Abstract
Background
Birth defects, which comprise a series of severe congenital abnormalities, impose a significant burden on society, families and individuals. Consequently, it is crucial to identify the underlying causes of birth defects and reduce their occurrence. Although an increasing number of risk factors for birth defects have been identified, few associations can be established as causal. Furthermore, the distribution of aetiology related to birth defects remains unclear. This study aims to analyse birth defect cases from the China Birth Cohort Study (CBCS) to elucidate the aetiological profile of these conditions.
Methods
A total of 3873 abnormal cases were recorded in the CBCS from November 2017 to August 2021. Abnormal fetuses (including both live births and foetal losses) were diagnosed by obstetricians, ultrasound specialists and geneticists based on prenatal screening and clinical examinations. The causes of birth defects were categorised into chromosomal anomalies, genetic anomalies, environmental exposures and twinning. Chromosomal and genetic anomalies were identified through genetic screening. Data on exposure, including the substances involved and the duration of exposure, were reviewed to determine whether environmental factors contributed to the birth defects.
Results
After excluding cases with minor malformations, a total of 2123 birth defect cases were reviewed. The most common birth defects among the included cases were congenital heart disease, polydactyly, trisomy 21 and cleft palate with cleft lip. Of these, only 22.4% (475/2123) had identifiable causes. Specifically, 415 cases were attributed to chromosomal anomalies, while 31 cases were diagnosed as monogenic disorders. Additionally, 23 cases were linked to environmental exposures, and 6 cases were associated with twinning. The proportions of birth defect cases with known causes were significantly higher in the spontaneous abortion group (12/27, 44.4%), the therapeutic abortion group (314/1044, 30.1%) and perinatal death group (13/36, 36.1%) compared with live births (136/1016, 13.4%).
Conclusions
Nearly 80% of birth defect cases in the CBCS lack a clear identifiable cause. Therefore, translating statistical associations between risk factors and birth defects into causal relationships is both necessary and important.
Keywords: Infant, Neonatology
WHAT IS ALREADY KNOWN ON THIS TOPIC
It is important to establish causality rather than associations for the prevention and control of birth defects. However, the figures on the distribution of aetiology within birth defect cases remain limited.
WHAT THIS STUDY ADDS
Based on the data of China Birth Cohort Study, only over 1/5th (22.4%) had a known cause, of which the majority were chromosomal anomalies.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
There are still significant challenges in the aetiological research of birth defects. The research on the causes of birth defects still needs to focus on the design of birth cohort studies, integrated with comprehensive birth defects register and innovative measurements of potential exposures and biomarkers.
Introduction
Birth defects refer to abnormalities and dysfunctions of organs, body parts or metabolic processes in infants during development in utero. These defects impose a significant burden on both society and families, leading to issues such as pregnancy termination, stillbirths and the potential for lifelong physical and psychological disorders in live-born infants. The global incidence of birth defects is estimated at 6.0% of total births, translating to approximately 7.9 million infants born with congenital abnormalities each year worldwide.1 The systematic review indicated that the estimated incidence of birth defects in China is 1.2%.2
Controlling and preventing birth defects is an urgent global challenge. The observed decline in the prevalence of neural tube defects in regions that have implemented folic acid fortification illustrates the importance of establishing causality between folic acid deficiency and these defects.3 It is crucial to confirm the true causes of birth defects, rather than simply identifying associated risk factors, to effectively reduce their incidence.4 While many epidemiological studies have identified various risk factors for birth defects, the number of well-established human teratogens remains limited,5 and the distribution of aetiology within birth defect cases is not fully understood.
This study is conducted based on the China Birth Cohort Study (CBCS) and aims to evaluate the aetiological profile of birth defects. The CBCS was initiated to explore the risk factors associated with adverse pregnancy outcomes.6 Inclusion criteria for the CBCS included: Chinese nationality, a gestational age of 6–13+6 days weeks, routine prenatal clinical tests and deliveries at study sites, and signed informed consent. Baseline information and exposure history during the 3 months before pregnancy and the first trimester were collected by questionnaire. Clarifying the aetiological profiles of birth defect cases in the CBCS will help illuminate the challenges of determining causes and can provide valuable evidence for the prevention of birth defects.
