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Addressing the hidden mortality in CDH: A population-based study
Journal of Pediatric Surgery 52 (2017) 522–525
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Original Articles
Addressing the hidden mortality in CDH: A population-based study Carmen Mesas Burgos ⁎, Björn Frenckner Department of Pediatric Surgery, Karolinska Institutet, Stockholm, Sweden
a r t i c l e
i n f o
Article history: Received 10 June 2016 Received in revised form 2 September 2016 Accepted 4 September 2016 Key words: Congenital diaphragmatic hernia (CDH) Incidence Mortality Hidden mortality Population-based study
a b s t r a c t Background: Improvements in the clinical management of CDH have led to overall improved reported result from single institutions. However, population-based studies have highlighted a hidden mortality. Aim: To explore the incidence in Sweden and to address the hidden mortality for CDH during a 27-year period in a population-based setting. Materials and methods: This is a population based cohort study that includes all patients diagnosed with CDH that were registered in the National Patient Register, the Medical Birth Register, the Register of Congenital Malformations and the Register for Causes of Death between 1987 and 2013. The mortality rates were calculated based on the number deaths divided by the number of live born cases. The hidden mortality was defined as the number of CDH cases that were not born (because of TOP or IUFD), cases of neonatal demise during birth or demise the same day of birth in patients who were in peripheral institutions and who never reached tertiary centers. Results: In total, 861 CDH patients were born in Sweden between 1987 and 2013, which corresponds to an incidence of 3.0 born CDH per 10,000 live births. When adding the cases of TOP and IUFD, the total incidence of CDH in Sweden was 3.5/10,000 live born. The mortality rate between 1987 and 2013 was 36%: 44% during the first time period 1987–1999 and 27% in the later period 2000–2013. The hidden mortality in the second period was 30%, resulting in a total mortality rate of 45%. Conclusion: The incidence of CDH during a 27-year period remained unchanged in the population. However, we observed a decrease in the prevalence because of the increasing numbers of TOP. A significant hidden mortality exists, with overall mortality rate of 45% for CDH in this population. Level of evidence: II (cohort). © 2017 Elsevier Inc. All rights reserved.
Congenital diaphragmatic hernia (CDH) has a reported incidence of 2–3/10,000 live births [1–3]. The heterogeneous etiology remains largely unknown, and the pathophysiological consequences can be devastating. Over the past two–three decades, improvements in the clinical management of CDH have led to overall improved reported result from single institutions [4–7]. However, population-based studies have highlighted the hidden mortality first described by Harrison in 1978 [8–10]. Advantages in prenatal diagnosis have led to an increasing number of prenatally diagnosed cases. Up to 60% of all CDH patients are today prenatally diagnosed [11], but it has also led to an increased number of termination of pregnancies (TOP) because of the diagnosis. Thus, the term “hidden mortality” described by Harrison in 1978 [8], today applies, not only to CDH patients who die before arriving to reporting institutions, but also to the increasing number of unborn cases because of TOP, since ultrasound diagnostic has developed considerably in the past 2 decades. The aim of this study was to explore the incidence and prevalence of CDH in Sweden and trend changes over time, taking into account ⁎ Corresponding author at: Department of Pediatric Surgery, Astrid Lindgren's Children's Hospital, Karolinska Institutet, Q3:03, SE-17176 Stockholm, Sweden. E-mail address: [email protected] (C.M. Burgos). http://dx.doi.org/10.1016/j.jpedsurg.2016.09.061 0022-3468/© 2017 Elsevier Inc. All rights reserved.
termination of pregnancies and mortality rates, and to address the hidden mortality for CDH during a 27-year-long period in a populationbased setting.
1. Materials and methods 1.1. Study design Population-based cohort study of the incidence, hidden mortality and long-term survival for CDH patients in Sweden during the period January 1, 1987 through December 31, 2013. The study cohort included all patients diagnosed with CDH, live born or not or aborted, as registered in the National Patient Register, the Medical Birth Register, the Register of Congenital Malformations and the Register for Causes of Death. The risk of missing a patient using a combination of these registers has been reported as negligible [12]. The following codes of the International Classification of Diseases (ICD) were used to identify the diagnosis of CDH: ICD-9756.6, ICD-10 Q79.0 and Q79.1. The personal identity number, a ten-digit unique personal identity code assigned to each Swedish resident at birth, was used for correct linkages between the registers used.
