municipal Hospital, Toyohashi, Aichi, Japan b
Received Feb 14, 2017; received in revised form Jun 5, 2017; accepted Sep 15, 2017
Available online - - -
Key Words extremely low birth weight infants; stillbirth; extreme prematurity; less than 500 g; survival rate
Background: Marked improvements have been achieved in the survival of extremely low birth weight infants, but survival rates and prognoses of extremely small infants with birth weights 500 g remain poor. The aim of this study was to clarify long-term outcomes for surviving infants with birth weights 500 g. Methods: The study population comprised fetuses of gestational age 22 weeks, expected live- or stillbirth weight 500 g, and birth date between 2003 and 2012. Developmental assessments were performed prospectively at 3 years old. Results: Data were obtained for 21 fetuses, including 10 live births and 11 stillbirths. Of the 10 live births, median gestational age was 25.2 weeks (range, 22.4e27.1 weeks), median birth weight was 426 g (range, 370e483 g), and two neonates died before discharge. One infant with severe asphyxia died within 12 h and another infant with Down syndrome died at 34 days. The survival rate was thus 80%. All surviving infants were small for gestational age. Seven of the 8 surviving infants (88%) weighed less than 2500 g at a corrected age of 40 weeks. Seven infants were available for developmental assessments at 3 years old. One infant could not be followed. Two of those seven infants (29%) showed normal development, three infants (42%) showed mild neurodevelopmental disability, and two infants (29%) showed severe neurodevelopmental disability. One infant had periventricular leukomalacia and cerebral palsy. Two of the seven infants (29%) had short stature (<3 SD) at 3 years old.
* Corresponding author. E-mail address: [email protected] (M. Kouwaki). https://doi.org/10.1016/j.pedneo.2017.09.005 1875-9572/Copyright ª 2017, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Nagara S, et al., Neurodevelopmental outcomes at 3 years old for infants with birth weights under 500 g, Pediatrics and Neonatology (2017), https://doi.org/10.1016/j.pedneo.2017.09.005
+
MODEL
2
S. Nagara et al Conclusion: Although the survival rate among live births was good (80%) in this study, neurodevelopmental outcomes remained poor in infants with birth weights 500 g. Further large studies are needed to assess long-term outcomes for extremely small infants. Copyright ª 2017, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).
1. Introduction With continuing advances in perinatal care, marked improvements in the survival of extremely low birth weight infants have been well documented.1,2 However, survival rates and prognoses of extremely small infants with birth weight less than 500 g are still poor. Many studies have defined live birth as requiring a birth weight 500 g, but increased reporting may account for the increased number of infants with birth weights 500 g.3 Although resuscitation of infants with birth weight 400 g was not recommended by the American College of Cardiology/American Heart Association 2005 guidelines,4 this criterion was discarded in 2015. Although the criteria defining human viability vary between countries, this has recently changed. Neonatal mortality rates are higher in infants with lower birth weights and greater degree of prematurity.2,3 Consequently, extending the gestational period and increasing the birth weight is recommended. However, intrauterine growth restriction represents an important risk factor for sudden stillbirth,5 and inadequate fetal growth may occasionally increase the risk of stillbirth even if the gestational period is extended. In cases with live- or stillbirth weight 500 g, no consensus has been reached and data are lacking on whether early delivery to preempt intrauterine hypoxia is preferable to delaying delivery to obtain maturity and growth even in view of the risk of stillbirth. Moreover, few studies have examined the long-term prognosis in infants with birth weights less than 500 g.6,7 Our strategy with regard to the timing of delivery for pregnancies with live- or stillbirth weight 500 g is to deliver cases where continued pregnancy would compromise maternal health or where non-reassuring fetal status (NRFS) is identified. Apart from the above-mentioned situations, we opt for expectant management rather than early delivery until 26 weeks of gestation, in anticipation of fetal growth. Beyond 26 weeks of gestation, we consider delivery if fetal growth has ceased. To evaluate our policy, the clinical characteristics of alive and stillborn or dead infants with body weights less than 500 g were compared retrospectively. In addition, to clarify the long-term outcomes of surviving infants with birth weights less than 500 g, developmental assessments were performed prospectively at a corrected age of 18 months old and at 3 years old.
