Risk of perinatal deaths for fetuses and early newborns with congenital heart defects

doi:10.21203/rs.3.rs-2185497/v1

Background

There are few studies on perinatal death with congenital heart defects (CHDs). This study analyzed the epidemiological features of CHD and the risk of perinatal death for fetuses and early newborns with CHDs.

Methods

We used data from the Birth Defects Surveillance System of Hunan Province, China, from 2016 to 2020. The surveillance data of perinatal infants (for stillbirth, dead fetus, or live birth between 28 weeks of gestation and seven days after birth) were analyzed. We computed the CHD prevalence and 95% confidence intervals (CI) by Poisson regression and analyzed the epidemiological features of perinatal deaths with CHD.

Results

From 2016 to 2020, a total of 847755 perinatal infants were registered, 14459 cases of birth defects and 4161 cases of CHDs were reported. The CHD prevalence was 4.908‰. Among the 4161 cases of CHDs, 976 cases (23.46%) of perinatal deaths were reported, and 941 cases (96.41%) of perinatal deaths were electively terminated of pregnancy. A relatively high proportion of perinatal deaths occurred in the maternal age group <20 and 20-24 years old. The CHD prevalence was higher in urban areas than in rural areas (6.844‰ vs. 3.598‰) (P<0.05). The most frequent CHD subtypes were ventricular septal defect (VSD), atrial septal defect (ASD), tetralogy of Fallot (TOF), and atrioventricular septal defect (AVSD), which accounted for 56.36%, 12.28%, 3.51% and 2.14% of total CHDs, respectively, and the prevalences were 2.766‰, 0.603‰, 0.172‰, and 0.105‰, respectively. The proportions of perinatal deaths with VSD (9.72%) and ASD (2.74%) were relatively low, while TOF (67.81%) and AVSD (34.83%) were relatively high. Low maternal age, rural residents, low income, low maternal educational background, zero parity, and low gestational age of diagnosis were risk factors for perinatal death.

Conclusion

Our study has revealed the CHD prevalence, major subtypes, and the proportion of perinatal deaths. Furthermore, we have identified risk factors for perinatal death due to CHD. It may be helpful for clinical and public health decisions.

Health sciences/Cardiology

Health sciences/Medical research

Congenital heart defects

Perinatal death

Stillbirth

Congenital heart defect (CHD) is the structural anomaly of the heart and (or) great vessels present at or before birth. CHDs are the most common birth defects, accounting for nearly one-third of all significant congenital anomalies [1–3]. About 20–25% of CHDs, have been described as critical congenital heart defects, requiring urgent and significant medical and surgical care to ensure survival [4–6]. CHD is one of the most critical risk factors for children’s death, and most CHDs related deaths occur in low- and middle-income countries, including China [7], which significantly burdens these countries.

Perinatal death is the death of a fetus of gestational age 28 weeks or more or the death of a live-born infant less than 28 days (7 days in China), including stillbirth and early neonatal death. Previous studies have shown that CHD is an essential risk factor for adverse obstetric and perinatal outcomes, such as fetal brain damage and neonatal death [8–12]. However, many studies regarded CHD as an adverse pregnancy outcome but not a risk factor for adverse obstetric and perinatal outcomes [1, 2]. Some studies have involved the risk of stillbirth for fetuses with specific birth defects [13–15], while few focused on the relationship between CHD and perinatal deaths and their epidemiological characteristics.

We conducted a retrospective study. In this study, we used data from the Birth Defects Surveillance System of Hunan Province, China, from 2016 to 2020 to analyze the CHD prevalence and perinatal deaths.

Data sources

This research used data from the Birth Defects Surveillance System of Hunan Province from 2016 to 2020. The Health Commission of Hunan Province runs the Birth Defects Surveillance System of Hunan Province. It is the only local, provincial representative surveillance system in Hunan Province, which involves 52 registered hospitals. The Health Commission of Hunan Province formulated the "Maternal and Child Health Monitoring Manual in Hunan Province" to conduct surveillance.

We analyzed surveillance data of perinatal infants (for stillbirth, dead fetus, or live birth between 28 weeks of gestation and seven days after delivery) and all birth defects (between 28 weeks of gestation and seven days after delivery) recorded born in the 52 hospitals during 2016-2020. Perinatal infants are reported quarterly (including information on perinatal deaths). Fetuses and infants with birth defects are reported in case cards (including information on maternal age, per-capita annual income, maternal education, gravidity history, parity history, region, gestational age of diagnosis, gender, methods of diagnosis, et al.).

