Survival Rate Changes in Children With Congenital Diaphragmatic Hernia Over the Past Three Decades: a Nationwide, Population-based Prospective Nested Case-control Study

doi:10.21203/rs.3.rs-5216210/v1

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Survival Rate Changes in Children With Congenital Diaphragmatic Hernia Over the Past Three Decades: a Nationwide, Population-based Prospective Nested Case-control Study

https://doi.org/10.21203/rs.3.rs-5216210/v1

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published 01 Nov, 2024

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PURPOSE: The survival rate (SR) for neonates born with congenital diaphragmatic hernia (CDH) remains high. Our aim was to investigate how changed the SR in children with CDH over the past decades.

METHODS: The study was a nationwide, population-based prospective nested case-control study within a cohort of newborn children who was born in Sweden during the observational period from 1^st January 1982 until 31^st December 2015.

RESULTS: In the study period 4654 (99.6%) control children, and 684 children with CDH (70.4%,p<0.001) were survival at 2-years of age. Any patients who were born with CDH has overall 5,8 times higher chance for not survive 2-years of age than children without CDH. The SR improved significantly in CDH in the past 3 decades. Significantly higher number of patients were premature born in the CDH group than in the controls (23.3%vs6.1%,p<0.001). The SR of premature and non-premature born CDH patients increased significantly over the past 3 decades.

CONCLUSION:

The SR of CDH patients were significantly increased in the past 3 decades. Although, the 2-years survival remains 5,8 times higher than those who were not born with CDH. These changes were mainly attributed to the improved SR of premature and non-premature born CDH patients.

Congenital diaphragmatic hernia

CDH

survival

overall survival rate

premature

Congenital diaphragmatic hernia (CDH) still remains a challenging problem for both surgeons and neonatologists (1). Improved knowledge in pathophysiology mechanism explaining the respiratory failure has led to continuous changes in the management of newborn infants with CDH (1). This involves antenatal steroids, planned delivery at specialized perinatal center, prophylactic administration of surfactant, gentle ventilation with permissive hypercapnea, high-frequency oscillatory ventilation to decrease the barotrauma, inhaled nitric oxide, extracorporeal membrane oxygenation (ECMO) for those infants failing to achieve adequate oxygenation, and delayed surgery after stabilization of respiratory and hemodynamic status (1). Despite these recent innovations, the survival rate of CDH infants is still low (1, 2). Population based studies from Australia and England reported 52% and 42% 1-year survival and 60% survival at 2-years in France (3–6). Most multicentre studies show a survival rate of around 65%, although survival can be as close as 90% at advanced centres (7).

Some studies have suggested that the outcomes for neonates with CDH have improved in a past decades, however, others have disputed these gains and attributed them to a possibility of a case selection bias (2, 3, 8–10). Survival reported from single institute may account only for neonates who were stable enough to survive transport, thus early mortality has not been accounted for (3). It has been estimated that between 32–60% of newborns with CDH die before reaching a treatment centre (3, 4). In contrast, population-based studies consider incident cases from the antenatal period to chosen outcome and therefore represent a better estimate of survival of all neonates with CDH (8).

Our aim was to investigate in a population-based study how changed the overall survival in children with CDH over the past 3 decades.

Study design

The study was a nationwide, population-based prospective nested case-control study within a cohort of newborn children who was born in Sweden during the observational period from 1st January 1982 until 31st December 2015. The study exposure was CDH and the study outcomes was survival. The primary outcome was survival at 2 years of age, and then the secondary outcome was to calculate estimated survival at 3 months, 1 years and after 2 years of age. Subgroup analysis was assessed regarding prematurity (gestational age at birth was < 32, 33–36 and 37 + weeks), gender (boys and girls) and changes of these in 3 different time interval (1982–1991, 1992–2001 and 2002–2015). All data were assessed through linkages between registries administrated by the Swedish National Board of Health and Welfare.

Registers

The Swedish National Board of Health and Welfare administered full-covered population health related registries. All Swedish residents are assigned a unique 10-digit personal identification number at the time of birth or following immigration, which enables linkage among the different national registries and a complete follow-up. The National Patient Register (NPR) contains prospectively collected information on all hospitals admissions in Sweden, including diagnoses according to the WHO ICD system and surgical procedures. The Medical Birth Register (MBR) contains prospective data on pregnancies and deliveries in Sweden.

Assessment of exposures and definition of cases and controls

Eligible case participants were all children born who was diagnosed with CDH during the observational period. Those who had genetic syndromes were excluded. The following codes of the International Classification of Diseases (ICD) were used to identify the diagnosis of CDH: ICD-9 756.6 ICD-10 Q79.0 and Q79.1.