2. Methods 2.1. Study design and patient population The study population comprised fetuses with gestational age 22 weeks and lives- or stillbirth weight 500 g delivered between January 1, 2003 and December 31, 2012. Toyohashi Municipal Hospital is a single tertiary perinatal medical center as well as a specialized clinic for all highrisk pregnancies in the East Mikawa district, where the population is approximately 700,000. The average delivery rate is 900e1100 infants per year. About 20 extremely low birth weight infants are admitted to our hospital each year. Our strategy of acute period treatment for extremely low birth weight infants includes: the use of a bronchial tube of maximum possible size; artificial respiration by intermittent positive-pressure ventilation during the acute period; raising the target mean blood pressure to the number of weeks of gestation by means of catecholamines, hydrocortisone, and volume bolus; fentanyl sedation; administration of indomethacin at 12 h after birth to prevent patent ductus arteriosus; glucose and insulin therapy; minimal enteral nutrition at an extremely early period; administration of probiotics; and parenteral nutrition from an early stage. Table 1a and b show the patient characteristics for live births and stillbirths, respectively. The clinical characteristics of alive and stillborn or dead infants were compared retrospectively. Finally, to investigate long-term outcomes, developmental assessments were carried out prospectively at 3 years old. Development was assessed using the new Kyoto Scale of Psychological Development (KSPD) test, which yields scores for neurodevelopment. The new KSPD test is a Japanese standard developmental test.8 This individualized face-to-face test is administered by experienced psychologists to assess child development in the following three areas: posture and movement (fine and gross motor functions); cognitive and adaptation [non-verbal reasoning and visuospatial perceptions assessed using materials (e.g., blocks, miniature cars, and marbles)]; and language and society (interpersonal relationships, socialization, and verbal abilities).9 Developmental quotient (DQ) was determined using developmental age (as determined from the new KSPD test)/chronological age 100. We defined DQ 80 as normal, DQ 40 and < 80 as indicating mild
Please cite this article in press as: Nagara S, et al., Neurodevelopmental outcomes at 3 years old for infants with birth weights under 500 g, Pediatrics and Neonatology (2017), https://doi.org/10.1016/j.pedneo.2017.09.005
+
MODEL
Less than 500 grams Table 1a
3
Patient characteristics (live births).
Body weight, g Gestational age, weeks Sex SGA Maternal age, y Ethnicity Pregnancy Parity Multiple births Tocolysis Antenatal steroid NRFS Maternal or fetal complication
Case 1
Case 2
Case 3
Case 4
Case 5
Case 6
Case 7
Case 8
Case 9
Case 10
428 232/7
392 235/7
483 242/7
472 252/7
370 263/7
384 264/7
436 264/7
416 271/7
472 223/7
450 250/7
Female þ 26 Japanese ART MP DD twin þ e e e
Female þ 35 Brazilian SP PP Singleton e e e HELLP syndrome
Female þ 30 Japanese SP MP Singleton þ e e TTTS
Female þ 36 Japanese ART MP MD twin e e e PIH
Male þ 35 Japanese SP PP MD twin e þ þ PIH
Female þ 37 Brazilian SP PP Singleton e e þ e
Female þ 40 Japanese SP MP Singleton þ e þ Hypertension
Female þ 42 Japanese SP MP Singleton e e e PIH
Male þ 34 Brazilian SP MP Singleton e e e e
Male þ 32 Japanese SP PP Singleton e e þ e
ART Z assisted reproductive technology; DD twin Z dichorionic diamniotic twin; HELLP syndrome Z hemolysis, elevated liver enzymes, and low platelet syndrome; MD twin Z monochorionic diamniotic twin; MP Z multiparity; NRFS Z non-reassuring fetal status; PIH Z pregnancy-induced hypertension; PP Z primiparity; SGA Z small for gestational age; SP Z spontaneous pregnancy; TTTS Z twinetwin transfusion syndrome.
neurodevelopmental disability, and DQ < 40 as indicating severe neurodevelopmental disability.
deceleration, or prolonged deceleration with lack of variability.
