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. 2023 Feb 10;18(2):e0281723. doi: 10.1371/journal.pone.0281723

Congenital diaphragmatic hernia in a middle-income country: Persistent high lethality during a 12-year period

Ana Sílvia Scavacini Marinonio 1,*, Milton Harumi Miyoshi 1, Daniela Testoni Costa-Nobre 1, Adriana Sanudo 1, Kelsy Catherina Nema Areco 1, Mandira Daripa Kawakami 1, Rita de Cassia Xavier Balda 1, Tulio Konstantyner 1, Paulo Bandiera-Paiva 1, Rosa Maria Vieira de Freitas 2, Lilian Cristina Correia Morais 2, Mônica La Porte Teixeira 2, Bernadette Cunha Waldvogel 2, Carlos Roberto Veiga Kiffer 1, Maria Fernanda Branco de Almeida 1, Ruth Guinsburg 1
Editor: Xiaohong Li3
PMCID: PMC9916629  PMID: 36763629

Abstract

Background

In high- and middle-income countries, mortality associated to congenital diaphragmatic hernia (CDH) is high and variable. In Brazil, data is scarce regarding the prevalence, mortality, and lethality of CDH. This study aimed to analyze, in São Paulo state of Brazil, the temporal trends of prevalence, neonatal mortality and lethality of CDH and identify the time to CDH-associated neonatal death.

Methods

Population-based study of all live births with gestational age ≥ 22 weeks, birthweight ≥400g, from mothers residing in São Paulo State, Brazil, during 2004–2015. CDH definition and its subgroups classification were based on ICD-10 codes reported in the death and/or live birth certificates. CDH-associated neonatal death was defined as death up to 27 days after birth of infants with CDH. CDH prevalence, neonatal mortality and lethality were calculated and their annual percent change (APC) with 95% confidence intervals (95%CI) was analyzed by Prais-Winsten. Kaplan-Meier estimator identified the time after birth that CDH-associated neonatal death occurred.

Results

CDH prevalence was 1.67 per 10,000 live births, with a significant increase throughout the period (APC 2.55; 95%CI 1.30 to 3.83). CDH neonatal mortality also increased over the time (APC 2.09; 95%CI 0.27 to 3.94), while the lethality was 78.78% and remained stationary. For isolated CDH, CDH associated to non-chromosomal anomalies and CDH associated to chromosomal anomalies the lethality was, respectively, 72.25%, 91.06% and 97.96%, during the study period. For CDH as a whole and for all subgroups, 50% of deaths occurred within the first day after birth.

Conclusions

During a 12-year period in São Paulo State, Brazil, CDH prevalence and neonatal mortality showed a significant increase, while lethality remained stable, yet very high, compared to rates reported in high income countries.

Introduction

Congenital Diaphragmatic Hernia (CDH) has an estimated global prevalence of 2.3:10,000 live births [1], ranging from 1.09:10,000 live births in Iran between 2011 and 2016 to 3.2:10,000 live births in Florida between 1998 and 2012 [2, 3]. In Florida, CDH prevalence among live births was stationary between 1998 and 2012 [3], as well as in Barbados, another high-income country, between 1993 and 2012 [4].

CDH phenotypic presentation is variable, being reported as isolated CDH in more than 70% of cases or associated to non-chromosomal anomalies in around 22% and to chromosomal anomalies in 3–4% [3, 5]. Several variables are related to survival of patients with CDH, such as the phenotypic presentation, the lung size, the presence of liver herniation and pulmonary hypertension, the pregnancy interruption practices, procedures performed in utero, the clinical management during transition from fetal to neonatal life, and the quality of perinatal care [6–8].

Lethality of patients with CDH is high [7], especially during the neonatal period, reaching up to 30% in high-income countries [8]. For Latin American Centers, isolated CDH lethality during the neonatal period is 68%, varying from 23% for mild cases to 97% for severe CDH [6]. Considering CDH associated to congenital anomalies, the lethality rate reported by one middle-income country referral center was 64% [9].

In Brazil, some single centers studies reported lethality rates in infants with CDH up to 27 days after birth between 27% and 89% [5, 10], reaching 100% for CDH associated to chromosomic anomalies [10]. One population-based study done in São Paulo, with data retrieved from live births and mortality information system without linkage, available at DATASUS (Informatic Department of the Brazilian Health System), showed 64% of lethality rate between 2006–2017 [11]. However, there are no studies that address the temporal trend of CDH prevalence, mortality, and lethality in the Brazilian states or in the country that can provide consistent information to guide public health policies for CDH management.