C.M. Burgos, B. Frenckner / Journal of Pediatric Surgery 52 (2017) 522–525
1.2. Registers 1. The National Patient Register was started in 1964 and it registers the diagnoses and surgical procedures of the in-patient care in Sweden. Since 1987, 100% of the Swedish population is covered by this register. Reporting is good with less than 2% of all hospitalizations missing. 2. The Medical Birth Register contains data on pregnancies and deliveries in Sweden since 1973. In 1982, a more detailed data reporting to the register were introduced, containing information of antenatal care, delivery, and medical examination of the newborn. It includes information of stillbirths. Records for only a small percentage of all infants (0.5–3.9%) are missing. 3. The Register of Congenital Malformations was started in 1964. In 1999, the register was expanded and included the personal identity number of the infant, and has contained information on pregnancies from the 28th week of gestation and also induced abortions because of malformations or chromosomal abnormalities. The registered data are based on compulsory reporting of chromosomal abnormalities or congenital malformations of infants from maternity wards, pediatric wards and cytogenetic laboratories. Data are missing for approximately 20% of all live born infants. 4. The Swedish Register for Causes of Death was started in 1961 and is updated every year. It contains information of all causes of death among the Swedish population. Only 1.3% of the data are missing. In Sweden, there are 4 pediatric surgical units at tertiary referral hospitals, and only 1 center has offered ECMO treatment when indicated (Stockholm) [13]. Nowadays, basically all pregnant women in Sweden undergo prenatal ultrasound examination at 18 gestational weeks, which is free of charge [12,14]. 1.3. Data analysis 1.3.1. Incidence The incidence of born CDH and the incidence of CDH in live born in Sweden were calculated for each calendar year. Two time periods were assessed: (1) 1987–1999, since the Patient Register was nationwide complete in 1987, and (2) 2000–2013, when all registers, including the Register of Congenital Malformations, were available. The incidence of born CDH was defined as the total number of newborns with CDH/10,000 live births and was assessed at both time periods. The total incidence of CDH/10,000 live born was defined as the total number of new cases (including TOP, intrauterine fetal demise and live born who died immediately after birth and before reaching tertiary centers reporting CDH) and could only be assessed for the second period. Data for all live births in Sweden, available from Statistics Sweden [14], are highly updated and were used as denominators in the analyses. Patients who were diagnosed of CDH after the neonatal period were excluded.
number of CDH cases that were not born (because of TOP or IUFD), cases of neonatal demise directly during or after birth or demise the same day of birth in patients, who were in peripheral centers and who never reached tertiary centers. The latter, thus, not being reported by the tertiary centers. This definition of hidden mortality differs from that used by Harrison, since we included the number of cases not born because of a prenatal diagnosis of CDH. The total number of CDH cases was calculated as the number of live born CDH cases, number of TOP because of CDH and IUFD or stillborn with CDH together. The total mortality was defined as the number of fatalities among newborns with CDH added to the number of TOP and IUFD divided by the total number of CDH. 1.4. Statistical analysis Data are presented as means ± SEM, median, absolute values (n) and frequencies (%). Linear regression was used to investigate differences in trends, and Kaplan–Meier curves and log-rank Mantel–Cox were used to explore differences in survival. Significance was defined as P ≤ 0.05. Analyses were performed using SPSS® version 23 and PRISM 6 (Graphpad Software Inc., La Jolla, CA). 1.5. Ethics The regional ethical committee in Stockholm approved the study, Dnr 2013/1550-31/3. 2. Results 2.1. Patient's demographics In total, 861 live newborn CDH patients were indicated by the ICD codes combining the different registers (The National Patient Register, The Medical Birth Register, The Register of Congenital Malformations and the Register for Causes of Death). 56% of the cases were male. The mean gestational age (GA) at birth was 37.8 weeks (± 3.1, median 38 weeks). The mean body weight was 3037 g (± 808, median 3120 g). In 44% of the cases, the patients were first born, and the average maternal age was 29.5 years (±5.4, median 29 years). 17 stillborn were recorded during the study period, 14 of them intrauterine fetal demise (IUFD) and 3 occurring during delivery. 2.2. Incidence Based on the 861 newborn CDH patients registered in the different registers during the period 1987–2013, the mean incidence of born CDH was 3.0 per 10,000 live born (prevalence in newborn). It was higher (3.4) during the first period (1987–1999) compared to 2.6 during the last period (p b 0.05) (Fig. 1, Table 1). The total incidence (also Incidence CDH /10 000 liverborn Incidence born CDH/ 10 000 liveborn
n/10 000 life births
6
4
TOP ratio
2
0 19 1987 1989 1991 1993 1995 1997 2099 2001 2003 2005 2007 2009 2011 13
1.3.2. Mortality The mortality rates were calculated based on the number deaths identified from the Swedish Register for Causes of death, divided by the number of live born with CDH within each calendar year. Two time periods were assessed: (1) 1987–1999 and (2) 2000–2013, to be able to compare if advances in treatment [15,16] in the recent years have led to an increased survival for CDH patients. Using the Kaplan–Meier method, not only deaths but also age at death was addressed. The rates of TOP were defined as the number of terminations because of CDH divided by the total number of cases of CDH during each calendar year and the TOP ratio was defined as the number of terminations per 10,000 live born. The hidden mortality was defined as the
523
Year Fig. 1. Incidence, prevalence and TOP ratio for CDH in Sweden 1987–2013. Results are expressed as ratio per 10,000 live born.
C.M. Burgos, B. Frenckner / Journal of Pediatric Surgery 52 (2017) 522–525
Table 1 Number of live born cases, TOP, IUFD, fatalities and deaths at peripheral institutions (n) during the study periods. Incidence/10,000 live born, TOP frequency, mortality and hidden mortality rates.