2.2. Definitions
2.3. Statistical analysis
Gestational age was calculated from fertilization in the case of assisted reproductive technology or evaluated from crown-rump length using ultrasonography during early pregnancy in the case of spontaneous pregnancy. Infants with live- or stillbirth weight below the 10th percentile using Japanese charts were classified as small for gestational age (SGA). Chronic lung disease (CLD) was defined as a requirement for supplemental oxygen at the postmenstrual age of 36 weeks. Intraventricular hemorrhage (IVH) was diagnosed from cranial imaging via cranial ultrasound by day 28 after birth. Severe IVH was diagnosed as grade 3 or 4.10 A diagnosis of cystic periventricular leukomalacia (PVL) was made using either ultrasonography or magnetic resonance imaging of the head, performed at 2 weeks of age or later. Necrotizing enterocolitis was defined according to the classification of Bell et al.11 as stage II or higher. Late-onset circulatory dysfunction (LCD) was defined as the sudden development of hypotension (20% decrease in systolic or mean blood pressure) during the post-transitional period and/or oliguria (50% decrease in urine volume, passage of <1 mL/kg/h of urine over 8 h, or absence of urination for >4 h) after a period of stable respiration and circulation, without any obvious cause such as hemorrhage, sepsis, or symptomatic patent ductus arteriosus.12 Pregnancy-induced hypertension (PIH) was defined as hypertension with or without proteinuria occurring after 20 weeks of gestation. Severe PIH was defined as proteinuria >2.0 g/24 h. Twinetwin transfusion syndrome (TTTS) was defined according to the classification of Quintero et al.13 NRFS was defined as the lack of baseline variability in fetal heart rate, variable decelerations, late
Comparisons between groups were performed using the ManneWhitney non-parametric rank test or Fisher’s exact test, as appropriate. Values of P < 0.05 were considered statistically significant, and data are reported as median and range. Statistical analysis was performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, EZR is a modified version of R Commander designed to add statistical functions frequently used in biostatistics.14 This study was approved by the ethics committee of the research institute at Toyohashi Municipal Hospital and followed the ethical principles indicated in the Declaration of Helsinki.
3. Results Table 2 shows short-term outcomes for live births. Among 21 cases, 10 cases were live births with a median gestational age of 25.2 weeks (range, 22.4e27.1 weeks) and median birth weight of 426 g (range, 370e483 g). Among the 10 live births, eight neonates were discharged from hospital alive, while two neonates died before discharge. Nine of the 10 live births (90%) were delivered by cesarean section. The survival rate was 38% (8 of 21) for all cases, and 80% (8 of 10) for live births. Among the live births without chromosomal anomalies or severe asphyxia, the survival rate (at gestational age 23.3e27.2 weeks and live birth weight 370e483 g) was 100% (8 of 8). Seven of the
Please cite this article in press as: Nagara S, et al., Neurodevelopmental outcomes at 3 years old for infants with birth weights under 500 g, Pediatrics and Neonatology (2017), https://doi.org/10.1016/j.pedneo.2017.09.005
+
MODEL
ART Z assisted reproductive technology; DD twin Z dichorionic diamniotic twin; MD twin Z monochorionic diamniotic twin; MP Z multiparity; NRFS Z non-reassuring fetal status; PIH Z pregnancy-induced hypertension; PP Z primiparity; SGA Z small for gestational age; SP Z spontaneous pregnancy; TTTS Z twinetwin transfusion syndrome.
