The prevalence of congenital anomalies: nationwide study in 2020 in Estonia

Abstract Objective To assess the prevalence of congenital anomalies (CAs), chromosomal abnormalities and monogenic diseases among births and terminated pregnancies due to fetal anomalies (TOPFA) in 2020 in Estonia. Up to 2020 no data on prevalence of CAs in Estonia is reported. Methods For retrospective observational study data of all births and terminations of pregnancies after 12th gestational week from (i) the Estonian Medical Birth Registry, (ii) Abortion Registy, (iii) Health Insurance Fund and (iv) hospital records were linked. To calculate the total, live birth, stillbirth and TOPFA prevalence of CAs with 95% confidence intervals (CI), guidelines issued by EUROCAT, European network for the epidemiological surveillance of CAs, https://eu-rd-platform.jrc.ec.europa.eu/eurocat_en were followed. Results In 2020 the total prevalence of CAs, chromosomal abnormalities and monogenic diseases in Estonia was 378.6 per 10,000 births (95% CI 346.0, 413.5). The most prevalent CAs were heart defects, 163.7 cases per 10,000 births (95%CI 142.5, 187.2). The prevalence of chromosomal abnormalities and genetic diseases was 92.6 per 10,000 births (95%CI 76.8, 110.6), 80% of cases were among TOPFAs. No newborns with major aneuploidies (Trisomy 21, 18, 13, polyploidy) were reported in 2020. Live birth prevalence of CAs, including chromosomal abnormalities and genetic diseases was 258.4 per 10,000 live births (95%CI 231.5, 287.5) and stillbirth prevalence of CAs 0.8 per 10,000 births. Conclusions The prevalence of CAs and genetic disorders in Estonia is one of the highest compared to prevalence reported by other European regions. It indicates to high population coverage with prenatal diagnostics in Estonia. Low number of major aneuploidies among live births may reflect good detection rate of major chromosomal abnormalities and cultural preferences.


Introduction
Congenital anomalies (CAs), also known as congenital malformations or birth defects, can be defined as structural or functional anomalies that develop during intrauterine life [1].Approximately 3-6% of children born are with CAs [1,2].CAs represent one of the main cause of fetal death, infant mortality and morbidity.Approximately 21-25% of infant mortality is estimated to be associated to CAs [3,4].
CAs may be caused by genetic, multifactoral or environmental factors [5].It is estimated that about 20% of all CAs are due to genetic factors, another 10% to exogenous factors, and the remaining 70% are multifactorial origin [3].
The prevalence of birth defects vary in great extent depending on the spectrum of congenital abnormalities included to the evaluation, data collection period, recruitment mode, etc [3].Some CAs cause early prenatal loss even before CAs could have been detected by ultrasound.Prenatal detection of CAs may lead to the decision to terminate pregnancy before reaching the viability of fetus.To assess the total prevalence of CA cases, all cases detected among liveborn infants, stillbirths and terminated pregnancies with affected fetuses should be collected [3,5].
According to WHO definition of CAs may be defined as major structural anomalies that account for most of the deaths, morbidity and disability; and minor congenital anomalies, that pose no significant health problem in the neonatal period and have limited social or cosmetic consequences for the affected individual [1].For practicality, the focus is commonly on major CAs.
One of the largest networks of population-based registries for the epidemiological surveillance of congenital anomalies in Europe is EUROCAT (European Surveillance of Congenital Anomalies) [6].The EUROCAT database contains about 800,000 CA cases of live births, stillbirths and terminations of pregnancies and uses standardized classification and coding rules.Data enables epidemiological surveillance of CAs, which includes estimating prevalence, prenatal diagnosis and perinatal mortality rates [6].
In Estonia the screening of CAs and chromosomal abnormalities is provided and fully covered by the Health Insurance Fund for every pregnant woman.The first trimester combined screening is carried out between 11-14 gestational weeks and fetal anatomy ultrasound scan at 19-21 gestational weeks.Additionally, in cases of increased risk for common trisomies noninvasive prenatal test is offered as a second -tier screening test.In cases of the detected or suspected CA at ultrasound scan or/and chromosomal abnormality, diagnostic procedures and tests are performed.
The prevalence of CAs in Estonia has not been reported due to a lack of systematically collected data.In 2020 Estonian Medical Birth Registry introduced a new birth data collection chart that contains information on malformations diagnosed at birth and during the early neonatal period.In addition, since 2020 the Abortion Registry contains the personal identity code enabling linking data with hospital records and assessing the prevalence of CAs, chromosomal abnormalities and genetic diseases among terminated pregnancies.
In this study we aimed to focus on major and mostly prenatally detectable CAs, chromosomal abnormalities and monogenic diseases in Estonia.This is the first nation-wide report of prevalence of CAs among neonates and terminated pregnancies (12-21 gestational weeks) due to fetal anomalies in 2020.