Methods
Study population
The CBCS is a large birth cohort study that includes 50 study sites across 17 provinces in China. Pregnant women were enrolled during the first trimester and followed up at 20–23+6 days weeks and 28–33+6 days weeks of gestation until delivery or pregnancy termination. Baseline information was collected through questionnaires and included reproductive-related factors, parental demographic information, parental lifestyle habits, maternal health conditions and other maternal exposure experiences from 3 months before pregnancy through the first trimester.
Prenatal screening, including ultrasound examinations, Down syndrome screening and non-invasive prenatal testing (NIPT), was conducted to detect fetal abnormalities.7 If an increased risk of genetic abnormalities or structural malformations was identified through the prenatal screening, pregnant women were advised to undergo the invasive procedures, such as amniocentesis or chorionic villus sampling, to collect biological samples for chromosomal analysis. Common techniques for chromosomal analysis included karyotyping, fluorescence in situ hybridisation (FISH), bacterial artificial chromosomes-on-beads (BoBs), chromosomal microarray analysis (CMA) and copy number variation sequencing (CNV-seq). Prenatal molecular genetic testing, such as targeted mutation analysis and next-generation sequencing (NGS) panel, was not performed on all fetuses but was recommended for pregnancies where: (1) a pathogenic gene could be clearly identified through the family history or ultrasound findings, such as in cases with a family history of hearing loss, spinal muscular atrophy (SMA) or thalassaemia; or (2) ultrasound examinations identified major structural abnormalities, but no anomalies were observed through the routine chromosome analysis results. The process for diagnosing genetic anomaly cases is illustrated in online supplemental figure 1. Records from prenatal screenings and biological samples were stored in an electronic data capturing and biobank system.6 All cases of birth defects were diagnosed by obstetricians, ultrasound specialists and geneticists. Structural malformations of the body surface and internal organs were identified through ultrasound examinations. Birth defects in live births were reviewed postnatally. For cases involving pregnancy loss or termination due to abnormalities in internal organs, autopsies were conducted to confirm the diagnoses with parental consent. The detailed prenatal examinations are summarised in table 1.
Table 1. Prenatal examinations in three gestation trimesters.
| Gestation trimesters | Prenatal examinations | Birth defects |
|---|---|---|
| First trimester | Ultrasound examination in the first trimester for fetal NT thickness. (11–14 gestation weeks) | According to the increased NT to identify fetuses with high risk of genetic or structural abnormalities. |
| Second trimester | CVS (11–14 gestation weeks), Down’s syndrome screening (14–20 gestation weeks), NIPT (12–22 gestation weeks) and amniocentesis (16–20 gestation weeks). | Amniocentesis and CVS are gold standards for the diagnosis of genetic abnormalities. |
| Ultrasound examination (20–24 gestation weeks) | Structural malformations of the fetal brain, lips, heart, liver, kidney, bladder and limbs (such as severe structural CHDs, spina bifida, gastroschisis, etc) | |
| Third trimester | Ultrasound examination (32–34 gestation weeks) | Further structural malformations and abnormalities of fetal growth (intrauterine growth restriction, abnormalities of the proportion of limbs, etc) |
CHDs, congenital heart diseases; CVS, chorionic villus sampling; NIPT, non-invasive prenatal testing; NT, nuchal translucency.
The diagnosis of each birth defect case was re-evaluated by clinical and genetic experts in accordance with the WHO’s International Classification of Diseases (version 10). Among all recorded cases of birth defects, we excluded those classified as normal variations or minor abnormalities, such as isolated patent foramen ovale, patent ductus arteriosus, single umbilical artery, simple venous catheter, pericardial effusion, subependymal cysts, posterior fossa cisterna widening, nasal bone dysplasia, isolated hepatosplenomegaly, peritoneal effusion, birthmarks, accessory auricles, choroid cysts, cryptorchidism, hydronephrosis and lymphangioma.