In average, 5 control participants for each case were randomly sampled from the population register and matched for birth year and gender. Those who had genetic syndromes were also excluded.

Statistical analysis

Categorical data are expressed as frequencies or proportions. Continues data are expressed as mean ± SD or median (IQR). In order to analyze an event over time a model called Cox Proportional Hazard (or Cox Regression) was used, and results are expressed as hazard ratio (HR) with 95% CI and p values < 0.05 were considered significant. The survival over time has been illustrated using Kaplan-Meier curves. From the curves and estimate of the survival at a given time-point was extracted, and p values < 0.05 were considered significant.

All statistics were performed in R software version 2.38 (http://CRAN.R-project.org/package=survival).

Ethics

The regional ethical committee in Stockholm approved the study, Dnr 2013/1550-31/3.

Overall survival

In the study period 972 children were born with non-syndromic CDH, and 4672 control cases were selected (Table 1). Out of 972, 684 (70.4%) children with CDH and 4654 (99.6%) control cases were alive at 2 years of age. Significantly decreased overall survival was observed in CDH than controls at 2 years of age (Fig. 1, p < 0.001). Any patients who were born with CDH has overall 5,8 times higher chance for not survive 2 years of age (p < 0.001) than children without CDH (Table 2).

We observed that the most event happened in the first 3 months of age in the CDH group (Fig. 2). There was no significant difference in the estimated survival of CDH between at 3 months, at 1 year and at 2 years (73.1% vs 71.1% vs 70.3%) (Table 3). There was also no significant difference in the estimated survival of 1 years of age when children survived 3 months between CDH and control cases (99.9% vs 97.2%)(Table 3). The overall survival after 2 years of age was similar in controls and children born with CDH (Fig. 3).

While the overall survival has not been changed significantly in the past 3 decades in controls, it was significantly improved in CDH group from 61.2% in 1982–1994 to 82.7% in 2006–2015 (p:0.002)(Fig. 4, Table 4).

Prematurity

Significantly higher number of patients were premature born in the CDH group than in the controls (227, 23.3% vs 284, 6.1%, p < 0.001)(Table 1).

The overall survival and the estimated survivals at 2 years were significantly lower in CDH in every gestational age group compared to respective gestational age group in controls (Fig. 5, Table 5). Among the extreme premature babies, the estimated survival at 2 years was nearly half in CDH group than in controls (45.1% vs 81.8%, p < 0.001)(Table 5).

In controls, the overall survival in children born with < 32 week gestational age was significantly lower than children born with 32–36 or 37 + gestational age (Fig. 5). The overall survival was significantly lower in both extreme premature and premature children born with CDH than non-premature children with CDH (Fig. 5).

The estimated survival at 2 years of age in control with < 32 week gestational age was significantly lower than in control compared with 32–36 or 37 + weeks (81.8% vs 99.2% or 99.8%, p < 0.05)(Table 5). While in CDH group, both extreme premature and premature subgroup had significantly lower estimated survival at 2 years compared to non-premature CDH children (45.1% and 54.4% vs 77%, p < 0.05)(Table 5).

We observed that the overall survival and estimated survival at 2 years of age was significantly improved from 40.6% in 1982–1994 to 73.4% in 2006–2015 in premature and from 69.6% in 1982–1994 to 85.8% in 2006–2015 in non-premature children with CDH in a past three decades (Fig. 6, Table 6). The overall survival and estimated survival at 2 years of age in extreme premature born babies with CDH were unchanged in the past three decades (Fig. 6, Table 6).

Gender

Among children with CDH, 549 (56.5%) were male. The distribution of gender and severity of prematurity were similar in controls and CDH group. Among boys and girls separative, those who had CDH had significantly lower overall survival and estimated survival at 2 years of age compared those who did not have CDH (72% vs 99.7% and 68.1% vs 99.5%, p < 0.05)(Fig. 7, Table 7). There was no significant difference in overall survival and estimated survival at 2 years of age between boys and girls both in controls and CDH group (Fig. 7, Table 7).

In the current study we observed that the 2-year survival of children born with non-syndromic CDH in the past three decades was 70.4% whereas at the same time it was 99.6% in the control population. Any patients who were born with CDH has striking overall 5,8 times higher chance for not survive 2-years of age than children without CDH.