Therefore, the objectives of this study were to analyze, in São Paulo state of Brazil, the temporal trends of prevalence, neonatal mortality and lethality of CDH and its subgroups (isolated CDH, CDH associated to chromosomal anomaly and CDH associated to non-chromosomal anomalies) and, finally, to identify the time to CDH-associated neonatal death.

Methods

This is a population-based study of all live births with gestational age ≥22 weeks and birthweight ≥400g from mothers residing in São Paulo State, Brazil, between 2004 and 2015. São Paulo State, with around 41 million inhabitants, is responsible for 32% of the national income, with the second highest Human Development Index in the country (HDI 0,783 in 2010) [12] and is listed as the 21st biggest economies of the world [13].

In the State, all information regarding births and deaths are filled in by physicians in the Live Births and Deaths certificates, respectively. The physician should follow a manual prepared by the Brazilian Ministry of Health [14, 15], in which the notification and codification of congenital anomalies is mandatory [16]. After completion, these certificates are forwarded to the Health Offices and Registry Offices [14, 15], which send monthly electronic records of the information on the Live Birth and Infant Death Certificates (up to 365 days after birth) to the SEADE Foundation. Based on live birth and death information, SEADE Foundation makes the deterministic linkage from death to live birth records in order to identify birth information from all infants who died within 365 days after birth [17]. The data set was organized according to the study design towards a final database integrating common birth variables among the neonatal death records and live birth records, ensuring 99% of success in linkage between both datasets [18].

The study was approved by the Ethics Committee of Universidade Federal de São Paulo, under the number 4.055.489, with waived informed consent.

CDH definition was based on ICD-10 codes found in any line of the death and/or live birth certificates and classified into 3 subgroups: isolated, CDH associated to chromosomal anomalies and CDH associated to non-chromosomal anomalies (Table 1).

Table 1. CDH definitions.

Classification ICD-10 codes
CDH Q79.0—congenital diaphragmatic hernia
K44—diaphragmatic hernia
K44.0—diaphragmatic hernia with obstruction, without gangrene
K44.1—diaphragmatic hernia with gangrene
K44.9—diaphragmatic hernia without obstruction or gangrene
Isolated CDH CDH codes with/or without the following:
Q33.6—pulmonary hypoplasia
Q33.3—pulmonary agenesis
Q25.0—patent ductus arteriosus
CDH associated to chromosomal anomaly CDH codes AND any code between
Q90 and Q99 (Chromosomal abnormalities)
CDH associated to non-chromosomal anomaly CDH codes AND any other chapter Q ICD-10 code except those used in the definition of isolated CDH or CDH associated to chromosomic anomaly)
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Non-chromosomal anomalies associated to CDH were further classified into nervous system (Q00-Q07), eye, ear, face, and neck (Q10-Q18), circulatory system (Q20-Q28), respiratory system (Q30-Q34), cleft lip and cleft palate (Q35-Q37), digestive system (Q38-Q45), genital organs (Q50-Q56), urinary system (Q60-Q64), musculoskeletal system (Q65-Q79), and other congenital anomalies (Q80-Q89). CDH-associated neonatal death was defined as any death of infants with CDH (according to Table 1) that occurred between 0 and 27 completed days after birth.

The following demographic characteristics were described for all CDH live births and CDH-associated neonatal deaths: maternal age (<20, 20–34 and ≥35 years), maternal schooling (<12 and ≥12 years), parity (primiparous or multiparous), number of prenatal care visits (0, 1–6 and ≥7), pregnancy (single or multiple), delivery mode (vaginal or cesarean section), gestational age (preterm or term), birthweight (<2500g or ≥2500g), sex (male or female), 1st and 5th minute Apgar score (0–6 and ≥7).

Prevalence, neonatal mortality, and lethality rates of CDH and its subgroups (isolated CDH, CDH associated to non-chromosomal anomalies and CDH associated to chromosomal anomaly) were calculated. Prevalence was calculated by the number of live births with CDH per 10,000 live births; neonatal mortality was obtained by the number of CDH-associated neonatal deaths per 10,000 live births; and lethality was calculated by the number of CDH-associated neonatal deaths per 100 live births with CDH. Prevalence, neonatal mortality, and lethality annual trends were analyzed by Prais-Winsten Model, and their annual percent change (APC) with 95% confidence intervals (95%CI) were calculated.

Kaplan-Meier estimator was applied to identify the time from birth to the CDH-associated neonatal death for each CDH group during the 12-year study period.

All procedures were done using Stata 15.1® (StataCorp LLC, Texas, USA).

Results

From 2004 to 2015, there were 7,317,611 live births in São Paulo State, Brazil. Among them, 7,314,257 were included in the study. CDH was reported in 1,225 (0.02%) live births, with 965 (78.8%) CDH-associated neonatal deaths (Fig 1).

Fig 1. Flowchart of included infants.