Aetiologic classification
Each birth defect case was classified based on whether a potential cause was identified. The causes of birth defects were categorised into three main groups: chromosomal/genetic causes, environmental causes and twinning.4
Chromosomal/genetic causes: this category includes abnormalities in the number or structure of chromosomes, gene mutations and anomalies in gene expression. Twinning malformations: malformations that arise from twinning include conditions such as anencephaly, acardiac twin, conjoined twins and twin transfusion syndrome. Environmental causes: also referred to as teratogenic causes, identifying a birth defect case with a known environmental cause requires clarifying three conditions. First, evidence of exposure. There must be evidence of exposure to a recognised human teratogen. The categories of human teratogens are identified according to the Human Malformations and Related Anomalies (third edition).8 Second, diagnosis correlation. The fetus or infant must be diagnosed with specific birth defects associated with the exposed teratogen. For instance, to classify gestational diabetes mellitus as a cause, the infant must be diagnosed with diabetic embryopathy.9 Alcohol is considered a cause only when the fetus presents with alcohol-related birth defects (ARBDs),10 which may include conotruncal heart defects, atrial septal defects, ventricular septal defects, horseshoe kidneys, ureteral duplications, kidney aplasia/dysplasia/hypoplasia, vertebral segmentation defects and hypoplastic nails. Third, a critical window of exposure. Exposure to teratogens must occur within the critical developmental window of the relevant organ to induce birth defects. For example, renal abnormalities can occur between the 4th and 36th gestational weeks,11 while congenital heart diseases (CHDs) primarily develop during the first trimester (human embryonic days 6 to 50).12
The distribution of aetiologies among birth defect cases was further stratified according to pregnancy outcomes, including live birth, spontaneous abortion, therapeutic abortion and perinatal death.13 Data analyses were performed using the Statistics Analysis System (SAS, version 9.4).
Patient and public involvement
Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research.
Results
A total of 3873 abnormal cases were identified among 132 386 pregnant women who completed follow-up from November 2017 to August 2021. Of these, 1592 anomalies were excluded due to minor malformations and self-healing, while 157 chromosomal abnormalities were excluded due to insufficient descriptions of the location and type of the abnormal chromosome. A flow chart illustrating the identification of birth defect cases is presented in figure 1.
Figure 1. Flow chart illustrating the identification of birth defect cases. CBCS, the China Birth Cohort Study; CHD, congenital heart disease.
Congenital heart disease (CHD) (669/2123, 31.5%), polydactyly (184/2123, 8.7%), trisomy 21 (175/2123, 8.2%), cleft palate with cleft lip (116/2123, 5.5%) and syndactyly (99/2123, 4.7%) were the five most common birth defects among the 2123 cases included in the study. Of the included birth defect cases, 475 (22.4%) were assigned potential causes. The most frequent pregnancy outcomes were therapeutic abortion and live birth, which constituted 49.2% (1044/2123) and 47.9% (1016/2123) of the total cases, respectively. The proportions of birth defect cases with known causes were significantly higher in the spontaneous abortion group (12/27, 44.4%), therapeutic abortion group (314/1044, 30.1%) and perinatal death group (13/36, 36.1%) compared with live births (136/1016) (p<0.001), as shown in table 2.
Table 2. Birth defects aetiologic distribution stratified by pregnancy outcome (n=2123).
| Birth defects cases with known causes | Pregnancy outcome | ||||
|---|---|---|---|---|---|
| Live birth n=1016 |
Spontaneous abortion n=27 |
Therapeutic abortion n=1044 |
Perinatal death n=36 |
Total n=2123 |
|
| Known aetiology n (%) | 136 (13.4) | 12 (44.4) | 314 (30.1) | 13 (36.1) | 475 (22.4) |
| Chromosome anomaly n (%) | 112 (11.0) | 12 (44.4) | 280 (26.8) | 11 (30.6) | 415 (19.5) |
| Structure | 75 | 1 | 52 | 3 | 131 |
| Number | 37 | 11 | 228 | 8 | 284 |
| Signal gene n (%) | 9 (0.9) | – | 22 (2.1) | – | 31 (1.5) |
| Environmental n (%) | 14 (1.4) | – | 9 (0.9) | – | 23 (1.1) |
| GDM | 10 | – | – | – | 10 |
| Infections of cytomegalovirus | – | – | 1 | – | 1 |
| Heavy alcohol | 4 | – | 8 | – | 12 |
| Twinning n (%) | 1 (0.1) | – | 3 (0.3) | 2 (5.6) | 6 (0.3) |
| Acardiac | 1 | – | 1 | – | 2 |
| Conjoined | – | – | 1 | – | 1 |
| Twin transfusion syndrome | – | – | 1 | 2 | 3 |
| Unknown aetiology n (%) | 880 (86.6) | 15 (55.6) | 730 (69.9) | 23 (63.9) | 1648 (77.6) |
GDM, gestational diabetes mellitus.