Female þ 34 Japanese ART MP Singleton e e e PIH Male þ 28 Japanese SP MP Singleton e e e e Female þ 27 Japanese SP PP Singleton e e e e Unknown þ 33 Japanese SP PP Singleton e e e Primary aldosteronism Male e 26 Japanese ART MP DD twin þ e þ e Female e 34 Japanese ART PP MD twin e e e TTTS Male e 38 Japanese SP PP Singleton e e e Fetal hydrops Female e 32 Chinese SP MP Singleton e e e Excessive torsion of umbilical cord Male þ 42 Japanese SP MP Singleton e e e e
Male e 28 Japanese SP MP Singleton e e e Chronic glomerulo-nephritis
Female e 34 Japanese ART PP MD twin e e e TTTS
260 252/7 320 240/7 320 240/7 500 232/7 500 232/7 500 232/7 380 223/7
Body weight, g Gestational age, weeks Sex SGA Maternal age, y Race Pregnancy Parity Multiple birth Tocolysis Antenatal steroid NRFS Maternal or fetal complication
280 222/7
500 224/7
450 232/7
Case 20 Case 19 Case 18 Case 17 Case 16 Case 15 Case 14 Case 13 Case 12 Case 11
Patient characteristics (stillbirths). Table 1b
400 253/7
S. Nagara et al
Case 21
4
eight surviving infants (88%) weighed less than 2500 g at a corrected age of 40 weeks. Table 3 shows a comparison between alive infants and stillbirths or deaths. Body weight, maternal age, race, pregnancy, parity, multiple births, tocolysis, antenatal steroid, and NRFS did not differ significantly between groups. Among the factors correlating strongly with live infants as compared to stillbirths or deaths, gestational age and SGA differed significantly. Median gestational age for alive infants was 25.9 weeks (range, 23.3e27.1 weeks) and all surviving infants were SGA. On the other hand, median gestational age was 23.3 weeks (range, 22.2e25.4 weeks) for stillbirth or death. No significant difference was found in sex, but seven of the eight surviving infants were female. Multivariate logistic regression analysis was conducted, using the backward stepwise elimination method. Gestational age, SGA, sex, and maternal age, as the only dependent variables showing values of P < 0.2 on univariate analysis, were included in the multiple logistic models. Gestational age was associated with an increased risk of death (odds ratio, 0.361; 95% confidence interval: 0.151e0.864; P Z 0.022). Mortality risk increased 2.8-fold per 1-week decrease in gestational age. Table 4 shows long-term outcomes at a corrected age of 18 months and at 3 years of age for surviving infants. Two of seven infants (29%) showed normal DQ, three infants (42%) showed mild neurodevelopmental disability, and two infants (29%) showed severe neurodevelopmental disability at 3 years. One infant (Case 3) had periventricular leukomalacia and cerebral palsy. Case 8 showed low DQ in language and society at a corrected age of 18 months. She was diagnosed with autism spectrum disorder according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition by a psychiatrist. Language development subsequently improved, and she showed normal DQ at 3 years old. Two infants (Cases 1 and 6) had dysopia, and one infant (Case 7) had hypacusia. One patient (Case 2) returned to Brazil and long-term outcomes were unable to be determined. Two of the seven infants (29%) had short stature at 3 years old (<3 SD).
4. Discussion Treatment strategy, including decisions on the timing of delivery for fetuses with expected live- or stillbirth weight 500 g, was determined based on the experience of the physician in charge, because these types of cases are uncommon, and reports on survival rates and long-term prognosis remain limited. In the present study, survival rate was 80% among live births with birth weights less than 500 g. Upon reaching 3 years old, two of the seven infants (29%) showed normal development, three infants (42%) showed mild neurodevelopmental disability, and two infants (29%) showed severe neurodevelopmental disability. Although the relationship between neurological outcomes at a corrected age of 18 months and at 3 years old showed a substantial correlation, it may be different, and long-term follow-up is needed. Rieger-Fackeldey et al.7 found that 26% of infants with birth weight 500 g who reached 5 years old had developed normally, and 58% showed mild disability. On the other hand, Keir et al.6 reported that 11%
Please cite this article in press as: Nagara S, et al., Neurodevelopmental outcomes at 3 years old for infants with birth weights under 500 g, Pediatrics and Neonatology (2017), https://doi.org/10.1016/j.pedneo.2017.09.005
+
MODEL
PDA with ligation, Cow’s milk allergy, CLD, ROP LCD, ROP NEC, CLD, ROP LCD PDA with ligation, LCD, Sepsis, PVL, ROP, Cataract LCD, CLD, ROP Severe IVH, CLD, ROP
CLD Z chronic lung disease; CS Z cesarean section; IVH Z intraventricular hemorrhage; LCD Z late-onset circulatory dysfunction; NEC Z necrotizing enterocolitis; PDA Z patent ductus arteriosus; PVL Z periventricular leukomalacia.