Fig 1

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LB: live births; CDH: congenital hernia diaphragmatic; GA: gestational age; BW: birthweight.

More than one anomaly group was found in 128 (35.8%) of the 358 live births with CDH associated to non-chromosomal anomalies. Anomalies in the musculoskeletal system were the most frequently group associated to CDH (S1 Table). Among the chromosomal anomalies associated to CDH, Trisomy 18 was the most frequent (S1 Table).

Demographic characteristics of CDH live births and CDH-associated neonatal deaths are described in Table 2.

Table 2. General characteristics of CDH live births and CDH-associated neonatal deaths.

CDH live births CDH-associated neonatal deaths
Maternal age (years) n = 1,225 n = 965
 <20 13% 14%
 20–34 68% 68%
 ≥ 35 19% 19%
Maternal schooling (years) n = 959 n = 751
 ≤ 7 26% 28%
 8–11 54% 55%
 ≥ 12 20% 17%
Primiparous n = 997 n = 795
 Yes 43% 41%
Prenatal care visits n = 1,195 n = 940
 0 1% 1%
 1–6 30% 31%
 ≥ 7 69% 67%
Pregnancy n = 1,225 n = 965
 Single 97% 97%
Delivery n = 1,225 n = 965
 Cesarean section 72% 72%
Gestational age (weeks) n = 1,204 n = 952
 22–27 2% 3%
 28–31 6% 7%
 32–36 28% 28%
 37–41 64% 62%
 ≥ 42 1% 1%
Birthweight (grams) n = 1,220 n = 963
 Mean (range) 2577 (500–4750) 2518 (500–4610)
 ≥ 2500 61% 57%
Sex n = 1,224 n = 965
 Male 57% 55%
1st minute Apgar score n = 952 n = 741
 ≥ 7 25% 17%
5th minute Apgar score n = 954 n = 743
 ≥ 7 57% 48%
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CDH: congenital diaphragmatic hernia; n: total number available for the variable.

Prevalence of CDH

CDH prevalence, during 12-year study period, was 1.67 (95%CI 1.60 to 1.77) per ten thousand live births. For isolated CDH, CDH associated to non-chromosomal anomalies, and CDH associated to chromosomal anomalies, the prevalence was, respectively, 1.12, 0.49 and 0.06 per ten thousand live births (S2 Table).

The annual trend of CDH prevalence rate showed an increasing pattern, with a positive Annual Percent Change (APC): 2.55; 95%CI 1.30 to 3.83. An increase in annual rates was also observed for isolated CDH (APC 2.11; 95%CI 0.54 to 3.70), and for CDH associated to non-chromosomal anomalies (APC 3.96; 95%CI 0.87 to 7.15). For CDH associated to chromosomal anomalies, the annual trend was stationary (APC 1.85; 95%CI -7,82 to 12,53) (Fig 2).

Fig 2. Annual trend of CDH prevalence rate adjusted by Prais-Winsten model.

Fig 2

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CDH prevalence rate per year adjusted by Prais-Winsten analysis; (A) Any CDH; (B) Isolated CDH; (C) CDH associated to non-chromosomal anomalies; (D) CDH associated to chromosomal anomalies. CDH: congenital diaphragmatic hernia; LB: live births.

CDH neonatal mortality and lethality

CDH neonatal mortality rate, was 1.32 per ten thousand live births, with an increasing annual trend (APC 2.09; 95%CI 0.27 to 3.94). The lethality rate during the study period was 78.78%, with a stationary pattern (APC -0.43; 95%CI -1.83 to 0.10) (Fig 3).

Fig 3. Annual trend of CDH neonatal mortality rate and CDH lethality adjusted by Prais-Winsten model.

Fig 3

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(A) CDH neonatal mortality rate per year adjusted by Prais-Winsten analysis; (B) CDH lethality per year adjusted by Prais-Winsten analysis. CDH: congenital diaphragmatic hernia; LB: live births.

The neonatal mortality and lethality data, as well as their annual trends, for CDH subgroups are shown in Table 3.

Table 3. Neonatal mortality rate, lethality and annual trends for Congenital Diaphragmatic Hernia subgroups.

Isolated CDH CDH associated to non-chromosomal anomalies CDH associated to chromosomal anomalies
Neonatal mortality
 • Per 10,000 live births 0.81 0.45 0.07
 • Annual trend stationary stationary stationary
 • Annual Percent Change—% (95% confidence interval 1.98 (-0,45 to 4.46) 2.38 (-0.71 to 5.58) 1.85 (-7.82 to 12.53)
Lethality
 • Per 100 live births with CDH (by CDH subgroup) 72.25 91.06 97.96
 • Annual trend stationary decreasing *
 • Annual percent change—% (95% confidence interval) -0.096 (-1.889 to 1.730) -1.57 (-2.34 to -0.79) *
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CDH: congenital diaphragmatic hernia;

*Prais-Winsten model do not fit, and it was not possible to calculate trends.

