317
Early Human Development, 29 (1992) 317-322 Elsevier Scientific Publishers Ireland Ltd.
EHD 01296
Readiness of Japan to participate in international collaborative studies M . Fujimura Department
of Neonatal
Medicine, Osaka Medical Health, 840 Murodo-cho,
Center and Research Izumi, Osaka 590-02
Institute (Japan)
for
Maternal
and Child
Summary A significant improvement has been achieved in perinatal mortality figures during the last decade in Japan with a neonatal mortality rate of 2.6 and a stillbirth rate of 4.1 for 1989. With its unique obstetric and neonatal services, there are advantages and also disadvantages in respect of clinical and basic research. The outlook for Japanese neonatal medicine is shown and the prospects for international collaborative studies in the future are given. Key words: Japan; neonatal intensive care; collaborative
study
Introduction Japanese neonatologists have not yet been much involved in the international collaborative studies. What is the reason for this? Is the Japanese clinical standard of neonatal care below the international level? This paper deals with the issue of how contemporary Japan could become a joint member of the international society. For many years this issue has been discussed in politics. I now would like to extend the discussion to neonatology. A summary of the requirements for any neonatal unit to participate in clinical collaborative studies might include the following criteria: (1) sufficient subjects, (2) acceptable standard of care, (3) ability to design the study, (4) willingness to participate, and (5) overall reliability. Overall reliability is rather empirical in nature to judge, and depends on the experience of personal communications between the study designer and the unit personnel. In this respect few Japanese Correspondence to: M. Fujimura, Department of Neonatal Medicine, Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodocho, Izumi, Osaka 590-02, Japan.
318
neonatologists are in good contact with western study planners. Two further requirements for international collaborative studies are: (1) ability in language (English) and (2) accessibility and communication media. Competence in English is required. Most Japanese neonatologists do read English articles very well. This does not necessarily mean that he or she is able to participate in an international setting. Language seems to be one of the major difficulties if international collaborative studies intend to involve a wide range of institutes in Japan. However, there may be pitfalls when dealing with international studies such as (a) environmental difference, (b) ethnic difference and (c) standardization of measurement. The environmental and ethnic differences are correlated with morbidity and mortality. These differences, unless taken into account in the clinical study, may bias the results. Medical care in Japan Medical care is covered in respect of medical costs from the following sources of medical care schemes in Japan: socialized in medical fares, National Medical Insurance, 100% Japanese insured (obstetric service is private), and free choice of medical service. However, the obstetric service for normal pregnancy and delivery is not paid by insurance. Patients have a free choice of medical service. They can either visit one of the clinics in the town or go straight to the general hospital. Sources of obstetric services fall into three main categories, hospital care ( 2 20 beds in size) accounting for 57%, the obstetric clinic (C 20 beds in size) accounting for 42%, and midwifery accounting for 1% of care. Special neonatal care is provided by the pediatrician at the hospital or an obstetrician at a neonatal clinic who may refer the patient to the hospital. Virtually no private practice exists in this country. Prenatal care and delivery are given either by the hospital or by obstetricians who operate a clinic of their own; in general it is the woman’s choice. A number of high risk pregnancies are referred to the hospital obstetric department. Very few pregnant women miss their regular prenatal care. Neonatal special care is available in most areas of Japan and will be discussed later.
TABLE I P&natal
statistics: Japan 1989
Population Number of births Birth rate Infant mortality Neonatal mortality Stillbirth rate ( t 28 weeks) Early neonatal mortality Perinatal mortality
122460000 I 246 802 10.2 4.6 2.6 4.1 1.9 6.0
319
Cohort of Japan
eel 58 40 38 a 10 El
w0-
mmBirth
weight
2&?a-24QD
(g)
Fig. 1. Improvements in neonatal mortality over the last decade. Seventy-five percent of ELBWs less than 1000 g survived in 1990.