Live borns Born CDH cases Fatalities TOP Stillborn/IUFD Died on DOL 0 in peripheral institution Total incidence per 10,000 Incidence live born CDH per 10,000 TOP ratio Mortality (classic way) Hidden mortality Total mortality
Period 1987–1999
Period 2000–2013
Total
1,400,002 480 210 6 9 72
1,467,770 381 104 116 8 28
2,867,772 861 314 122 17 100
3.5 3.4
3.4 2.6
3.5 3.0
1.2% 43.8% 17.6% 45.5%
23.3% 27.3% 30.1% 45.1%
12.4% 36.5% 23.9% 45.3%
counting TOP and stillborn) was 3.5 cases/10,000 live born, with no difference between the two time periods (Table 1). Associated anomalies were present in 22% of all born CDH patients and in addition chromosomal abnormalities in 5%. 2.3. Mortality 314 fatalities occurred during the study period. The average mortality rate (fatalities divided by the number of live born cases) for CDH patients born in Sweden between 1987 and 2013 was 36%. For the first time period, 1987–1999, the average mortality rate was 44%, whereas in the later period, 2000–2013, it was 27%. (Fig. 2, Table 1). Although fluctuations in survival over time occurred, there was a statistically significant trend of improved survival over time (p for trend = 0.04) (Fig. 3). 62% (100 cases) of the fatalities that occurred within the same day of birth (0 Day of Life, DOL) were not born in tertiary hospitals with access to pediatric surgical units and will, therefore, not be reported by these institutions. There were 17 cases of stillbirths (3 died during delivery, 14 cases of intrauterine fetal demise, IUFD). A total of 122 cases with prenatally diagnosed CDH did not continue the pregnancy. These cases (stillbirths and fatalities occurring at 0 DOL), together with the number of TOP because of CDH, accounted for the hidden mortality. The hidden mortality in the study period was 24%. It was lower during the first period (18%) compared to that during the second period (30%) (Table 1). The rate of TOP because of prenatal diagnosis of CDH was 23% during the second period compared to only 1.2% during the first period (Fig. 2, Table 1). When taking into account the TOP rates and hidden mortality, the total mortality rate for the entire CDH cohort, nationwide, was 45% (Table 1), and it was similar in both time periods, 1987–1999 and 2000–2013.
Fig. 2. Mortality, hidden mortality and TOP rates for CDH in Sweden 1987–2013. Results are expressed as rate, dividing by the number of live born with CDH within each calendar year.
100
Percent survival
524
All 1987-1999
90
2000-2013 80 70 60 50 0
5000
10000
Follow-up time (days) Fig. 3. Kaplan–Meier curve of survival for the entire CDH cohort and for the two time points, 1987–1999 and 2000–2013.
51% (161) of the fatalities occurred within hours after birth (DOL 0) and a further 14% (43) later during the first day of life (DOL). 85% of the fatalities occurred within the first month of life, and only 5% died after 1 year of age. 3. Discussion The incidence of CDH in Sweden, when including TOP fetuses, remained unchanged over time and is similar to that previously reported [1,17]. However, we observed a decrease in the prevalence because of the increasing numbers of TOP, as it has been reported in other studies [2]. The overall mortality rate for CDH in this population-based study was 45%, consistent to Harrison's previous estimation more than 30 years ago [8]. The hidden mortality was considerably higher during the second period, which can be explained by the increasing numbers of TOP. Improvements in prenatal diagnosis have probably led to the increased numbers of TOP observed during the second period [15]. In spite of numerous papers reporting improved survival [15,18–24], the total mortality including hidden mortality remains high. In the present material, it was 45% with no difference between the two time periods. However, the “classic” mortality with no reference to TOP or IUFD was significantly lower during the later time period. This is most likely an effect of improved neonatal care of these patients but may also partly be explained by a selection bias, since prenatally diagnosed CDH is correlated to worse outcome [15,25–28]. Furthermore, it can be assumed that parents to fetuses with CDH are more prone to TOP when there are prenatal signs of bad prognosis such as low O/E LHR [15,25] than else. On the other hand, many fetuses subjected to TOP should probably have survived if they had been born. Increased rate of TOP will therefore lead to an increase of the total mortality. In the present material, the total mortality was the same (45%) in both time periods, while the TOP rate was considerably higher in the latter period. This may be explained by improved survival among the live born cases in the latter period. It should be noted that the “classic mortality” plus the hidden mortality does not equal the total mortality in the present material. The hidden mortality includes patients who have succumbed on the first day of life in peripheral institutions and who therefore not will be reported by the tertiary institutions taking care of these patients. These deaths are also included in the fatalities reported in the national registers and are therefore also included when calculating the “classic mortality”. At our institution, we prospectively record data on all patients with CDH managed in Stockholm since 1990, with the same standardized protocol [15,18]. The average annual number of Swedish patients in our institution has been 9.25 [18,29], which corresponds to 250 patients out of the study cohort, i.e. approximately 29% of all patients born with CDH in Sweden during the study period and approximately 34% of patients, who did not succumb at peripheral institutions on the first day of life. Our overall mortality to discharge was less than 20%, with
C.M. Burgos, B. Frenckner / Journal of Pediatric Surgery 52 (2017) 522–525