Data collection
Estonian legislation permits elective abortion on demand before the twelfth week of gestation and therapeutic abortion until 21 gestational weeks and 6 days, if the unborn child may have severe mental or physical damage to health [7].All pregnancies ending at or after 22 gestational weeks are registered as births of a child in Estonia.
Data on CAs, chromosomal abnormalities and monogenic diseases of all children born in 2020 was obtained from the Estonian Medical Birth Registry [8] and Estonian Health Insurance Fund.The information about therapeutic termination of pregnancies or spontaneous abortions from the gestational age of 12 to 21 weeks (further referred to as TOPFA -termination of pregnancy for a fetal anomaly) occurred in 2020 in Estonia and was queried by Estonian Abortion Registry and Estonian Health Insurance Fund.Data from registries and databases were linked using the personal identity code of newborn and/or mothers, duplicated cases were excluded.
The newborns whose medical records contained diagnoses Q00-Q99 (Congenital malformations, deformations and chromosomal abnormalities) based on the International Disease Classification (ICD-10) were extracted from all births in 2020.In unspecified cases or in cases of discrepancies queries to health care providers were issued to confirm the presence or absence of CAs and specify a correct diagnosis of an anomaly.Among terminations of pregnancies the mothers whose diagnoses included the ICD-10 codes indicating abnormal findings of antenatal screening tests or ultrasound scans (O28.3,O28.4,O28.5, O28.8, O28.9); maternal care for known or suspected fetal abnormality and damage or other fetal problems (O35, O36) data were retrieved from registries and hospital queries.Data of invasive diagnostic procedures (chorionic biopsy, amniocentesis), genetic testing and pathoanatomical findings were also collected from Estonian Health Insurance Fund database and queries to health care providers performing these procedures.If any of CAs, chromosomal abnormalities and monogenic diseases were described, the case was classified as TOPFA and a diagnose indicating CA according to ICD-10 was applied (Q00-Q99).All data were retrieved as encrypted files from different registries, databases and medical records.

Definitions of congenital anomalies
EUROCAT guidelines for registration of congenital anomalies version 1.5 (31.05.2022) were taken as a reference for defining major CAs in the current study [9].The calculations of the total prevalence of CAs, chromosomal abnormalities and genetic diseases included cases diagnosed either prenatally (from 12 gestational weeks onwards) or during the first month after birth.
Only major CAs were included in the study.The cases of minor CAs and those not detectable prenatally (e.g.tongue tie, cryptorhism, hypospadia, pyloric stenosis, etc.) were excluded.The list of included CAs in the study is given in Supplementary Table 1.If a subject presented both one major and one minor CAs, the case was classified as an isolated malformation.If a fetus or newborn had two or more major malformations (e.g.congenital heart defect and gastrointestinal anomaly) it was classified as a multiple malformation case.If there were both chromosomal abnormalities or genetic diseases and congenital malformation it was counted as one total case, specific malformations were calculated separately.The cases with genetic disorders without any CAs were excluded from the statistical monitoring of structural congenital anomalies.All prevalence estimates and counts for different subgroups were based on cases, not on specific malformations.