Perinatal statistics Table I shows some perinatal statistics from Japan [ 11, which result from its being a densely populated archipelago as 70% of the land area is not suitable for habitation. The annual birth rate is 10.2 per 1000 of the population. The infant mortality per 1000 births is 4.6 which is the lowest in the world while neonatal mortality at less than 4 weeks is 2.6 which is again one of the lowest, but with a relatively high stillbirth rate of 4.1 perinatal mortality is 6.0 per thousand. The birthweight specific neonatal mortality improved rapidly in the last decade. Seventy-five percent of ELBW less than 1000 g survived in 1990 (Fig. 1). Neonatal Medicine of 1990s in Japan Modern neonatal intensive care has developed in Japan during the last 15 years. By 1980 most infants with respiratory distress syndrome were treated with artificial
TABLE II Birth weight specific neonatal mortality 511 NICUs, 1990 (Japan Pediatric Society) Birth weight (g)
Number of admissions
O-27 day mortality
National mortality 1989
500-999 lOOO- 1499 1500- 1999
2000 3786 7634
26.9% 6.9% 3.3%
31.0% 10.3% 3.5%
320
ventilation. Table II shows the number of ELBW infants cared for in a year in major NICUs [ 21, Among 114 NICUs only 15 admitted more than 15 ELBW infants; the majority look after less than 10 in a year. In 1990 a large part of low birth weight infants below 2000 g was admitted to one of 511 special care baby units (Table II). More than 90% of ELBW less than 1000 g were admitted to one of these units. Thus it can be concluded that the perinatal care in Japan achieved one of the best mortality figures in the world with relatively small numbers of large perinatal facilities and a large number of small units. Majority of high risk neonates are well looked after by one of 500 small special care baby units. Research Compared with the extensive developments in neonatal clinical services in Japan, the research system is not as satisfactory as expected. There are 99 medical schools and the majority has one post for professor of pediatrics. Less than 10 professors now specialise in neonatology. Consequently there is a limit to basic research being carried out in medical schools. Clinical research in neonatology have been actively performed in most of the tertiary NICUs throughout the country. There were 280 papers presented at the annual meeting of Japan Society for Premature and Newborn Medicine October 199 1. This society represents the neonatology of Japan. Academic meeting is held once a year, gathering nearly 800 neonatologists and pediatricians. Major collaborative studies during the last five years Several nation-wide multicenter controlled clinical trials have been organized in Japan and reported in the international journals. The major collaborative studies in neonatology have included surfactant TA from 1985-91 carried out by 20 NICUs, a study of high frequency oscillation from 1989-90 carried out by 9 NICUs, and a study of recombinant erythropoietin begun in 1990 and is currently underway in 19 NICUs. Among those the largest was the clinical trial of surfactant from cows lung extract for the treatment of respiratory distress syndrome. On surfactant, four multi-center double blind controlled trials were organized by major NICUs in Japan (Table III), of which two studies are in progress at this
TABLE III Surfactant replacement therapy. Purpose and/or method
Years
No. of NICUs
A’
1. High versus low dose 2. Immediate and long-term effects 3. Single versus multiple dose 4. Early versus late treatment
1984 1985-86 19901990-
20 20
56 91
321 TABLE IV Surfactant replacement therapy - immediate and long-term effects. S-TA (n = 50) Deaths Pneumothorax PDA IVH BPD
Control (n=41)
8 (15%) 4 (7%)
10 (22%) 18 (39%)
NS P < 0.001
25 (46%) 11 (20%) 5(9%)
17 (37%) 25 (54%) 11 (24%)
NS P < 0.001 P < 0.085
moment. The largest was on the immediate and long-term effects of surfactant TA [31. The Japan Surfactant-TA Study Group aimed to examine, with a single dose of surfactant: (1) the decrease in severe RDS, (2) the reduction of the frequency of PIE, (3) the increase of neonatal survival by 30% without increasing BPD and/or ICH The subjects were randomized with envelope and stratified for birth-weight 750-1250-1800 g. It was eligible only for those with a diagnosis of RDS made by clinical, radiographic and semiquantitative estimate of surfactant in the gastric aspirate. The longterm results are shown in Table IV. No difference can be seen in the number of deaths. Considering the mean birth weight of 1250 g in the subjects, mortality of the controls is already quite small. The incidence of bronchopulmonary dysplasia are smaller in the STA group, but because of the small number it just failed to reach statistical significance. The author should like to add that the collaboration in the surfactant study not only proved its effects on RDS, but also offered us unexpected results. That is the standardization of neonatal intensive care. It also realized us that the collaboration is essential to explore new world. With the introduction of high frequency oscillatory ventilation, a large controlled trial using Japanese Hummingbird was reported by US HIFI study group in 1989. The results which suggested an increased incidence of air leaks, intraventricular hemorrhage and periventricular leukomalacia surprised the Japanese investigators
TABLE V High frequency oscillatory ventilation - safety and efficacy (Japan HFOV Study Group). Methods Subjects Control Eligibility
Piston oscillator (Hummingbird BMO 20 N) Conventional mechanical ventilation Birth weight 750-2000 g requiring artificial ventilation soon after birth
322 TABLE VI High frequency oscillatory ventilation (Japan HFOV Study Group)
Death
Early Human Development, 29 (1992) 317-322 Elsevier Scientific Publishers Ireland Ltd.