approximately 5% late mortality rate [15]. Being the only ECMO Center in Sweden with large transport experience [13], we most likely get a negative selection bias in our patient cohort, with sicker newborns being referred to our institution because of need of ECMO. As a highvolume center, our institutional survival rate of 80% is slightly higher than the average in the CDH Study Group Registry (70% survival rate) [30] and overall reported results from Scandinavia, with an average of 70% survival [31,32]. This is in consistence with the fact that highvolume centers generally have been shown to have better results compared to institutions treating less than 5 CDH patients per year [31,33]. When comparing the results of the current study with our institution's own database, however, we observe gap between our own reported survival rates and the real survival for this group. This is consistent with previously published population-based data that consistently report lower survival rates for CDH, compared to institutionbased studies [34–36], highlighting the fact that the “hidden mortality” still persists. In conclusion, the incidence of CDH in Sweden including fetuses subjected to TOP has remained unchanged during the study period and is similar to what has previously reported. The TOP rate has increased and thereby also the hidden mortality. The total mortality remains high and is higher than that reported from institutional data. References [1] Wright JC, Budd JL, Field DJ, et al. Epidemiology and outcome of congenital diaphragmatic hernia: a 9-year experience. Paediatr Perinat Epidemiol 2011;25:144–9. [2] McGivern MR, Best KE, Rankin J, et al. Epidemiology of congenital diaphragmatic hernia in Europe: a register-based study. Arch Dis Child Fetal Neonatal Ed 2015; 100:F137–44. [3] Forrester MB, Merz RD. Epidemiology of congenital diaphragmatic hernia, Hawaii, 1987-1996. Hawaii Med J 1998;57:586–9. [4] Masumoto K, Teshiba R, Esumi G, et al. Improvement in the outcome of patients with antenatally diagnosed congenital diaphragmatic hernia using gentle ventilation and circulatory stabilization. Pediatr Surg Int 2009;25:487–92. [5] Fredly S, Aksnes G, Viddal KO, et al. The outcome in newborns with congenital diaphragmatic hernia in a Norwegian region. Acta Paediatr 2009;98:107–11. [6] Chiu P, Hedrick HL. Postnatal management and long-term outcome for survivors with congenital diaphragmatic hernia. Prenat Diagn 2008;28:592–603. [7] Abdullah F, Zhang Y, Sciortino C, et al. Congenital diaphragmatic hernia: outcome review of 2,173 surgical repairs in US infants. Pediatr Surg Int 2009;25:1059–64. [8] Harrison MR, Bjordal RI, Langmark F, et al. Congenital diaphragmatic hernia: the hidden mortality. J Pediatr Surg 1978;13:227–30. [9] Ontario Congenital Anomalies Study Group. Apparent truth about congenital diaphragmatic hernia: a population-based database is needed to establish benchmarking for clinical outcomes for CDH. J Pediatr Surg 2004;39:661–5. [10] Levison J, Halliday R, Holland AJ, et al. A population-based study of congenital diaphragmatic hernia outcome in New South Wales and the Australian Capital Territory, Australia, 1992-2001. J Pediatr Surg 2006;41:1049–53. [11] Garne E, Haeusler M, Barisic I, et al. Congenital diaphragmatic hernia: evaluation of prenatal diagnosis in 20 European regions. Ultrasound Obstet Gynecol 2002;19:329–33. [12] Centre for Epidemiology the Swedish National Board of Health and Welfare. The Swedish Medical Birth Register—a summary of content and quality. http://www. socialstyrelsen.se/Lists/Artikelkatalog/Attachments/10655/2003-112-3_20031123. pdf; 2003.
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[13] Broman LM, Holzgraefe B, Palmer K, et al. The Stockholm experience: interhospital transports on extracorporeal membrane oxygenation. Crit Care 2015;19:278. [14] Statistics Sweden. http://www.statistikdatabasen.scb.se. [15] Mesas Burgos C, Hammarqvist-Vejde J, Frenckner B, et al. Differences in Outcomes in Prenatally Diagnosed Congenital Diaphragmatic Hernia Compared to Postnatal Detection: A Single-Center Experience. Fetal Diagn Ther 2015. [16] Reiss I, Schaible T, van den Hout L, et al. Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe: the CDH EURO Consortium consensus. Neonatology 2010;98:354–64. [17] Pober BR. Overview of epidemiology, genetics, birth defects, and chromosome abnormalities associated with CDH. Am J Med Genet C: Semin Med Genet 2007; 145C:158–71. [18] Burgos CM, Ost E, Wannberg M, et al. High survival rate among newborns with congenital diaphragmatic hernia. 20-year follow up of patients treated in Stockholm. Lakartidningen 2012;109:287–91. [19] Group CDHS, Lally KP, Lally PA, et al. Defect size determines survival in infants with congenital diaphragmatic hernia. Pediatrics 2007;120:e651–7. [20] Downard CD, Jaksic T, Garza JJ, et al. Analysis of an improved survival rate for congenital diaphragmatic hernia. J Pediatr Surg 2003;38:729–32. [21] Logan JW, Rice HE, Goldberg RN, et al. Congenital diaphragmatic hernia: a systematic review and summary of best-evidence practice strategies. J Perinatol 2007;27: 535–49. [22] Hedrick HL. Management of prenatally diagnosed congenital diaphragmatic hernia. Semin Pediatr Surg 2013;22:37–43. [23] Lally KP, Lally PA, Van Meurs KP, et al. Treatment evolution in high-risk congenital diaphragmatic hernia: ten years' experience with diaphragmatic agenesis. Ann Surg 2006;244:505–13. [24] van den Hout L, Schaible T, Cohen-Overbeek TE, et al. Actual outcome in infants with congenital diaphragmatic hernia: the role of a standardized postnatal treatment protocol. Fetal Diagn Ther 2011;29:55–63. [25] Jani JC, Benachi A, Nicolaides KH, et al. Prenatal prediction of neonatal morbidity in survivors with congenital diaphragmatic hernia: a multicenter study. Ultrasound Obstet Gynecol 2009;33:64–9. [26] Cannie M, Jani J, Meersschaert J, et al. Prenatal prediction of survival in isolated diaphragmatic hernia using