Down syndrome Neonatal asphyxia
34 12 h 139 1476 164 1800 129 1950 107 1201 117 2344 156 2446 138 3430
110 1024
34 12 h 22 95 8 109 42 42 50
75
þ þ e e e þ þ þ þ
þ
Dead CS 4/7 Dead Vaginal 2/3 Alive CS 1/6 Alive CS 3/9 Alive CS 5/7 Alive CS 3/8 Alive CS 3/9 Alive CS 4/5 Alive CS 1/2 Alive CS 2/5
Case 2 Case 1
5
Alive or dead Delivery method Apgar score (1 min/5 min) Surfactant replacement Duration of ventilation, days Hospital stay, days Body weight at corrected age of 40 weeks Complications
Table 2
Short-term outcomes of live birth.
Case 3
Case 4
Case 5
Case 6
Case 7
Case 8
Case 9
Case 10
Less than 500 grams Table 3 death.
Comparison between alive and stillbirth or
Body weight, g Gestational age, weeks Male SGA Maternal age, y Japanese Spontaneous pregnancy Multiparity Singleton Tocolysis Antenatal steroid NRFS
Alive (n Z 8)
Stillbirth or death (n Z 13)
n (%) or median (range)
n (%) or median (range)
P value
422 (370e483) 450 (260e500) 0.47 25.9 (23.3e27.1) 23.3 (22.2e25.4) <0.05 1 (12.5) 8 (100) 35.5 (26e42) 6 (75.0) 6 (75.0)
7 (58.3) 6 (46.1) 33 (26e42) 11 (84.6) 9 (69.2)
0.15 <0.05 0.14 0.62 1
5 5 3 1
7 (53.8) 10 (76.9) 1 (7.7) 0 (0)
1 0.63 0.25 0.38
2 (15.3)
0.33
(62.5) (62.5) (37.5) (12.5)
3 (37.5)
NRFS Z non-reassuring fetal status; SGA Z small for gestational age.
of infants with a birth weight 500 g at a corrected age of 3 years displayed no developmental disability, while 89% had moderate or severe developmental disability. Table 5 shows a comparison of neurodevelopmental outcomes for infants with birth weights under 500 g. Such findings suggest that, in addition to strong growth restriction in utero, high rates of morbidity due to several complications after birth, artificial ventilation, and long hospital stay can affect neural development. Seven of the eight surviving infants (88%) showed extrauterine growth restriction at a corrected age of 40 weeks. However, two of the seven infants examined at 3 years old (14%) had short stature. Further nutritional improvement is needed to prevent extrauterine growth restriction and allow catch-up. In the present study, expectant management in anticipation of fetal growth and maturity resulted in stillbirth and death (13 of 21; 62%). Significant differences in gestational age and SGA were seen between alive infants and stillbirths or deaths. In our study, risk of mortality increased 2.8-fold per 1-week decrease in gestational age. Maturity is important for survival, but intrauterine growth restriction is an important risk factor for sudden stillbirth.5 A dilemma thus surrounds determination of the appropriate time of delivery, and Case 17 in the present study involved NRFS and stillbirth during tocolysis. We believe that these data can be used as a reference for the appropriate time of delivery. In retrospect, among cases of stillbirth in the present study, Case 21, a female at 25 weeks, may have survived if she had been promptly delivered without waiting for further fetal growth. However, more than half of the survivors in the present study exhibited poor neurological development. Therefore, in clinical practice, discussion about the timing of delivery among obstetricians, neonatologists, and parents is important. Furthermore, large studies are needed to determine the appropriate timing of delivery for infants weighing less than 500 g.