Chromosomal anomalies were the predominant cause, accounting for 87.4% (415/475) of all birth defect cases with known causes. Chromosomal number anomalies included trisomy 21, 18, 13 and 16, as well as abnormal numbers of sex chromosomes (45,X; 47,XXX/XXY/XYY). Trisomy 21 represented more than half of the cases of chromosomal number anomalies (175/284, 61.6%). Chromosome structural abnormalities were further classified into deletions, duplications, inversions, translocations, mosaicism, complex chromosomal rearrangements, etc. Among these, deletions, inversions and duplications were the most common anomalies, accounting for 22.9% (30/131), 20.6% (27/131) and 19.8% (26/131), respectively. Monogenic disorders were another significant cause of birth defects in this cohort, accounting for 6.5% (31/475) of cases with a known cause. This included 18 fetuses with genetic mutations linked to deafness, three fetuses who were homozygous for the –SEA (Southeast Asian) deletion in the α-globin gene and diagnosed with thalassaemia, two fetuses diagnosed with SMA, and one fetus was diagnosed with Noonan syndrome, among others. Additionally, the distribution of different prenatal chromosomal examinations for fetuses with chromosomal anomalies is shown in table 3. The majority of fetuses with chromosomal number anomalies were diagnosed by karyotyping (259/284, 91.2%), while only 4.9% (14/284) were diagnosed using the CMA or CNV-seq. However, the proportion of fetuses diagnosed by CMA or CNV-seq was significantly higher in the group with chromosomal structure anomalies (46/131, 35.1%).
Table 3. Prenatal chromosomal examinations in chromosomal abnormalities cases.
| Prenatal chromosomal examination | Chromosome anomaly | |
|---|---|---|
| Number, n (%) | Structure, n (%) | |
| Karyotyping | 259 (91.2) | 79 (60.3) |
| FISH | 9 (3.2) | 4 (3.1) |
| BOBs | 2 (0.7) | 2 (1.5) |
| CMA or CNV-seq | 14 (4.9) | 46 (35.1) |
| Total | 284 | 131 |
BOBs, bacterial artificial chromosome on beads; CMA, chromosomal microarray; CNV-seq, copy number variant sequencing; FISH, fluorescence in situ hybridisation.
Among birth defect cases with known causes, only 23 cases (4.8%) were related to environmental teratogen exposure. This group included 10 cases associated with gestational diabetes mellitus (GDM) exposure, one case involving a pregnant woman infected with cytomegalovirus, and 12 cases of heavy alcohol exposure during the first trimester. Additionally, six cases of birth defects were attributed to twinning, which included three cases of twin transfusion syndrome, two cases of acardiac twins and one case of conjoined twins, as illustrated in figure 2.
Figure 2. Number and percentage of birth defect cases with known cause. GDM, gestational diabetes mellitus.
Discussion
This study found that only 22.4% of all included birth defect cases had potential causes identified. Although numerous risk factors have been suggested by epidemiological studies, the underlying causes of the majority of birth defect cases remain unclear.
In contrast, a study based on a single hospital-based surveillance population reported that the percentage of birth defect cases with potential causes reached 56.8%, having excluded cases prior to 20 weeks of gestation.14 In that study, researchers used a combination of physical examinations, consultations, diagnostic tests, family histories and pregnancy histories, along with known risk factors, to determine whether cases could be attributed to potential causes. This more lenient standard may be a significant factor contributing to the higher percentage of identified potential causes in their study. As a first step to bridge the gap between identified risk factors and actual causes, one population-based study evaluated the aetiological profile of birth defects.4 Notably, slight defects and those lacking a standardised definition were excluded from the Utah surveillance system, where all records were thoroughly reviewed by clinicians, and found that birth defects with known causes accounted for 20.2% of all cases, which is similar to our study’s finding of 22.4%.