Kaplan-Meier analysis showed that the median time of CDH-associated neonatal deaths was 24 hours after birth (95%CI 24 to 25 hours). For isolated CDH the median time of deaths was 26 hours (95%CI 24 to 31 hours); for CDH associated to non-chromosomal anomalies the median time to death was 24 hours (95%CI 16 to 24 hours), and for CDH associated to chromosomal anomalies, 23 hours (95%CI 7 to 48 hours) (S1 Fig).

Discussion

This populational study evaluated the temporal trends of CDH prevalence, neonatal mortality, and lethality during a 12-year period in São Paulo State, Brazil. CDH prevalence was 1.67 per 10,000 live births, with a significant increase throughout the period. CDH neonatal mortality also increased throughout the period, while the lethality remained stable between 2004–2015. Considering all CDH subgroups, isolated CDH represented the majority of cases, and its prevalence increased over the years. No change in neonatal mortality rate temporal trends was identified among CDH subgroups. Lethality for CDH and for all subgroups were high, and most CDH-associated neonatal deaths occurred within the first day after birth.

In the present study, CDH prevalence was lower than 2.1 per 10,000 live births reported by some high and middle-income countries between 2004 and 2015 [19], nevertheless similar to that found in São Paulo State between 2006 and 2017 [11]. However, contrasting to a stationary prevalence reported by high income countries [3, 4], our study showed that CDH prevalence increased over the years. This finding is similar to those observed for all congenital anomalies in Brazil and may be the result of case notification increase due to training and monitoring for congenital anomalies report, promoted by the Brazilian Ministry of Health [16]. In addition, improved access to the health care system [20] and better perinatal emergency care, with a greater chance of survival beyond the delivery room [21], may have contributed to improvements in CDH identification.

The increased prevalence and the fact that CDH lethality remained high during the study period may have resulted in the CDH neonatal mortality increase observed over the years in São Paulo State. The lethality of CDH reported in our study is much higher than the 20.2% found in high-income countries [3], or the 33.5% found in a multi country population-based study [8]. Considering that CDH is a rare congenital malformation that requires complex and multidisciplinary care, antenatal diagnosis is important for maternal referral to tertiary and surgical centers prior to delivery [22, 23], where experts are available, as well as protocols for initial stabilization in the delivery room, postnatal care, and optimal clinical and surgical treatment options [22]. Based on these considerations, the high CDH neonatal mortality and lethality observed in our study may reflect São Paulo State health inequities [24]. São Paulo State has discrepancies in access to primary and qualified health care [24], a lack of adequate strategic planning to intensive care development [25], inequities in resources distribution and care effectiveness [26]. All these factors, associated with the lack of evidence-based literature to guide neonatal care in terms of ventilatory, hemodynamic and sedation for the CDH management [27], possibly contribute with the high neonatal mortality rate and lethality observed in São Paulo State during the study years [28].

Furthermore, comparing our CDH lethality with the 65% reported by another population-based study carried out in the state of São Paulo using DATASUS [11], possibly the greatest consistency of our database, with more than 99% of linkage between neonatal death records and live birth records, resulted in better retrieval of information and the higher lethality found in our study [18, 29].

CDH-associated neonatal deaths occurred earlier in São Paulo State, compared to South American data reported by ECLAMC, which showed 0.2% of deaths on the first day after birth [8]. Probably most CDH-associated neonatal deaths in São Paulo State occurred during the first day after birth due to the lack of strategies for initial stabilization and inadequate infrastructure to implement cardiopulmonary support, critical to enhance survival chances of newborn infants with CDH [7, 30].

In terms of lethality, our study showed higher rates than the Latin American CDH Study Group, which reported 68.1% of lethality for isolated left CDH [6]. In our study, 553/818 (67.6%) of isolated CDH were reported on the live birth certificates, but it is possible for the rate of antenatal diagnosis to be much lower. The isolated CDH subgroup is the one which benefits the most from antenatal diagnosis [31] and prenatal procedures, thus improving the prognosis of neonates with moderate pulmonary hypoplasia [32].

Associated non-chromosomal anomalies considerably reduce survival rates in neonates with specific congenital anomalies [3]. The fact that the lethality of this CDH subgroup decreased over the study period deserves further analysis in order to identify these survivors. Despite this trend, lethality was exceddingly high in this subgroup, over 90% throughout the period.