Please cite this article in press as: Nagara S, et al., Neurodevelopmental outcomes at 3 years old for infants with birth weights under 500 g, Pediatrics and Neonatology (2017), https://doi.org/10.1016/j.pedneo.2017.09.005
+
MODEL
6
S. Nagara et al Table 4
Long-term outcomes at 3 years.
Developmental quotient
Case 1
Case 2 Case 3
Case 4 Case 5 Case 6
Case 7
Case 8
Posture and movement
95 67 67 69 95 86 75 78 1 2.1 Dysopia
NA NA NA NA NA NA NA NA NA NA
71 84 78 93 95 87 78 91 0.7 1.1
54 56 53 50 53 47 53 50 3.3 3.6 Hypacusia
80 102 112 100 73 102 102 102 1.8 2.4 Autism spectrum disorder
18 mo 3y Cognitive and adaptation 18 mo 3y Language and society 18 mo 3y All areas 18 mo 3y Stature (SD) 3y Body weight (SD) 3y Complications
NA <40 NA <40 NA <40 NA <40 1.9 2.7 Cerebral palsy
41 35 54 43 40 30 50 41 3.4 3.6
94 103 81 31 94 42 85 39 0.9 2.4 Dysopia
A developmental quotient 80 was normal. NA Z not available; SD Z standard deviation; 18 mo Z at corrected age of 18 months; 3 y Z at 3 years old.
Table 5
Comparison of neurodevelopmental outcomes for infants with birth weights under 500 g.
Number of infants
Neurodevelopmental outcomes Normal
Mild
9 19 7
1 (11%) 5 (26%) 2 (29%)
0 (0%) 11 (58%) 3 (42%)
Hearing impairment
Evaluation age
Country
Reference
Moderate-severe
Visual impairment
8 (89%) 3 (16%) 2 (29%)
2 (22%) 8 (42%) 2 (28%)
1 (11%) 3 (16%) 1 (14%)
5 years 3 years 3 years
Australia Germany Japan
6 9 This study
Two factors limit the viability of infants: prematurity (gestational age of 22 or 23 weeks); and extremely low birth weight (birth weight 500 g). Stoll et al.15 and Ishii et al.1 found that infants born at 22 or 23 gestational weeks displayed a high risk of death and morbidity compared with infants born at 24e28 weeks. However, in our hospital, all six extremely low birth weight infants born at a gestational age of 22 weeks were discharged from hospital alive. We were thus able to report a satisfactory survival rate for infants born at 22 weeks.16 On the other hand, the 80% survival rate for live infants with birth weight 500 g in the present study and the 100% survival rate among live infants without congenital anomalies or severe asphyxia were higher than the survival rates described in previous reports, which ranged from 11% to 60%.6 Our strategy of acuteperiod treatment for extremely low birth weight infants is presumably conducted at many institutions throughout Japan, and determining how these treatment policies contribute to the high survival rate is difficult. However, differences in treatment policy may be related to differences in prognosis, and a comparative investigation of treatment policies in multiple institutions, including obstetric administration, may contribute to the improvement of prognoses for infants in the future. In 1991, because of rapid advances in neonatal intensive care, the limit of viability as defined in the Maternal Protection Law (formerly the Eugenic Protection Law) in Japan was revised from 24 to 22 completed weeks of gestation. Since then, Japanese clinicians have aimed at resuscitating infants at 22 weeks of gestation. However, responses differ among institutions in practice. In anticipation of pending delivery, we schedule antenatal visits as much as
possible. During these visits, the general prognosis of such cases in Japan is explained to the parents. A discussion is held with the parents on the status of the fetus to inform them about treatment decisions. In our hospital, we resuscitate babies born at gestational ages >22 weeks irrespective of birth weight. We believe that the active treatment of cases in which fetuses are close to viability thresholds leads to improvements in prognosis. The present study has some limitations. The sample size was small and the study was carried out in a single center over a long period. The results thus may not be representative of all hospitals in Japan and the possibility of selection bias exists because this hospital was chosen by mothers or referral patients. Nevertheless, the present data will provide useful information for obstetricians and neonatologists regarding the timing of delivery for babies with expected birth weights 500 g, because reports on neurodevelopmental outcomes based on gestational age and birth weight are few. Further large population-based studies are needed on the survival and neurodevelopmental outcomes of extremely small infants with birth weights less than 500 g.