observed to expected total fetal lung volume determined by magnetic resonance imaging based on either gestational age or fetal body volume. Ultrasound Obstet Gynecol 2008;32:633–9. [27] Klaassens M, Galjaard RJ, Scott DA, et al. Prenatal detection and outcome of congenital diaphragmatic hernia (CDH) associated with deletion of chromosome 15q26: two patients and review of the literature. Am J Med Genet A 2007;143A: 2204–12. [28] Jani J, Keller RL, Benachi A, et al. Prenatal prediction of survival in isolated left-sided diaphragmatic hernia. Ultrasound Obstet Gynecol 2006;27:18–22. [29] Ost E, Joelsson MO, Burgos CM, et al. Self-assessed physical health among children with congenital diaphragmatic hernia. Pediatr Surg Int 2016;32:493–503. [30] Harting MT, Lally KP. The Congenital Diaphragmatic Hernia Study Group registry update. Semin Fetal Neonatal Med 2014;19:370–5. [31] Skari H, Bjornland K, Frenckner B, et al. Congenital diaphragmatic hernia: a survey of practice in Scandinavia. Pediatr Surg Int 2004;20:309–13. [32] Skari H, Bjornland K, Frenckner B, et al. Congenital diaphragmatic hernia in Scandinavia from 1995 to 1998: Predictors of mortality. J Pediatr Surg 2002;37: 1269–75. [33] Grushka JR, Laberge JM, Puligandla P, et al. Effect of hospital case volume on outcome in congenital diaphragmatic hernia: the experience of the Canadian Pediatric Surgery Network. J Pediatr Surg 2009;44:873–6. [34] Mah VK, Chiu P, Kim PC. Are we making a real difference? Update on 'hidden mortality' in the management of congenital diaphragmatic hernia. Fetal Diagn Ther 2011;29:40–5. [35] Mah VK, Zamakhshary M, Mah DY, et al. Absolute vs relative improvements in congenital diaphragmatic hernia survival: what happened to "hidden mortality". J Pediatr Surg 2009;44:877–82. [36] Brownlee EM, Howatson AG, Davis CF, et al. The hidden mortality of congenital diaphragmatic hernia: a 20-year review. J Pediatr Surg 2009;44:317–20.
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Original Articles
Addressing the hidden mortality in CDH: A population-based study Carmen Mesas Burgos ⁎, Björn Frenckner Department of Pediatric Surgery, Karolinska Institutet, Stockholm, Sweden
a r t i c l e
i n f o
Article history: Received 10 June 2016 Received in revised form 2 September 2016 Accepted 4 September 2016 Key words: Congenital diaphragmatic hernia (CDH) Incidence Mortality Hidden mortality Population-based study
a b s t r a c t Background: Improvements in the clinical management of CDH have led to overall improved reported result from single institutions. However, population-based studies have highlighted a hidden mortality. Aim: To explore the incidence in Sweden and to address the hidden mortality for CDH during a 27-year period in a population-based setting. Materials and methods: This is a population based cohort study that includes all patients diagnosed with CDH that were registered in the National Patient Register, the Medical Birth Register, the Register of Congenital Malformations and the Register for Causes of Death between 1987 and 2013. The mortality rates were calculated based on the number deaths divided by the number of live born cases. The hidden mortality was defined as the number of CDH cases that were not born (because of TOP or IUFD), cases of neonatal demise during birth or demise the same day of birth in patients who were in peripheral institutions and who never reached tertiary centers. Results: In total, 861 CDH patients were born in Sweden between 1987 and 2013, which corresponds to an incidence of 3.0 born CDH per 10,000 live births. When adding the cases of TOP and IUFD, the total incidence of CDH in Sweden was 3.5/10,000 live born. The mortality rate between 1987 and 2013 was 36%: 44% during the first time period 1987–1999 and 27% in the later period 2000–2013. The hidden mortality in the second period was 30%, resulting in a total mortality rate of 45%. Conclusion: The incidence of CDH during a 27-year period remained unchanged in the population. However, we observed a decrease in the prevalence because of the increasing numbers of TOP. A significant hidden mortality exists, with overall mortality rate of 45% for CDH in this population. Level of evidence: II (cohort). © 2017 Elsevier Inc. All rights reserved.
Congenital diaphragmatic hernia (CDH) has a reported incidence of 2–3/10,000 live births [1–3]. The heterogeneous etiology remains largely unknown, and the pathophysiological consequences can be devastating. Over the past two–three decades, improvements in the clinical management of CDH have led to overall improved reported result from single institutions [4–7]. However, population-based studies have highlighted the hidden mortality first described by Harrison in 1978 [8–10]. Advantages in prenatal diagnosis have led to an increasing number of prenatally diagnosed cases. Up to 60% of all CDH patients are today prenatally diagnosed [11], but it has also led to an increased number of termination of pregnancies (TOP) because of the diagnosis. Thus, the term “hidden mortality” described by Harrison in 1978 [8], today applies, not only to CDH patients who die before arriving to reporting institutions, but also to the increasing number of unborn cases because of TOP, since ultrasound diagnostic has developed considerably in the past 2 decades. The aim of this study was to explore the incidence and prevalence of CDH in Sweden and trend changes over time, taking into account ⁎ Corresponding author at: Department of Pediatric Surgery, Astrid Lindgren's Children's Hospital, Karolinska Institutet, Q3:03, SE-17176 Stockholm, Sweden. E-mail address: [email protected] (C.M. Burgos). http://dx.doi.org/10.1016/j.jpedsurg.2016.09.061 0022-3468/© 2017 Elsevier Inc. All rights reserved.
termination of pregnancies and mortality rates, and to address the hidden mortality for CDH during a 27-year-long period in a populationbased setting.