Finally, in the present study, the subgroup of infants with CDH associated to chromosomal anomalies represented 4% of total CDH infants, with Trisomy 13 and 18 accounting for 67% of the cases. European and Brazilian studies also report Trisomy 18 as the most common chromosomal anomaly associated to CDH, followed by Trisomy 13 and 21 [5, 21]. In this subgroup of CDH infants, stationary trends with wide confidence intervals were observed for prevalence and neonatal mortality rates during the study period. The inability to analyze the lethality temporal trend may have been influenced by the number of infants in this subgroup each year. However, in our study, lethality in this group was close to 100%, similar to a report from a Brazilian specialized tertiary center [10], although higher than the 40% observed in a population-based study in a high-income country [3]. In Brazil, there is no specific guideline for the perinatal management of newborn infants with Trisomy 13 or 18 and many of them do not receive active care, resulting in early deaths [33].

This study has several limitations. The database was provided by SEADE Foundation after linking and anonymization, and this process rely on a manual component which is time-consuming; therefore, the most recent year available for the study was 2015. The database is based on live birth and death certificates; thus, there is a risk of information bias since it depends on the notification of the diagnosis (including the impossibility of confirming the performance of chromosomal tests, which may have influenced the prevalence of chromosomal and non-chromosomal anomalies associated with CDH). The database does not include information on maternal diseases, treatments and procedures during pregnancy, CDH characteristics and management. Despite these limitations, this study is one of the first population-based evaluations of the temporal trends of CDH prevalence and neonatal deaths in a middle-income country and was done using a database that covers a greater volume of data compared to other available databases in Brazil [29], allowing a more reliable understanding of low-occurrence diseases. Considering the economic, social, and health inequities in São Paulo State, further research is necessary to identify CDH prevalence and outcome variation across the state.

In conclusion, during a 12-year period in São Paulo State, Brazil, CDH prevalence and neonatal mortality showed a significant increase, while lethality remained stable, yet high compared to rates reported in high income countries.

Supporting information

S1 Fig. Age in hours at the time of CDH-associated neonatal deaths, according to Kaplan-Meier survival estimate.

(PDF)

Click here for additional data file. (201.1KB, pdf)
S1 Table. Frequency of chromosomal and non-chromosomal anomalies associated with CDH, per diagnoses.

(PDF)

Click here for additional data file. (32.9KB, pdf)
S2 Table. Number of live births, CDH live births and CDH-associated neonatal deaths, per year.

(PDF)

Click here for additional data file. (42.1KB, pdf)

Acknowledgments

We thank all technical staff of Fundação Sistema Estadual de Análise de Dados (SEADE Foundation) for their work with the database and Josiane Quintiliano Xavier de Castro, MD, for helping in the deterministic linkage between Live Birth Certificates and Death Certificates.

Data Availability

The database of the study was uploaded and available in the ZENODO public repository. The DOI for the data is: 10.5281/zenodo.6992692.

Funding Statement

This research was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Project # 2017/03748-7. FAPESP had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Decision Letter 0

Xiaohong Li

13 Dec 2022

PONE-D-22-22879Congenital diaphragmatic hernia in a middle-income country: persistent high lethality during a 12-year period.PLOS ONE

Dear Dr. SCAVACINI MARINONIO,

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Additional Editor Comments:

Abstract

1. Line 26 of page 2, I strongly suggest that the incidence of CDH should be modified to birth prevalence of CDH throughout the manuscript. It is very difficult to estimate the incidence of birth defects.

2. Line 42 of page 2, The results showed that the median time of CDH-associated neonatal deaths was 24 hours after birth, so I think the statement 'most deaths occurred within the first day after birth' is not exactly, '50% deaths occurred within the first day after birth' might be more sound.

Introduction

1. Line 51 of page 4, the contents of reference 1 is about prevalence, not incidence.

2. Line 54 of page 4, birth prevalence of CDH is preferred.

3. Line 72 of page 4, please clarify the age group of lethality rate, in neonatal period or in infancy, or others?

Methods

1. I think more details about death certificates and live birth certificates should be given in the methods section, such as who, when and how collect death certificates, as well live birth certificates; the process of birth defect ascertainment; the quality measures of the two dataset.

2. Line 102, The definition and classification of CDH are shown in Table 1. Why are the diagnostic ICD-10 codes, such as K44, classified as CDH? So It's important to clarify the ascertainment time of CDH. Besides, if babies are diagnosed as CDH, will all cases undergo further chromosome examination? This is important to access the trend of prevalence of CDH associated with non-chromosome abnormality.

3. I would like to see the results about survival curve for newborns affected with CDH. That will give the readers more information.

Results

1. Line 138 of Page 8, please check the number '35.8%'. Also, please check all the data shown in Supplementary Table 1. The order of ' Other chromosomal anomalies' and 'Other trisomy' should be inter-changed.