Statistical analysis
Prevalences and 95% confidence intervals were calculated as recommended in EUROCAT guidelines [10].The following parameters were calculated: 1. total prevalence: total number of congenital anomaly cases (live births, stillbirths,TOPFA) divided by the total number of births (live births and stillbirths) and calculated per 10,000 births.

prevalence of live birth's congenital anomaly
cases: number of children with anomaly born alive divided by the total number of live births and calculated per 10,000 births.3. prevalence of TOPFA: therapeutic termination of pregnancies and spontaneous abortions with congenital anomaly from gestational week 12 to 21 weeks divided by the total number of births (live births and stillbirths) and calculated per 10,000 births.4. prevalence of stillbirth's congenital anomaly cases: number of children born dead with congenital anomaly divided by the total number of births (live births and stillbirths) and calculated per 10,000 births.
In prevalence calculations, a child/fetus with several anomalies is counted once within each subgroup of anomaly.For data compilation from different sources, the STATA software version 13.1 (StataCorp TX, USA) was applied and statistical analysis was carried out using MS Excel.

The prevalence of birth defects, chromosomal abnormalities and monogenic diseases among newborns and termination of pregnancies
In 2020 there were 13,073 births in Estonia: 13,043 liveborn (99.8%) and 30 (0.2%) stillborn children.The prevalence of CAs, chromosomal abnormalities and monogenic diseases among live births was 258.4 (95% CI 231.5, 287.5) per 10,000 live births (Table 1).There was one case of stillbirth with multiple congenital anomalies registred in our study population.The stillbirth prevalence of CAs was 0.8 (95% CI 0.00, 4.3) per 10,000 births.
During the study period, there were 308 cases of therapeutic termination of pregnancies or spontaneous abortions from gestational age 12 to 21 weeks.In 157 (51%) cases the major CAs and/or genetic disorders (chromosomal abnormalities and/or genetic diseases) were confirmed by antenatal ultrasound, genetic testing or pathoanatomical examination of the fetus.The prevalence of CA, chromosomal abnormalities and monogenic diseases among TOPFAs was 120.1 (95% CI 102.1, 140.4) per 10,000 births.
There were 495 cases with registered CAs, chromosomal abnormalities and monogenic diseases diagnosed prenatally and/or during the first month of child's life and therapeutic termination of pregnancies or spontaneous abortions.The total prevalence of CAs in our study sample was 378.6 (95% CI 346.0, 413.5) per 10,000 births (Table 1).

The prevalence of organ-specific anomalies
The most prevalent CAs were heart defects, diagnosed in a total of 214 cases with a prevalence of 163.7 per 10,000 births.Among newborns congenital heart defects account for almost half of the live birth CAs, with a prevalence of 144.1 per 10,000 live births.(Table 1).Among TOPFAs the prevalence of heart defects was also the most frequent structural anomaly.The commonest heart defects were atrial and/or ventricular septal defects, accounting for 69% of total and 72% of live birth's heart defects prevalence.There were 43 critical congenital heart defects with a birth      THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE prevalence of 22.2 per 10,000 in the live births and 10.7 in the TOPFAs.There were proportionally more severe heart defects among TOPFAs 54% vs.15% of the live birth sample.Kidney and urinary tract anomalies with a total prevalence of 62.0 per 10,000 births were the second most frequent structural anomalies both among live births and TOPFAs.Uni-or bilateral hydronephrosis accounted for 63% of kidney and urinary tract anomalies among births.The structural defects affecting the respiratory, nervous, gastrointestinal and genital tract occurred less frequently.There were 17 multiple congenital anomaly cases, 10 in the live birth, 1 in stillbirth and 6 in TOPFA samples.
In cases of nervous tract anomalies or abdominal wall defects the number TOPFA exceeded the number of births.In all other structural anomalies, including severe heart defects pregnancies ended with birth rather than termination of pregnancy (Table 1).