EHD 01296
Readiness of Japan to participate in international collaborative studies M . Fujimura Department
of Neonatal
Medicine, Osaka Medical Health, 840 Murodo-cho,
Center and Research Izumi, Osaka 590-02
Institute (Japan)
for
Maternal
and Child
Summary A significant improvement has been achieved in perinatal mortality figures during the last decade in Japan with a neonatal mortality rate of 2.6 and a stillbirth rate of 4.1 for 1989. With its unique obstetric and neonatal services, there are advantages and also disadvantages in respect of clinical and basic research. The outlook for Japanese neonatal medicine is shown and the prospects for international collaborative studies in the future are given. Key words: Japan; neonatal intensive care; collaborative
study
Introduction Japanese neonatologists have not yet been much involved in the international collaborative studies. What is the reason for this? Is the Japanese clinical standard of neonatal care below the international level? This paper deals with the issue of how contemporary Japan could become a joint member of the international society. For many years this issue has been discussed in politics. I now would like to extend the discussion to neonatology. A summary of the requirements for any neonatal unit to participate in clinical collaborative studies might include the following criteria: (1) sufficient subjects, (2) acceptable standard of care, (3) ability to design the study, (4) willingness to participate, and (5) overall reliability. Overall reliability is rather empirical in nature to judge, and depends on the experience of personal communications between the study designer and the unit personnel. In this respect few Japanese Correspondence to: M. Fujimura, Department of Neonatal Medicine, Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodocho, Izumi, Osaka 590-02, Japan.
318
neonatologists are in good contact with western study planners. Two further requirements for international collaborative studies are: (1) ability in language (English) and (2) accessibility and communication media. Competence in English is required. Most Japanese neonatologists do read English articles very well. This does not necessarily mean that he or she is able to participate in an international setting. Language seems to be one of the major difficulties if international collaborative studies intend to involve a wide range of institutes in Japan. However, there may be pitfalls when dealing with international studies such as (a) environmental difference, (b) ethnic difference and (c) standardization of measurement. The environmental and ethnic differences are correlated with morbidity and mortality. These differences, unless taken into account in the clinical study, may bias the results. Medical care in Japan Medical care is covered in respect of medical costs from the following sources of medical care schemes in Japan: socialized in medical fares, National Medical Insurance, 100% Japanese insured (obstetric service is private), and free choice of medical service. However, the obstetric service for normal pregnancy and delivery is not paid by insurance. Patients have a free choice of medical service. They can either visit one of the clinics in the town or go straight to the general hospital. Sources of obstetric services fall into three main categories, hospital care ( 2 20 beds in size) accounting for 57%, the obstetric clinic (C 20 beds in size) accounting for 42%, and midwifery accounting for 1% of care. Special neonatal care is provided by the pediatrician at the hospital or an obstetrician at a neonatal clinic who may refer the patient to the hospital. Virtually no private practice exists in this country. Prenatal care and delivery are given either by the hospital or by obstetricians who operate a clinic of their own; in general it is the woman’s choice. A number of high risk pregnancies are referred to the hospital obstetric department. Very few pregnant women miss their regular prenatal care. Neonatal special care is available in most areas of Japan and will be discussed later.
TABLE I P&natal
statistics: Japan 1989
Population Number of births Birth rate Infant mortality Neonatal mortality Stillbirth rate ( t 28 weeks) Early neonatal mortality Perinatal mortality
122460000 I 246 802 10.2 4.6 2.6 4.1 1.9 6.0
319
Cohort of Japan
eel 58 40 38 a 10 El
w0-
mmBirth
weight
2&?a-24QD
(g)
Fig. 1. Improvements in neonatal mortality over the last decade. Seventy-five percent of ELBWs less than 1000 g survived in 1990.