The 2-years survival has been chosen since neonatal death with CDH was reported to be most common within 24 hours and late death within the first 2 years of life can occur because of associated co-morbidities such as pulmonary hypertension or iatrogenic complications (1, 11). We saw also that the most event happened in the first 3 months of age. However, our data clearly shows that there was no significant difference between children born with or without CDH in the estimated survival of 1 and 2 years of age when children survived the first 3 months of life. Moreover, the overall survival after 2 years of age was similar in both general and CDH population.

Weber et al (12) investigated how improved the survival rates in their institute with evolving therapeutic strategies. In 1970–1983 their survival rate was 42% where patients had immediate operative repair of CDH without regard to clinical condition. The survival rate was increased to 58% when they started to use ECMO between 1984–1988 and risen up to 79% in 1989–1997 when they started the delayed repair, use of ECMO for moribund patients and postoperative inhaled nitric oxide.

We observed that the overall survival rate was increased in a past three decades from 61.2% in 1982–1991 to 82.7% in 2002–2015 in a population-based level. Since the study design was a population-based study, we did not have any detailed information on every patient such as side of the CDH, liver up, type of surgery, usage of ECMO or postoperative inhaled nitric oxide, or lung area to head circumference ratio (LHR). The lack of these information prevented us to do more detailed subgroup analysis on the overall survival on a population level.

Our subgroup analysis revealed that gender was no influence on survival rate in either general nor in CDH population; and extreme premature (< 32 weeks) and premature (32–36 weeks) babies with CDH have significantly lower overall survival than non-premature (37+) children at 2 years of age. However, the 2 years survival rates of extreme premature babies with CDH have not changed in the past 3 decades, the 2 years survival rates were significantly improved from 40.6% in 1982–1994 to 73.4% in 2006–2015 in premature and from 69.6% in 1982–1994 to 85.8% in 2006–2015 in non-premature born children with CDH.

The limitation of this study was that we focused only on the survival of patients who was born, and we did not focus on the hidden mortality by termination of pregnancies (TOP), stillborn or intrauterin fetal demise. However, our previous publication (13) focusing on the mortality in the same study period demonstrated that the hidden mortality was increased by 12% from 18% in 1987–1999 to 30% in 2000–2013. This was mainly related with the significantly increased prenatal diagnosis and TOP. We do not know how the survival of those fetuses who had TOP, would be. However, it has been reported that children with prenatally diagnosed CDH have lower survival (6, 9). Theoretically, cases of CDH that are prenatally diagnosed are those with earlier or larger herniation, which may result in more severe lung hypoplasia (3). Moreover, Harrison et al (14) suggested that prenatal diagnosis uncovers a population of foetuses with CDH who previously died in utero, were stillborn or died immediately after birth before admittance to a perinatal centre.

In the current study we observed that the overall survival of CDH was increased nearly double more in the past 3 decades than the previously reported increased hidden mortality, it is increased by 21.5% from 61.2% in 1982–1991 to 82.7% in 2002–2015. Therefore, it is tempting to speculate that the increased overall survival in the past 3 decades was caused by improved postnatal care, and not the increased TOP with selection out of the lower survival possibility cases. Subgroup analysis reviled that these improved survival changes in CDH patients in the past three decades were mainly attributed to the improved postnatal care and improved overall survival of premature and non-premature born CDH patients in a population-based level.

Table 1

Study cohort. (1: vs control, p < 0.05)
		Controls N = 4672	CDH N = 972
Gender	Boys	2658 (56.9%)	549 (56.5%)
Gender	Girls	2014 (43.1%)	423 (43.5%)
Two year survival	Alive	4654 (99.6%)	684 (70.4%)
Two year survival	Dead	19 (0.4%)	288 (29.6%)
Prematurity	< 32 w	44 (0.9%)	51 (5.2%)¹
	32–36 w	242 (5.2%)	176 (18.1%)¹
	37 + w	4319 (92.4%)	690 (71%)¹
	No data	67 (1.4%)	55 (5.7%)

Table 2

Overall survival cases compared to controls (given survived first two years).
	Estimate	HR	se	z-value	p-value	CI-lower	CI-upper
CDH	1.766	5.845	0.376	4.696	< 0.001	2.798	12.213

Table 3

Estimated survivals. (1: vs control, p > 0.05)
	time	n	n.risk	n.event	n.censor	surv	lower	upper
Estimated survival at 3 months (0.25 year)
Control	0.25	4672	4648	14	10	0.997	0.995	0.999
CDH	0.25	972	709	261	2	0.731¹	0.704	0.760
Estimated survival at 1 year
Control	1	4672	4519	18	135	0.996	0.994	0.998
CDH	1	972	666	281	25	0.711¹	0.683	0.740
Estimated survival at 2 years
Control	2	4672	4420	18	234	0.996	0.994	0.998
CDH	2	972	641	288	43	0.703¹	0.675	0.732
Estimated survival at 1 year, given has survived 3 months
Control	1	4648	4519	4	125	0.999	0.998	1.000
CDH	1	709	666	20	23	0.972	0.959	0.984