The Birth Defects Surveillance System classified birth defects (Q00-Q99) according to the International Classification of Disease, Tenth Revision (ICD-10), and ICD codes for CHD were Q20-Q26. Combined CHDs were arranged in a one-dimensional approach, with the leading malformation being either the primary anatomical defect or the defect which would require the earliest intervention. It is according to the last guide by "Prognosis Grading and Perinatal Risk Assessment of Fetal Heart Disease" Expert Panel in China in 2022 [16]. For some complicated combined CHD, we ask experienced experts to identify it.

Informed Consent

Doctors obtain consent from pregnant women before collecting surveillance data, which is witnessed by their families and heads of the obstetrics departments or neonatal departments. For live births, doctors obtain consent from their parents or guardians, which is witnessed by their families and heads of the obstetrics departments or neonatal departments. Since the Health Commission of Hunan Province collects those data, and the government had emphasized the privacy policy in the "Maternal and Child Health Monitoring Manual in Hunan Province", there is no additional written informed consent.

The study was approved by the Medical Ethics Committee of the Maternal and Children Hospital of Hunan. (NO: 2022-S64). It is a retrospective study of medical records; all data were fully anonymized before we accessed them. Moreover, we de-identified the patient records before analysis.

Data quality control

Experienced doctors collected and reported all surveillance data. To ensure the integrity rate of monitoring data reached 100% and the information error rate less than 1%, the Health Commission of Hunan Province asked technical guidance departments to carry out comprehensive quality control each year.

Statistical analysis

CHD prevalence is the number of CHD per 10000 perinatal infants. We computed the CHD prevalence and 95% confidence intervals (CI) by Poisson regression and analyzed the epidemiological features of perinatal death due to CHD. We used the chi-square trend test (χ²_trend) to identify the rate trends by year (performed by SPSS 18.0, International Business Machines Corporation, New York City, United States). P<0.05 was considered statistically significant.

From 2016 to 2020, a total of 847755 perinatal infants were registered, including 14459 cases of birth defects and 4161 cases of CHDs, and the CHD prevalence was 4.908‰. Among the 4161 cases of CHDs, we found 976 cases of perinatal deaths, accounting for 23.46% of the total CHDs, and 96.41% (941 cases) of perinatal deaths were electively terminated.

CHDs contributed 28.78% to the total burden of birth defects, with an increasing trend from 26.49% in 2016 to 31.72% in 2020 (χ²_trend=16.59, P<0.01). In contrast, perinatal deaths contributed 23.46% to the total CHDs, decreasing from 28.55% in 2016 to 19.94% in 2020 (χ²_trend=9.86, P<0.01). The CHD prevalence increased with age. A relatively high proportion of perinatal deaths occurred in the maternal age group <20 and 20-24 years old.

The CHD prevalence was higher in urban areas than in rural areas (6.844‰ vs. 3.598‰) (P<0.05). The proportion of CHD in birth defects was higher in urban areas than in rural areas (32.49% vs. 25.09%) (P<0.05). The proportion of perinatal deaths with CHD was higher in rural areas than in urban areas (35.62% vs. 14.01%) (P<0.05).

There was no significant difference in the CHD prevalence between males and females (4.916‰ vs. 4.888‰) (P>0.05). The proportion of CHD in the birth defects was higher in women than in men (34.61% vs. 25.09%) (P<0.05). There was no significant difference in the proportion of perinatal deaths with CHD between males and females (23.32% vs. 23.41%) (P>0.05). (Table 1)