2. Line 147-150 of page 9, could you please show 95%CI of birth prevalence of CDH in the main text.

3. Line 152 of page 9, the abbreviated 'CI' need to be defined earlier.

[Note: HTML markup is below. Please do not edit.]

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #2: Yes

**********

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Reviewer #1: This is an important contribution to the knowledge on CDH. The authors have presented the data clearly, pointing out the limitations of the data. My once comment relates to the use of the term incidence. Incidence is not used to report the occurrence of congenital anomalies, as the total number of conceptions cannot be measured. Instead, birth prevalence is used. This correction may be made throughout the manuscript.

Reviewer #2: The authors have presented a really nice review of population based data on CDH births, mortality, and lethality in the Sao Paulo State of Brazil. The introduction and methodology of the manuscript are sound. I also thought that the results are presented clearly and succinctly for the limited data available on the topic. The discussion was thorough, but it seemed to go on for a little too long. I would recommend that the authors work to cut some of the discussion wording to make it a quicker and more streamlined read. Otherwise, I think it is worthy of publication and adds to the worldwide education about the status of CDH care in this middle-income country.

**********

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Reviewer #2: No

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PLoS One. 2023 Feb 10;18(2):e0281723. doi: 10.1371/journal.pone.0281723.r002

Author response to Decision Letter 0

3 Jan 2023

Here is a point-by-point response to the editor and reviewers’ comments and concerns.

Comments from Editor

Abstract

• Comment 1. Line 26 of page 2, I strongly suggest that the incidence of CDH should be modified to birth prevalence of CDH throughout the manuscript. It is very difficult to estimate the incidence of birth defects.

Thank you for the comment. We agree with the question and we have changed “incidence” for “prevalence” throughout the text.

• Comment 2. Line 42 of page 2, The results showed that the median time of CDH-associated neonatal deaths was 24 hours after birth, so I think the statement 'most deaths occurred within the first day after birth' is not exactly, '50% deaths occurred within the first day after birth' might be more sound.

Thank you. We corrected the sentence in the abstract - last line of results (page 2, lines 43-44) as follows: “For CDH as a whole and for all subgroups, 50% of deaths occurred within the first day after birth.”

Introduction

• Comment 1. Line 51 of page 4, the contents of reference 1 is about prevalence, not incidence.

Thank you again for your considerations. Similar to abstract, after your consideration, “incidence” was changed to “prevalence” throughout the text.

• Comment 2. Line 54 of page 4, birth prevalence of CDH is preferred.

Thank you again. The term “incidence” was changed to “prevalence” throughout the text.

• Comment 3. Line 72 of page 4, please clarify the age group of lethality rate, in neonatal period or in infancy, or others?

After the suggestion, the age group was inserted. The text now reads (page 5, lines 71-73) as follows: “In Brazil, some single center studies reported lethality rates in infants with CDH up to 27 days after birth between 27% and 89% [5,10], reaching 100% for CDH associated to chromosomic anomalies [10].”

Methods

• Comment 1. I think more details about death certificates and live birth certificates should be given in the methods section, such as who, when and how collect death certificates, as well live birth certificates; the process of birth defect ascertainment; the quality measures of the two dataset.

Thank you for the questions regarding data collection and quality. The answer is reported in two steps: 1. acquisition and quality of the data and, 2. verification of birth defects.

1. Acquisition and quality of the data: all births and deaths that occur in Brazil are registered through certificates called, respectively, Live Birth and Death Certificates. Completing these certificates is a legal responsibility of the physician, who fills them out in accordance with manuals prepared by the Brazilian Ministry of Health (Brasil, 2022-a; Brasil, 2022-b). Congenital anomalies notification is compulsory, and those detected at birth must be reported in Live Births Certificates, which contain an objective question about the presence or absence of congenital anomalies detected at birth and a field for recording all visible congenital anomalies, which must be described and coded according to the 10th version of the International Statistical Classification of Diseases and Related Problems to Health (ICD-10) (WHO, 2010). Death Certificates are completed after any death and contain information about the cause of death and any diagnoses that contributed to the death, which may include congenital anomalies. Once completed, these declarations are forwarded to the registry offices (Brasil, 2022-a; Brasil, 2022-b). The registry offices of the 645 municipalities in the State of São Paulo send monthly the electronic Live Birth and Infant Death Certificates (up to 365 days after birth) to the SEADE Foundation, which is the institution responsible for collecting, organizing, analyzing and disseminating records of deaths and live births in the State. Based on death and live birth information, SEADE Foundation databases of live births and infant deaths are built using deterministic linkage from death to live birth records in order to identify birth information from all infants who died within 365 days after birth. Identification and creation of true pairs of both certificates is achieved either by equality or similarity, aiming to detect divergences, allowing corrections, and incorporating available information in only one instrument. This procedure is decisive in improving the statistics of the civil registry of the São Paulo State (Waldvogel, 2019).