Perinatal statistics Table I shows some perinatal statistics from Japan [ 11, which result from its being a densely populated archipelago as 70% of the land area is not suitable for habitation. The annual birth rate is 10.2 per 1000 of the population. The infant mortality per 1000 births is 4.6 which is the lowest in the world while neonatal mortality at less than 4 weeks is 2.6 which is again one of the lowest, but with a relatively high stillbirth rate of 4.1 perinatal mortality is 6.0 per thousand. The birthweight specific neonatal mortality improved rapidly in the last decade. Seventy-five percent of ELBW less than 1000 g survived in 1990 (Fig. 1). Neonatal Medicine of 1990s in Japan Modern neonatal intensive care has developed in Japan during the last 15 years. By 1980 most infants with respiratory distress syndrome were treated with artificial
TABLE II Birth weight specific neonatal mortality 511 NICUs, 1990 (Japan Pediatric Society) Birth weight (g)
Number of admissions
O-27 day mortality
National mortality 1989
500-999 lOOO- 1499 1500- 1999
2000 3786 7634
26.9% 6.9% 3.3%
31.0% 10.3% 3.5%
320
ventilation. Table II shows the number of ELBW infants cared for in a year in major NICUs [ 21, Among 114 NICUs only 15 admitted more than 15 ELBW infants; the majority look after less than 10 in a year. In 1990 a large part of low birth weight infants below 2000 g was admitted to one of 511 special care baby units (Table II). More than 90% of ELBW less than 1000 g were admitted to one of these units. Thus it can be concluded that the perinatal care in Japan achieved one of the best mortality figures in the world with relatively small numbers of large perinatal facilities and a large number of small units. Majority of high risk neonates are well looked after by one of 500 small special care baby units. Research Compared with the extensive developments in neonatal clinical services in Japan, the research system is not as satisfactory as expected. There are 99 medical schools and the majority has one post for professor of pediatrics. Less than 10 professors now specialise in neonatology. Consequently there is a limit to basic research being carried out in medical schools. Clinical research in neonatology have been actively performed in most of the tertiary NICUs throughout the country. There were 280 papers presented at the annual meeting of Japan Society for Premature and Newborn Medicine October 199 1. This society represents the neonatology of Japan. Academic meeting is held once a year, gathering nearly 800 neonatologists and pediatricians. Major collaborative studies during the last five years Several nation-wide multicenter controlled clinical trials have been organized in Japan and reported in the international journals. The major collaborative studies in neonatology have included surfactant TA from 1985-91 carried out by 20 NICUs, a study of high frequency oscillation from 1989-90 carried out by 9 NICUs, and a study of recombinant erythropoietin begun in 1990 and is currently underway in 19 NICUs. Among those the largest was the clinical trial of surfactant from cows lung extract for the treatment of respiratory distress syndrome. On surfactant, four multi-center double blind controlled trials were organized by major NICUs in Japan (Table III), of which two studies are in progress at this
TABLE III Surfactant replacement therapy. Purpose and/or method
Years
No. of NICUs
A’
1. High versus low dose 2. Immediate and long-term effects 3. Single versus multiple dose 4. Early versus late treatment
1984 1985-86 19901990-
20 20
56 91
321 TABLE IV Surfactant replacement therapy - immediate and long-term effects. S-TA (n = 50) Deaths Pneumothorax PDA IVH BPD
Control (n=41)
8 (15%) 4 (7%)
10 (22%) 18 (39%)
NS P < 0.001
25 (46%) 11 (20%) 5(9%)
17 (37%) 25 (54%) 11 (24%)
NS P < 0.001 P < 0.085
moment. The largest was on the immediate and long-term effects of surfactant TA [31. The Japan Surfactant-TA Study Group aimed to examine, with a single dose of surfactant: (1) the decrease in severe RDS, (2) the reduction of the frequency of PIE, (3) the increase of neonatal survival by 30% without increasing BPD and/or ICH The subjects were randomized with envelope and stratified for birth-weight 750-1250-1800 g. It was eligible only for those with a diagnosis of RDS made by clinical, radiographic and semiquantitative estimate of surfactant in the gastric aspirate. The longterm results are shown in Table IV. No difference can be seen in the number of deaths. Considering the mean birth weight of 1250 g in the subjects, mortality of the controls is already quite small. The incidence of bronchopulmonary dysplasia are smaller in the STA group, but because of the small number it just failed to reach statistical significance. The author should like to add that the collaboration in the surfactant study not only proved its effects on RDS, but also offered us unexpected results. That is the standardization of neonatal intensive care. It also realized us that the collaboration is essential to explore new world. With the introduction of high frequency oscillatory ventilation, a large controlled trial using Japanese Hummingbird was reported by US HIFI study group in 1989. The results which suggested an increased incidence of air leaks, intraventricular hemorrhage and periventricular leukomalacia surprised the Japanese investigators
TABLE V High frequency oscillatory ventilation - safety and efficacy (Japan HFOV Study Group). Methods Subjects Control Eligibility
Piston oscillator (Hummingbird BMO 20 N) Conventional mechanical ventilation Birth weight 750-2000 g requiring artificial ventilation soon after birth
322 TABLE VI High frequency oscillatory ventilation (Japan HFOV Study Group)
Death