Table 1. CHD prevalence and perinatal deaths in Hunan Province, China, 2016–2020

Indicators	Number of perinatal infants (n)	Number of birth defects (n)	Number of CHDs (n)	Prevalence of CHD (‰)	95%CI	Proportion of birth defects (%)	Number of perinatal deaths (n)	Proportion with CHD (%)	Number of elective termination (n)	Proportion of perinatal deaths (%)
Year
2016	170688	3107	823	4.822	4.492,5.151	26.49	235	28.55	231	98.30
2017	196316	3533	1055	5.374	5.050,5.698	29.86	220	20.85	214	97.27
2018	177762	2900	734	4.129	3.830,4.428	25.31	195	26.57	185	94.87
2019	164840	2643	827	5.017	4.675,5.359	31.29	182	22.01	174	95.60
2020	138149	2276	722	5.226	4.845,5.607	31.72	144	19.94	137	95.14
Maternal age
<20 years	13711	272	69	5.032	3.845,6.220	25.37	32	46.38	30	93.75
20-24 years	118531	1846	474	3.999	3.639,4.359	25.68	176	37.13	172	97.73
25-29 years	357582	6017	1700	4.754	4.528,4.980	28.25	388	22.82	372	95.88
30-34 years	243649	4141	1270	5.212	4.926,5.499	30.67	248	19.53	241	97.18
≥35 years	114282	2183	648	5.670	5.234,6.107	29.68	132	20.37	126	95.45
Region
Urban	342178	7208	2342	6.844	6.567,7.122	32.49	328	14.01	310	94.51
Rural	505577	7251	1819	3.598	3.433,3.763	25.09	648	35.62	631	97.38
Gender
Male	448288	8783	2204	4.916	4.711,5.122	25.09	514	23.32	495	96.30
Female	399368	5640	1952	4.888	4.671,5.105	34.61	457	23.41	441	96.50
Unknown	99	36	5	-	-	13.89	5	100.00	5	100.00
Total	847755	14459	4161	4.908	4.759,5.057	28.78	976	23.46	941	96.41

Abbreviation: CHD = congenital heart defect; CI = confidence intervals

Table 2 shows the top ten CHD subtypes. The most frequent types of CHD were ventricular septal defect (VSD), atrial septal defect (ASD), tetralogy of Fallot (TOF), and atrioventricular septal defect (AVSD), which accounted for 56.36%, 12.28%, 3.51% and 2.14% of CHDs, respectively. The prevalences of VSD, ASD, TOF, and AVSD were 2.766‰, 0.603‰, 0.172‰, and 0.105‰, respectively. The proportions of perinatal deaths with VSD (9.72%) and ASD (2.74%) were relatively low, while TOF (67.81%) and AVSD (34.83%) were relatively high. (Table 2)

Table 2. The prevalences of the leading ten CHD subtypes and perinatal deaths with CHD in Hunan Province, China, 2016–2020

ICD code	CHD subtype	Number of CHD subtypes (n)	Prevalence of CHD subtypes (‰)	95%CI	Proportion of CHD subtypes in total CHDs (%)	Number of perinatal deaths (n)	Proportion of perinatal deaths with CHD subtypes (%)
Q21.0	Ventricular septal defect	2345	2.766	2.654,2.878	56.36	228	9.72
Q21.1	Atrial septal defect	511	0.603	0.551,0.655	12.28	14	2.74
Q21.3	Tetralogy of Fallot	146	0.172	0.144,0.200	3.51	99	67.81
Q21.2	Atrioventricular septal defect	89	0.105	0.083,0.127	2.14	31	34.83
Q25.0	Patent ductus arteriosus	77	0.091	0.071,0.111	1.85	2	2.60
Q20.1	Double outlet right ventricle	58	0.068	0.051,0.086	1.39	39	67.24
Q25.6	Stenosis of pulmonary artery	56	0.066	0.049,0.083	1.35	32	57.14
Q22.1	Congenital pulmonary valve stenosis	55	0.065	0.048,0.082	1.32	28	50.91
Q25.3	Stenosis of aorta	53	0.063	0.046,0.079	1.27	38	71.70
Q25.1	Coarctation of aorta	45	0.053	0.039,0.071	1.08	26	57.78

Abbreviation: CHD = congenital heart defect; CI = confidence intervals

The proportion of perinatal deaths with CHD decreases with the increase in per-capita annual income and maternal education. The proportion of perinatal deaths with CHD was high (78.95%) when the parity was 0. The proportion of perinatal death with CHD decreased with the increase in the gestational age of diagnosis. B-Ultrasound was the primary diagnostic method (82.00%). (Table 3).