2. Verification of birth defects: despite mandatory notification, the quality of completion and coding of fields related to congenital anomalies in the Live Birth and Death Certificates may vary among municipalities and health centers. Some anomalies are not visible at delivery and others, although diagnosable at birth, require instruments or specific technical knowledge not always available in all public or supplementary health services, which may result in suboptimal or incorrect records (Nhoncanse, 2012; Brasil, 2021).

After your suggestion, we included, in the methods section (page 6, lines 92-101), a summary of this information, as follow: “In the State, all information regarding births and deaths are filled in by physicians in the Live Births and Deaths Certificates, respectively. The physician should follow a manual prepared by the Brazilian Ministry of Health [14,15], in which the notification and codification of congenital anomalies is mandatory [16]. After completion, these certificates are forwarded to the Health Offices and Registry Offices [14,15], which send monthly electronic records of the information on the Live Birth and Infant Death Certificates (up to 365 days after birth) to the SEADE Foundation. Based on live birth and death information, SEADE Foundation makes the deterministic linkage from death to live birth records in order to identify birth information from all infants who died within 365 days after birth [17]”

Brasil-a. Declaração de nascido vivo: manual de instruções para preenchimento [cited 28 Dec 2022]. Available from: http://bvsms.saude.gov.br/bvs/publicacoes/declaracao_nascido_vivo_manual_4ed.pdf.

Brasil-b. Declaração de óbito: manual de instruções para preenchimento [cited 28 Dec 2022]. Available from: https://www.gov.br/saude/pt-br/centrais-de-conteudo/publicacoes/publicacoes-svs/vigilancia/declaracao-de-obito-manual-de-instrucoes-para-preenchimento.pdf/view

World Health Organization. International statistical classification of diseases and related health problems. 10th rev. Geneve: World Health Organization; 2010.

Waldvogel BC, Morais LCC, Perdigão ML, Teixeira MLP, Freitas RMV, Aranha VJ. Experiência da Fundação Seade com a aplicação da metodologia de vinculação determinística de bases de dados. Ensaio Conjuntura. 2019;1:1-25.

Nhoncanse, Geiza César e Melo, Débora Gusmão. Confiabilidade da Declaração de Nascido Vivo como fonte de informação sobre os defeitos congênitos no Município de São Carlos, São Paulo, Brasil. Ciência & Saúde Coletiva [online]. 2012, v. 17, n. 4, pp. 955-963. Disponível em: <https://doi.org/10.1590/S1413-81232012000400017>. Epub 23 Abr 2012. ISSN 1678-4561.

Brasil. Saúde Brasil 2020/2021: anomalias congênitas prioritárias para a vigilância ao Nascimento. Available from: https://bvsms.saude.gov.br/bvs/publicacoes/saude_brasil_anomalias_congenitas_prioritarias.pdf.

• Comment 2. Line 102, The definition and classification of CDH are shown in Table 1. Why are the diagnostic ICD-10 codes, such as K44, classified as CDH? So It's important to clarify the ascertainment time of CDH. Besides, if babies are diagnosed as CDH, will all cases undergo further chromosome examination? This is important to access the trend of prevalence of CDH associated with non-chromosome abnormality.

Thank you for your question. Although Q79.0 is specific code for CDH, we chose to include codes K40, K44.0, K44.1 and K44.9 which indicate the presence of diaphragmatic hernia and may be coded in a neonate if the physician does not write the word “congenital” in the live birth or death certificate. Considering that our study was based on clinical information recorded by the physician at the time of birth and/or death of each neonate and it includes only the neonatal period, we understand that the inclusion of these codes may reduce the possibility of sample losses without overestimating the actual cases of CDH. The database used for the research contains clinical and demographic information, but it has limitations, and, among them, it is not possible to know which tests were performed or requested, including chromosomal tests, which can influence the prevalence of chromosomal and non-chromosomal anomalies associated to CDH. Thus, we understand the importance of adding a specific concern in the limitations of the study, as follows (page 17, lines 286-289): “…. thus, there is a risk of information bias since it depends on the notification of the diagnosis (including the impossibility of confirming the performance of chromosomal tests, which may have influenced the prevalence of chromosomal and non-chromosomal anomalies associated with CDH).”

• Comment 3. I would like to see the results about survival curve for newborns affected with CDH. That will give the readers more information.