1. Materials and methods 1.1. Study design Population-based cohort study of the incidence, hidden mortality and long-term survival for CDH patients in Sweden during the period January 1, 1987 through December 31, 2013. The study cohort included all patients diagnosed with CDH, live born or not or aborted, as registered in the National Patient Register, the Medical Birth Register, the Register of Congenital Malformations and the Register for Causes of Death. The risk of missing a patient using a combination of these registers has been reported as negligible [12]. The following codes of the International Classification of Diseases (ICD) were used to identify the diagnosis of CDH: ICD-9756.6, ICD-10 Q79.0 and Q79.1. The personal identity number, a ten-digit unique personal identity code assigned to each Swedish resident at birth, was used for correct linkages between the registers used.
C.M. Burgos, B. Frenckner / Journal of Pediatric Surgery 52 (2017) 522–525
1.2. Registers 1. The National Patient Register was started in 1964 and it registers the diagnoses and surgical procedures of the in-patient care in Sweden. Since 1987, 100% of the Swedish population is covered by this register. Reporting is good with less than 2% of all hospitalizations missing. 2. The Medical Birth Register contains data on pregnancies and deliveries in Sweden since 1973. In 1982, a more detailed data reporting to the register were introduced, containing information of antenatal care, delivery, and medical examination of the newborn. It includes information of stillbirths. Records for only a small percentage of all infants (0.5–3.9%) are missing. 3. The Register of Congenital Malformations was started in 1964. In 1999, the register was expanded and included the personal identity number of the infant, and has contained information on pregnancies from the 28th week of gestation and also induced abortions because of malformations or chromosomal abnormalities. The registered data are based on compulsory reporting of chromosomal abnormalities or congenital malformations of infants from maternity wards, pediatric wards and cytogenetic laboratories. Data are missing for approximately 20% of all live born infants. 4. The Swedish Register for Causes of Death was started in 1961 and is updated every year. It contains information of all causes of death among the Swedish population. Only 1.3% of the data are missing. In Sweden, there are 4 pediatric surgical units at tertiary referral hospitals, and only 1 center has offered ECMO treatment when indicated (Stockholm) [13]. Nowadays, basically all pregnant women in Sweden undergo prenatal ultrasound examination at 18 gestational weeks, which is free of charge [12,14]. 1.3. Data analysis 1.3.1. Incidence The incidence of born CDH and the incidence of CDH in live born in Sweden were calculated for each calendar year. Two time periods were assessed: (1) 1987–1999, since the Patient Register was nationwide complete in 1987, and (2) 2000–2013, when all registers, including the Register of Congenital Malformations, were available. The incidence of born CDH was defined as the total number of newborns with CDH/10,000 live births and was assessed at both time periods. The total incidence of CDH/10,000 live born was defined as the total number of new cases (including TOP, intrauterine fetal demise and live born who died immediately after birth and before reaching tertiary centers reporting CDH) and could only be assessed for the second period. Data for all live births in Sweden, available from Statistics Sweden [14], are highly updated and were used as denominators in the analyses. Patients who were diagnosed of CDH after the neonatal period were excluded.