Table 3. CHD prevalence and perinatal deaths by epidemiological characteristics in Hunan Province, China, 2016–2020

Basic information	Number of CHDs (n)	Number of perinatal deaths (n)	Proportion with CHD (%)	Number of elective terminations (n)	Proportion of perinatal deaths (%)
Per-capita annual income (￥)
<2000	36	17	47.22	17	100.00
2000-	367	127	34.60	126	99.21
4000-	1235	219	17.73	209	95.43
8000-	2523	613	24.30	589	96.08
Maternal education
Illiteracy or primary school	50	20	40.00	19	95.00
Secondary school	537	181	33.71	173	95.58
Senior school	1540	396	25.71	381	96.21
University or above	2034	379	18.63	368	97.10
Parity history
No	38	30	78.95	30	100.00
Once	2122	486	22.90	467	96.09
Twice	1756	397	22.61	383	96.47
≥3 times	245	63	25.71	61	96.83
Gestational age of diagnosis
<34 weeks	910	701	77.03	690	98.43
34-36 weeks	717	170	23.71	166	97.65
≥37 weeks	2534	105	4.14	85	80.95
Methods of diagnosis
B-Ultrasound	3412	907	26.58	885	97.57
B-Ultrasound + Clinical	546	27	4.95	16	59.26
Clinical	78	2	2.56	1	50.00
Other	125	40	32.00	39	97.50
Total	4161	976	23.46	941	96.41

Abbreviation: CHD = congenital heart defect

The main findings of this study were as follows: 1) The most frequent types of CHD were VSD, ASD, TOF, and AVSD, among which the proportions of perinatal deaths with TOF and AVSD were relatively high. 2) Perinatal deaths accounted for 23.46% of the total CHDs, and 96.41% were electively terminated. 3) The CHD prevalence is relatively high in maternal age ≥35, while the proportion of perinatal deaths with CHD is relatively high in maternal age <25. 4) The CHD prevalence was higher in urban areas than in urban areas, while the proportion of perinatal deaths with CHD was higher in rural areas than in urban areas. 5) The proportion of perinatal deaths with CHD is related to income, maternal education, and gestational age of diagnosis.

The CHD prevalence in this study was 4.908‰. CHD prevalence was 4.905‰ in China from 2015 to 2019, reporting in a meta-analysis from 1980 to 2019 in China [2]. It is close to this study. CHD prevalence globally was 8.224‰ from 2010 to 2017, reporting in a meta-analysis of 260 studies from 1970 to 2017 [1]. It is higher than this study. It may be the result of several factors. First, it is related to the diagnosis window of birth defects surveillance system. For example, we monitor stillbirths, dead fetuses, or live birth between 28 weeks of gestation and seven days after delivery in China. Some developed countries monitor perinatal infants aged between 20 weeks of gestation and 5-6 years after birth, which detects more CHDs and leads to a higher CHD prevalence [17]. Second, access to healthcare and diagnostic technologies for CHDs in developing areas is more complicated than in developed areas, leading to a high rate of missed diagnoses in developing areas [1, 17, 18]. It is also the reason for the difference in CHD prevalence in eastern, central, and western China [2]. Furthermore, it also explains why the CHD prevalence was significantly higher in urban areas than in rural areas in this study, as well as over time. Third, the monitoring models may also significantly impact the monitoring results. Some previous studies show that the prevalence of birth defects was lower in the hospital monitoring model than in the population monitoring model [2]. This study is based on a hospital-based monitoring model, while some foreign studies are based on population-based monitoring models [19]. Fourth, up-and-up prenatal diagnosis and elective termination may also impact the prevalence of birth defects [20].

The main CHD subtypes reported in this study were VSD (2.766‰), ASD (0.603‰), TOF (0.172‰), and AVSD (0.105‰). According to a meta-analysis of 617 studies from 1980 to 2019, the main CHD subtypes reported in China were VSD (1.410‰), ASD (1.314‰), patent ductus arteriosus (PDA) (1.294‰), TOF (0.210‰) and AVSD (0.146‰) [2]. It is different in the CHD subtypes from our study, such as PDA. According to a meta-analysis of 260 studies from 1970 to 2017 all over the world, the major CHD subtypes were VSD (3.071‰), ASD (1.441‰), PDA (1.004‰), pulmonary artery stenosis (0.546‰), and TOF (0.356‰) [1]. It is also different in the CHD subtypes from this study, such as PDA and pulmonary artery stenosis. In our monitoring system, we considered minor PDA, not a defect, and we required the defect diameter of PDA to be greater than 3mm to be reported. It may be the reason for this study's relatively low prevalence of PDA. Compared with previous studies, there was a significant difference in the CHD prevalence subtypes. For example, compared with previous studies in China, the prevalence of VSD reported in this study was relatively high (2.766‰ vs. 1.410‰), while the prevalence of ASD was relatively low (0.603‰ vs. 1.314‰) [2]. Similar to PDA, we considered minor patent foramen ovale not a defect, which may lead to a lower prevalence of ASD. The advance in prenatal diagnosis technology may significantly impact the perinatal prevalence of various types of CHD [6, 21, 22].