Ethical approval All procedures performed in this paper are in accordance with the ethical standards of the institutional committee on human research.
Conflicts of interests The authors have no conflicts of interests to disclose.
Please cite this article in press as: Nagara S, et al., Neurodevelopmental outcomes at 3 years old for infants with birth weights under 500 g, Pediatrics and Neonatology (2017), https://doi.org/10.1016/j.pedneo.2017.09.005
+
MODEL
Less than 500 grams
Acknowledgements We are grateful to Dr. Tomohiro Iwasaki (Juntendo University Shizuoka Hospital) for his help.
References 1. Ishii N, Kono Y, Yonemoto N, Kusuda S, Fujimura M, Neonatal Research Network, Japan. Outcomes of infants born at 22 and 23 weeks’ gestation. Pediatrics 2013;132:62e71. 2. Itabashi K, Horiuchi T, Kusuda S, Kabe K, Itani Y, Nakamura T, et al. Mortality rates for extremely low birth weight infants born in Japan in 2005. Pediatrics 2009;123:445e50. 3. Lau C, Ambalavanan N, Chakraborty H, Wingate MS, Carlo WA. Extremely low birth weight and infant mortality rates in the United States. Pediatrics 2013;131:855e60. 4. ECC Committee, Subcommittees and Task Forces of the American Heart Association. 2005 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2005;112. IV1-203. 5. Frøen JF, Gardosi JO, Thurmann A, Francis A, StrayPedersen B. Restricted fetal growth in sudden intrauterine unexplained death. Acta Obstet Gynecol Scand 2004;83: 801e7. 6. Keir A, McPhee A, Wilkinson D. Beyond the borderline: outcomes for inborn infants born at 500 grams. J Paediatr Child Health 2014;50:146e52. 7. Rieger-Fackeldey E, Blank C, Dinger J, Steinmacher J, Bode H, Schulze A. Growth, neurological and cognitive development in infants with a birthweight <501 g at age 5 years. Acta Paediatr 2010;99:1350e5.
7 8. Uesugi M, Tokuhisa K, Shimada T. The reliability and validity of the alberta infant motor scale in Japan. J Phys Ther Sci 2008; 20:169e75. 9. Koyama T, Osada H, Tsujii H, Kurita H. Utility of the Kyoto scale of psychological development in cognitive assessment of children with pervasive developmental disorders. Psychiatry Clin Neurosci 2009;63:241e3. 10. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978;92:529e34. 11. Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 1978;187:1e7. 12. Koyama N, Kouwaki M, Tanaka T, Ohki S, Iwase K, Terasawa S, et al. Clinical features of late-onset circulatory dysfunction in premature infants. Res Rep Neonatol 2014;4:139e45. 13. Quintero RA, Morales WJ, Allen MH, Bornick PW, Johnson PK, Kruger M. Staging of twin-twin transfusion syndrome. J Perinatol 1999;19:550e5. 14. Kanda Y. Investigation of the freely available easy-to-use software ’EZR’ for medical statistics. Bone Marrow Transplant 2013;48:452e8. 15. Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC, et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 2010;126:443e56. 16. Sugiura T, Kouwaki M, Togawa Y, Sugimoto M, Togawa T, Koyama N. Neurodevelopmental outcomes at 18 months’ corrected age of infants born at 22 weeks of gestation. Neonatology 2011;100:228e32.
Please cite this article in press as: Nagara S, et al., Neurodevelopmental outcomes at 3 years old for infants with birth weights under 500 g, Pediatrics and Neonatology (2017), https://doi.org/10.1016/j.pedneo.2017.09.005