number of CDH cases that were not born (because of TOP or IUFD), cases of neonatal demise directly during or after birth or demise the same day of birth in patients, who were in peripheral centers and who never reached tertiary centers. The latter, thus, not being reported by the tertiary centers. This definition of hidden mortality differs from that used by Harrison, since we included the number of cases not born because of a prenatal diagnosis of CDH. The total number of CDH cases was calculated as the number of live born CDH cases, number of TOP because of CDH and IUFD or stillborn with CDH together. The total mortality was defined as the number of fatalities among newborns with CDH added to the number of TOP and IUFD divided by the total number of CDH. 1.4. Statistical analysis Data are presented as means ± SEM, median, absolute values (n) and frequencies (%). Linear regression was used to investigate differences in trends, and Kaplan–Meier curves and log-rank Mantel–Cox were used to explore differences in survival. Significance was defined as P ≤ 0.05. Analyses were performed using SPSS® version 23 and PRISM 6 (Graphpad Software Inc., La Jolla, CA). 1.5. Ethics The regional ethical committee in Stockholm approved the study, Dnr 2013/1550-31/3. 2. Results 2.1. Patient's demographics In total, 861 live newborn CDH patients were indicated by the ICD codes combining the different registers (The National Patient Register, The Medical Birth Register, The Register of Congenital Malformations and the Register for Causes of Death). 56% of the cases were male. The mean gestational age (GA) at birth was 37.8 weeks (± 3.1, median 38 weeks). The mean body weight was 3037 g (± 808, median 3120 g). In 44% of the cases, the patients were first born, and the average maternal age was 29.5 years (±5.4, median 29 years). 17 stillborn were recorded during the study period, 14 of them intrauterine fetal demise (IUFD) and 3 occurring during delivery. 2.2. Incidence Based on the 861 newborn CDH patients registered in the different registers during the period 1987–2013, the mean incidence of born CDH was 3.0 per 10,000 live born (prevalence in newborn). It was higher (3.4) during the first period (1987–1999) compared to 2.6 during the last period (p b 0.05) (Fig. 1, Table 1). The total incidence (also Incidence CDH /10 000 liverborn Incidence born CDH/ 10 000 liveborn
n/10 000 life births
6
4
TOP ratio
2
0 19 1987 1989 1991 1993 1995 1997 2099 2001 2003 2005 2007 2009 2011 13
1.3.2. Mortality The mortality rates were calculated based on the number deaths identified from the Swedish Register for Causes of death, divided by the number of live born with CDH within each calendar year. Two time periods were assessed: (1) 1987–1999 and (2) 2000–2013, to be able to compare if advances in treatment [15,16] in the recent years have led to an increased survival for CDH patients. Using the Kaplan–Meier method, not only deaths but also age at death was addressed. The rates of TOP were defined as the number of terminations because of CDH divided by the total number of cases of CDH during each calendar year and the TOP ratio was defined as the number of terminations per 10,000 live born. The hidden mortality was defined as the
523
Year Fig. 1. Incidence, prevalence and TOP ratio for CDH in Sweden 1987–2013. Results are expressed as ratio per 10,000 live born.
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Table 1 Number of live born cases, TOP, IUFD, fatalities and deaths at peripheral institutions (n) during the study periods. Incidence/10,000 live born, TOP frequency, mortality and hidden mortality rates.
Live borns Born CDH cases Fatalities TOP Stillborn/IUFD Died on DOL 0 in peripheral institution Total incidence per 10,000 Incidence live born CDH per 10,000 TOP ratio Mortality (classic way) Hidden mortality Total mortality
Period 1987–1999
Period 2000–2013
Total
1,400,002 480 210 6 9 72
1,467,770 381 104 116 8 28
2,867,772 861 314 122 17 100
3.5 3.4
3.4 2.6
3.5 3.0
1.2% 43.8% 17.6% 45.5%
23.3% 27.3% 30.1% 45.1%
12.4% 36.5% 23.9% 45.3%
counting TOP and stillborn) was 3.5 cases/10,000 live born, with no difference between the two time periods (Table 1). Associated anomalies were present in 22% of all born CDH patients and in addition chromosomal abnormalities in 5%. 2.3. Mortality 314 fatalities occurred during the study period. The average mortality rate (fatalities divided by the number of live born cases) for CDH patients born in Sweden between 1987 and 2013 was 36%. For the first time period, 1987–1999, the average mortality rate was 44%, whereas in the later period, 2000–2013, it was 27%. (Fig. 2, Table 1). Although fluctuations in survival over time occurred, there was a statistically significant trend of improved survival over time (p for trend = 0.04) (Fig. 3). 62% (100 cases) of the fatalities that occurred within the same day of birth (0 Day of Life, DOL) were not born in tertiary hospitals with access to pediatric surgical units and will, therefore, not be reported by these institutions. There were 17 cases of stillbirths (3 died during delivery, 14 cases of intrauterine fetal demise, IUFD). A total of 122 cases with prenatally diagnosed CDH did not continue the pregnancy. These cases (stillbirths and fatalities occurring at 0 DOL), together with the number of TOP because of CDH, accounted for the hidden mortality. The hidden mortality in the study period was 24%. It was lower during the first period (18%) compared to that during the second period (30%) (Table 1). The rate of TOP because of prenatal diagnosis of CDH was 23% during the second period compared to only 1.2% during the first period (Fig. 2, Table 1). When taking into account the TOP rates and hidden mortality, the total mortality rate for the entire CDH cohort, nationwide, was 45% (Table 1), and it was similar in both time periods, 1987–1999 and 2000–2013.
Fig. 2. Mortality, hidden mortality and TOP rates for CDH in Sweden 1987–2013. Results are expressed as rate, dividing by the number of live born with CDH within each calendar year.
100
Percent survival
524
All 1987-1999
90
2000-2013 80 70 60 50 0
5000
10000
Follow-up time (days) Fig. 3. Kaplan–Meier curve of survival for the entire CDH cohort and for the two time points, 1987–1999 and 2000–2013.