Among the main CHD subtypes, the proportion of perinatal death with VSD and ASD is relatively low, while the proportion of perinatal death with TOF and AVSD is relatively high. However, most perinatal deaths with CHD are electively terminated, the proportions of perinatal deaths reflecting the severity of CHD subtypes [12, 23-25]. A critical significance of this study is to describe the proportions of perinatal deaths with CHD subtypes, which may have been less involved in previous studies.

We also found that the CHD prevalence increased with maternal age, associated with the rapid decline in producing healthy and high-quality oocytes [26]. Some previous studies have shown that the prevalence of many birth defects, including CHD, increases with age [27, 28]. We also found that the proportion of perinatal deaths with CHD was relatively high in maternal age < 25 years old, and most perinatal deaths are electively terminated. It may be related to the higher requirements for healthy babies in young pregnant women younger enough to have babies in the future. Moreover, it is also the reason for the relatively high proportion of perinatal deaths with CHD when the parity was 0. Some previous studies showed that adverse pregnancy outcomes were related to advanced age [29], while perinatal deaths with CHD were the opposite. Pregnant women may choose to have babies with advanced gestational age because the older the fetuses, the more likely they are to survive, and it is advantageous to the health of pregnant women. It may explain the relatively low proportion of perinatal deaths in fetuses with an advanced gestational age of diagnosis.

We found that the CHD prevalence was higher in urban areas, while the proportion of perinatal deaths with CHD was higher in rural than urban areas. With the increase in per-capita annual income and education level, the proportions of perinatal deaths with CHD showed downward trends. It may be mainly related to medical conditions and economic conditions. Better medical conditions and economic conditions in cities benefit children with CHDs surviving [30, 31]. From 2016 to 2020, the proportion of perinatal deaths with CHD decreased year, which may also be related to improving economic and medical conditions.

There are also some deficiencies in this study. For example, due to the improvement in prenatal screening and diagnosis technology, many fetuses with birth defects were diagnosed and miscarried before 28 weeks of gestation, including many CHDs, which may significantly impact the CHD prevalence after 28 weeks. It may need further research.

In conclusion, our study revealed how many perinatal deaths are due to CHDs and several leading CHD subtypes. The main CHD subtypes were VSD, ASD, TOF, and AVSD, and the proportions of perinatal deaths with TOF and AVSD were relatively high. High maternal age and urban residents were risk factors for CHD. In contrast, low maternal age, rural residents, low income, low maternal educational background, zero parity, and low gestational age of diagnosis were risk factors for perinatal death. Our results may be helpful for clinical and public health decisions.

CHD: Congenital heart defect

ICD-10: International Classification of Disease, Tenth Revision

CI: confidence intervals

VSD: ventricular septal defect

ASD: atrial septal defect

TOF: tetralogy of Fallot

AVSD: atrioventricular septal defect

PDA: patent ductus arteriosus

Acknowledgments

The authors wish to thank the staff working for the Birth Defects Surveillance System of Hunan Province, China, from 2016 to 2020.

Author Contributions

Conceptualization: XZ, JF, HW

Data Curation: XZ, JH, DX

Formal Analysis: XZ

Methodology: XZ, HK

Project administration: JF, HW

Supervision: JF, HW, ZX

Visualization: XZ

Writing - Original Draft Preparation: XZ

Writing - Review & Editing: JF, HW, HK, TL, JX, YZ, LY, CC, QY

Availability of data and materials

All data generated or analysed during this study are included in this published article.

Competing interests

No.

Ethics declarations

The study was approved by the Medical Ethics Committee of the Maternal and Children Hospital of Hunan. (NO: 2022-S64)

Funding

The science and technology innovation Program of Hunan Province：Major Scientific and Technological Projects for Collaborative Prevention and Control of Birth Defects in Hunan Province, Grant Number:2019SK1010 and 2019SK1011.

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No competing interests reported.

Risk of perinatal deaths for fetuses and early newborns with congenital heart defects

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Version 1

Abstract

Introduction

Methods

Data sources

Informed Consent

Data quality control

Statistical analysis

Results

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1