Table 4

Estimated survival at 2 years in three different time intervals. (1: vs control 1982–1991, p < 0.001; 2: vs control 1992–2001, p < 0.001; 3: vs control 2002–2015, p < 0.001; 4; vs CDH 1982–1991, p:0.002; 5: vs CDH 1992–2001, p:0.009)
	Gest. age	time	n	n.risk	n.event	n.censor	surv	lower	upper
Control	1982–1991	2	1081	1075	6	0	0.994	0.990	0.999
	1992–2001	2	1541	1538	3	0	0.998	0.996	1.000
	2002–2015	2	1939	1706	1	232	0.999	0.998	1.000
CDH	1982–1991	2	201	123	78	0	0.612¹	0.548	0.683
	1992–2001	2	285	190	95	0	0.667²	0.614	0.724
	2002–2015	2	380	272	65	43	0.827^3,4,5	0.790	0.867

Table 5

Estimated survivals at 2 years of age regarding gestational age in controls and in CDH group. (1: vs control 32–36; 2: vs control 37+; 3: vs control < 32; 4: vs CDH 37+; p < 0.05)
	Gest. age	time	n	n.risk	n.event	n.censor	surv	lower	upper
Control	< 32	2	44	34	8	2	0.818^1,2	0.711	0.940
	32–36	2	242	230	2	10	0.992	0.980	1.000
	37+	2	4319	4089	8	222	0.998	0.997	0.999
CDH	< 32	2	51	23	28	0	0.451 ^1,2,3,4	0.333	0.610
	32–36	2	176	86	80	10	0.544 ^1,2,3,4	0.475	0.623
	37+	2	690	499	158	33	0.770 ^1,2,3	0.740	0.803

Table 6

Estimated survival at 2 years of age regarding gestational age in CDH group in three different time intervals. (1: vs 32–36 weeks in 1982–1994 cohort; 2: vs 37 + weeks in 1982–1994 cohort; p < 0.05)
Gest. Age	Time intervals	time	n	n.risk	n.event	n.censor	surv	lower	upper
< 32 weeks	1982–1994	2	17	6	11	0	0.353	0.185	0.672
	1995–2005	2	20	11	9	0	0.550	0.370	0.818
	2006–2015	2	14	6	8	0	0.429	0.234	0.785
32–36 weeks	1982–1994	2	69	28	41	0	0.406	0.305	0.540
	1995–2005	2	54	29	25	0	0.537	0.419	0.688
	2006–2015	2	53	29	14	10	0.734¹	0.623	0.864
37 + weeks	1982–1994	2	237	165	72	0	0.696	0.640	0.757
	1995–2005	2	231	176	55	0	0.762	0.709	0.819
	2006–2015	2	222	158	31	33	0.858²	0.813	0.906

Table 7

Estimated survivals at 2 years of age regarding gender. (1: vs Boys in Control group; 2: vs Girls in Control group; p < 0.05)
	Sex	time	n	n.risk	n.event	n.censor	surv	lower	upper
Control	Boys	2	2658	2489	8	161	0.997	0.995	0.999
Control	Girls	2	2014	1931	10	73	0.995	0.992	0.998
CDH	Boys	2	549	367	153	29	0.720¹	0.684	0.759
CDH	Girls	2	423	274	135	14	0.681²	0.638	0.727

Author Contribution

B.K. wrote the main manuscript. CM. B. organised all the administrative work (ethical approval, download data from governmental site, etc.). All authors reviewed the manuscript.

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No competing interests reported.

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Journal Publication

published 01 Nov, 2024

Read the published version in Pediatric Surgery International →

Editorial decision: Accepted
16 Oct, 2024
Reviews received at journal
16 Oct, 2024
Reviewers agreed at journal
16 Oct, 2024
Reviewers invited by journal
15 Oct, 2024
Editor assigned by journal
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You are reading this latest preprint version

Survival Rate Changes in Children With Congenital Diaphragmatic Hernia Over the Past Three Decades: a Nationwide, Population-based Prospective Nested Case-control Study

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Materials and methods

Study design

Registers

Assessment of exposures and definition of cases and controls

Statistical analysis

Ethics

Results

Overall survival

Prematurity

Gender

Discussion

Declarations

Author Contribution

References

Additional Declarations

Status:

Journal Publication

Version 1