Information regarding to survival curve is described in the methods (page 8, lines 137-138) and in last paragraph of results (on page 14, lines 193-197), and showed in a supplemental file 1, as follows: “Kaplan-Meier analysis showed that the median time of CDH-associated neonatal deaths was 24 hours after birth (95%CI 24 to 25 hours). For isolated CDH the median time of deaths was 26 hours (95%CI 24 to 31 hours); for CDH associated to non-chromosomal anomalies the median time to death was 24 hours (95%CI 16 to 24 hours), and for CDH associated to chromosomal anomalies, 23 hours (95%CI 7 to 48 hours) (S1 Fig.).”

Results

• Comment 1. Line 138 of Page 8, please check the number '35.8%'. Also, please check all the data shown in Supplementary Table 1. The order of ' Other chromosomal anomalies' and 'Other trisomy' should be inter-changed.

Regarding to 35.8%, this number is correct – in 35.8% of live births with non-chromosomal anomalies associated to CDH, there was more than one group of non-chromosomal congenital anomalies registered. To better clarify this point, we included on page 9, line 149-150, the number of representing the 35.8%, as follows: “More than one anomaly group was found in 128 (35.8%) of the 358 live births with CDH associated to non-chromosomal anomalies.” Regarding the Reviewer’s concern about the interchange between 'Other chromosomal anomalies' and 'Other trisomy', the correction was made on supplementary Table 1.

• Comment 2. Line 147-150 of page 9, could you please show 95%CI of birth prevalence of CDH in the main text.

Thank you for the suggestion. The 95%CI of CDH prevalence was inserted on page 11, lines 160-161, as follows: “CDH prevalence, during 12-year study period, was 1.67 (95%CI 1.60 to 1.77) per ten thousand live births.”

• Comment 3. Line 152 of page 9, the abbreviated 'CI' need to be defined earlier.

Thank you for the suggestion. The definition was included on page 8, lines 134-136, as follows: “Prevalence, neonatal mortality, and lethality annual trends were analyzed by Prais-Winsten Model, and their annual percent change (APC) with 95% confidence intervals (95%CI) were calculated.”

Comments from Reviewer 1

• Comment. This is an important contribution to the knowledge on CDH. The authors have presented the data clearly, pointing out the limitations of the data. My once comment relates to the use of the term incidence. Incidence is not used to report the occurrence of congenital anomalies, as the total number of conceptions cannot be measured. Instead, birth prevalence is used. This correction may be made throughout the manuscript.

Thank you for your careful review of our manuscript. We understand the question and change “incidence” for “prevalence” throughout the manuscript.

Comments from Reviewer 2

• The authors have presented a really nice review of population based data on CDH births, mortality, and lethality in the Sao Paulo State of Brazil. The introduction and methodology of the manuscript are sound. I also thought that the results are presented clearly and succinctly for the limited data available on the topic. The discussion was thorough, but it seemed to go on for a little too long. I would recommend that the authors work to cut some of the discussion wording to make it a quicker and more streamlined read. Otherwise, I think it is worthy of publication and adds to the worldwide education about the status of CDH care in this middle-income country.

Thank you for your careful review of our manuscript and for your suggestion. We worked on the discussion and shortened it, removing the text to single-center studies.

We are grateful to the editor and to both reviewers for the suggestions to improve our manuscript. We hope that the revised manuscript fulfills the requirements of your prestigious journal. We thank you for your consideration and we are looking forward to hearing from you.

Yours sincerely,

Ana Silvia Scavacini Marinonio on behalf of all authors.

Email: anascavacini@gmail.com

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file. (50.1KB, docx)

Decision Letter 1

Xiaohong Li

31 Jan 2023

Congenital diaphragmatic hernia in a middle-income country: persistent high lethality during a 12-year period.

PONE-D-22-22879R1

Dear Dr. SCAVACINI MARINONIO,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Xiaohong Li

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Xiaohong Li

2 Feb 2023

PONE-D-22-22879R1

Congenital diaphragmatic hernia in a middle-income country: persistent high lethality during a 12-year period.

Dear Dr. Scavacini Marinonio:

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Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Fig. Age in hours at the time of CDH-associated neonatal deaths, according to Kaplan-Meier survival estimate.

    (PDF)

    Click here for additional data file. (201.1KB, pdf)
    S1 Table. Frequency of chromosomal and non-chromosomal anomalies associated with CDH, per diagnoses.

    (PDF)

    Click here for additional data file. (32.9KB, pdf)
    S2 Table. Number of live births, CDH live births and CDH-associated neonatal deaths, per year.

    (PDF)

    Click here for additional data file. (42.1KB, pdf)
    Attachment

    Submitted filename: Response to Reviewers.docx

    Click here for additional data file. (50.1KB, docx)

    Data Availability Statement

    The database of the study was uploaded and available in the ZENODO public repository. The DOI for the data is: 10.5281/zenodo.6992692.

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