It is important to note that cases of birth defects attributed to environmental exposure were rare in both this study and in the research conducted by Feldkamp et al.4 There are two primary reasons for this finding. First, the strict criteria employed to identify birth defects with known causes resulted in only a limited number of cases being attributed to environmental exposures. Only cases associated with specific birth defects and documented exposure during critical developmental periods could be identified. Second, the number of established human teratogens remains limited, partly due to the complexity involved in establishing causality and the etiopathogenesis of birth defects. According to Shepard’s Criteria, seven key standards must be considered when identifying a human teratogen.15 For example, exposure should occur during a critical period of development, the exposure must have a significant correlation with the occurrence of birth defects, and this association should be substantiated by multiple high-quality epidemiological studies, along with a careful delineation of clinical cases. Furthermore, the relationship between the exposure and the birth defect should be biologically plausible. The low incidence of birth defects further complicates the task of identifying their causes. One study attempted to explore similar etiopathogenesis across various birth defects using associations estimated through graph theory to maximise the utilisation of known aetiologies.16
This study also found that the proportion of abnormal cases diagnosed by the CMA or CNV-seq was significantly higher in the chromosomal structural anomalies group compared with the chromosomal number anomalies group (35.1% vs 4.9%). While karyotyping remains the most commonly used technique for diagnosing chromosomal number anomalies, its resolution is limited, as it can only detect structural changes larger than 5–10 Mb. In contrast, CMA and CNV-seq with higher resolution are capable of identifying microdeletions and microduplications that are undetectable by karyotype analysis.17
This study evaluated the distribution of aetiologies in birth defects and emphasised the importance of translating statistical associations into causality within the field. Notably, this research is based on the CBCS, currently the largest birth cohort study in China. The CBCS collected valuable data on exposure experiences from 3 months before pregnancy through to delivery, which facilitated the identification of potential causes for individual birth defect cases. Additionally, the CBCS gathered data on birth defect outcomes for both live births and fetal losses. Due to the lethality and severity of malformations in abortion and perinatal death cases, the abnormalities in fetal loss cases were particularly noteworthy, which partly explains why higher proportions of cases with known causes were found in the groups with spontaneous or therapeutic abortion and perinatal death compared with the live birth group.
The major limitation of this study is the possibility of missing certain cases with potential causes due to the stringent criteria outlined above. Although numerous studies have reported associations between various risk factors and increased risk of birth defects,18 such as maternal hypertension,19 20 maternal obesity21 22 and paternal smoking,23 24 these associations are often observed at the population level. However, identifying the true causes of individual birth defect cases continues to pose challenges.4 25 Researchers can only conduct preliminary evaluations of potential causes for individual cases. Furthermore, the unclear dose-dependency of teratogens presents additional challenges in establishing environmental exposure as a cause of birth defects. Ascertaining the threshold levels of teratogen exposure will enhance the accuracy of risk assessments for pregnant women exposed to these agents.25 Another limitation of this study is the lack of detailed information on the molecular genetic testing techniques employed, such as targeted gene testing, NGS panel, or whole exome sequencing (WES). This gap in data impacted the ability to provide a more thorough report on cases with monogenic anomalies.
Conclusions
Nearly 80% of birth defect cases did not have identifiable causes. There is an urgent need for high-quality evidence from epidemiological, biological and pathophysiological studies to support the translation of statistical associations between risk factors and birth defects into established causality.
Supplementary material
Footnotes
Funding: The work was supported by Beijing Natural Science Foundation (L222124), National Key Research and Development Program of China (2016YFC1000105) and Beijing Hospitals Authority Youth Programme (QML20231208).
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Ethics approval: The CBCS was approved by the Ethics Committee of Beijing Obstetrics and Gynecology Hospital, Capital Medical University (approval number: 2018-KY-003-02). Participants gave informed consent to participate in the study before taking part.
Data availability free text: Data will be available on reasonable request when the recruitment and follow-up of the CBCS have been completed. Before the use of the data, a request form which includes the proposed analysis strategy should be submitted to the CBCS committee. The applications will be evaluated, and once approved, data will be shared.
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Data availability statement
Data are available upon reasonable request.
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