51% (161) of the fatalities occurred within hours after birth (DOL 0) and a further 14% (43) later during the first day of life (DOL). 85% of the fatalities occurred within the first month of life, and only 5% died after 1 year of age. 3. Discussion The incidence of CDH in Sweden, when including TOP fetuses, remained unchanged over time and is similar to that previously reported [1,17]. However, we observed a decrease in the prevalence because of the increasing numbers of TOP, as it has been reported in other studies [2]. The overall mortality rate for CDH in this population-based study was 45%, consistent to Harrison's previous estimation more than 30 years ago [8]. The hidden mortality was considerably higher during the second period, which can be explained by the increasing numbers of TOP. Improvements in prenatal diagnosis have probably led to the increased numbers of TOP observed during the second period [15]. In spite of numerous papers reporting improved survival [15,18–24], the total mortality including hidden mortality remains high. In the present material, it was 45% with no difference between the two time periods. However, the “classic” mortality with no reference to TOP or IUFD was significantly lower during the later time period. This is most likely an effect of improved neonatal care of these patients but may also partly be explained by a selection bias, since prenatally diagnosed CDH is correlated to worse outcome [15,25–28]. Furthermore, it can be assumed that parents to fetuses with CDH are more prone to TOP when there are prenatal signs of bad prognosis such as low O/E LHR [15,25] than else. On the other hand, many fetuses subjected to TOP should probably have survived if they had been born. Increased rate of TOP will therefore lead to an increase of the total mortality. In the present material, the total mortality was the same (45%) in both time periods, while the TOP rate was considerably higher in the latter period. This may be explained by improved survival among the live born cases in the latter period. It should be noted that the “classic mortality” plus the hidden mortality does not equal the total mortality in the present material. The hidden mortality includes patients who have succumbed on the first day of life in peripheral institutions and who therefore not will be reported by the tertiary institutions taking care of these patients. These deaths are also included in the fatalities reported in the national registers and are therefore also included when calculating the “classic mortality”. At our institution, we prospectively record data on all patients with CDH managed in Stockholm since 1990, with the same standardized protocol [15,18]. The average annual number of Swedish patients in our institution has been 9.25 [18,29], which corresponds to 250 patients out of the study cohort, i.e. approximately 29% of all patients born with CDH in Sweden during the study period and approximately 34% of patients, who did not succumb at peripheral institutions on the first day of life. Our overall mortality to discharge was less than 20%, with
C.M. Burgos, B. Frenckner / Journal of Pediatric Surgery 52 (2017) 522–525
approximately 5% late mortality rate [15]. Being the only ECMO Center in Sweden with large transport experience [13], we most likely get a negative selection bias in our patient cohort, with sicker newborns being referred to our institution because of need of ECMO. As a highvolume center, our institutional survival rate of 80% is slightly higher than the average in the CDH Study Group Registry (70% survival rate) [30] and overall reported results from Scandinavia, with an average of 70% survival [31,32]. This is in consistence with the fact that highvolume centers generally have been shown to have better results compared to institutions treating less than 5 CDH patients per year [31,33]. When comparing the results of the current study with our institution's own database, however, we observe gap between our own reported survival rates and the real survival for this group. This is consistent with previously published population-based data that consistently report lower survival rates for CDH, compared to institutionbased studies [34–36], highlighting the fact that the “hidden mortality” still persists. In conclusion, the incidence of CDH in Sweden including fetuses subjected to TOP has remained unchanged during the study period and is similar to what has previously reported. The TOP rate has increased and thereby also the hidden mortality. The total mortality remains high and is higher than that reported from institutional data. References [1] Wright JC, Budd JL, Field DJ, et al. Epidemiology and outcome of congenital diaphragmatic hernia: a 9-year experience. Paediatr Perinat Epidemiol 2011;25:144–9. [2] McGivern MR, Best KE, Rankin J, et al. Epidemiology of congenital diaphragmatic hernia in Europe: a register-based study. Arch Dis Child Fetal Neonatal Ed 2015; 100:F137–44. [3] Forrester MB, Merz RD. Epidemiology of congenital diaphragmatic hernia, Hawaii, 1987-1996. Hawaii Med J 1998;57:586–9. [4] Masumoto K, Teshiba R, Esumi G, et al. Improvement in the outcome of patients with antenatally diagnosed congenital diaphragmatic hernia using gentle ventilation and circulatory stabilization. Pediatr Surg Int 2009;25:487–92. [5] Fredly S, Aksnes G, Viddal KO, et al. The outcome in newborns with congenital diaphragmatic hernia in a Norwegian region. Acta Paediatr 2009;98:107–11. [6] Chiu P, Hedrick HL. Postnatal management and long-term outcome for survivors with congenital diaphragmatic hernia. Prenat Diagn 2008;28:592–603. [7] Abdullah F, Zhang Y, Sciortino C, et al. Congenital diaphragmatic hernia: outcome review of 2,173 surgical repairs in US infants. Pediatr Surg Int 2009;25:1059–64. [8] Harrison MR, Bjordal RI, Langmark F, et al. Congenital diaphragmatic hernia: the hidden mortality. J Pediatr Surg 1978;13:227–30. [9] Ontario Congenital Anomalies Study Group. Apparent truth about congenital diaphragmatic hernia: a population-based database is needed to establish benchmarking for clinical outcomes for CDH. J Pediatr Surg 2004;39:661–5. [10] Levison J, Halliday R, Holland AJ, et al. A population-based study of congenital diaphragmatic hernia outcome in New South Wales and the Australian Capital Territory, Australia, 1992-2001. J Pediatr Surg 2006;41:1049–53. [11] Garne E, Haeusler M, Barisic I, et al. Congenital diaphragmatic hernia: evaluation of prenatal diagnosis in 20 European regions. Ultrasound Obstet Gynecol 2002;19:329–33. [12] Centre for Epidemiology the Swedish National Board of Health and Welfare. The Swedish Medical Birth Register—a summary of content and quality. http://www. socialstyrelsen.se/Lists/Artikelkatalog/Attachments/10655/2003-112-3_20031123. pdf; 2003.
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