Genetic disorders
From a total of 13,381 births and aborted fetuses older than 12 gestational weeks chromosomal abnormalities or monogenic diseases were diagnosed in 122 offsprings with prevalence of 92.6 per 10,000 births, 101 cases (80%) among TOPFAs (Figure 1(A)).
The most frequent genetic disorders were numerical chromosomal abnormalities (n ¼ 78).Trisomy 21 (Down syndrome) was diagnosed in a total of 52 fetuses with a total prevalence of 39.8 per 10,000 births (Table 1).All pregnancies with prenatally diagnosed aneuploid fetuses (Down, Edwards, Turner syndrome, Triploidy) were terminated in 2020.
Among 21 newborns with genetic disorders, diagnosed either prenatally or within the first month of life, 14 carried chromosomal structural abnormalities (microdeletions, -duplications etc.) and 7 had a monogenic disease.In 14 newborns (67%) concomitant major congenital structural anomaly was diagnosed (Figure 1(B)) and 7 newborns had minor defects according to EUROCAT nomeclature for CAs.
Among the cases of TOPFA approximately one-half of fetuses with a genetic disease and/or chromosomal anomaly had concominant CAs (Figure 1(B)).In 72 TOPFA cases, the genetic disorder was detected after abnormal result of the first trimester combined screening and confirmed by genetic testing of fetal tissue.Confirmatory analyses included karyotype, fluorescent in-situ hybridization and/or submicroscopic chromosomal microarray.In the majority of these cases, no pathoanatomical examination was done after termination of pregnancy.In 29 cases of TOPFAs the genetic disease or chromosomal anomaly was diagnosed after detection of structural anomaly.In 56 TOPFA cases with a structural anomaly, the genetic disorder was not detected or the genetic testing was not performed (1B).

Discussion
This is the first systematic report of CAs among neonates and TOPFAs (12-21 gestational weeks) in 2020 in Estonia.The total prevalence of CAs including chromosomal abnormalities and genetic diseases in Estonia exceeded nearly 1.5 times the average prevalence reported in EUROCAT registry in the year 2020 (378.6 vs. 253.4per 10,000 births, respectively).The CAs observed 1.4 times more frequently among the live births (258.4 vs.190.0 per 10,000 live births, respectively) and the prevalence of CAs and genetic disorders among the TOPFAs exceeded 2 times the average reported in Europe (120.1 vs. 58.2 per 10,000 births, respectively) [11].
Based on EUROCAT registry, the prevalence of CAs varies to a great extent in different regions of Europe ranging from 188 to 337 per 10,000 births in 2020.Estonia stays in line with the regions reporting higher prevalence rates (e.g. total prevalence of 337 per 10,000 births in France) [11].Based on data from Finnish Registry of Congenital Malformations, the prevalence of CAs there is even higher reported as 610 per 10,000 births in 2019 [12].
In our study, we included only cases with major, potentially prenatally detectable anomalies (Supplementary Table 1), possibly causing fetal death, infant mortality or morbidity for the calculation of the prevalence of CAs.If we had included additional data on minor or antenatally undetectable CAs (for example cryptorhism, hypospadia or tongue tie), the prevalence of CAs in our study population would be also higher.
In our study we collected data about CAs diagnosed during the first month of child's life, thus the malformations, first detected posterior to the first month, were omitted.The content of data from EUROCAT countries and regions that report their data to the registry varies.For example, in Ireland, Malta and Poland no TOPFA data are collected [6].Maximum age at diagnosis of registered congenital anomalies also varies enormously.In Germany, data are collected during the first week, in Portugal during the first month, in Belgium, Austria and France through the first year of child's life, and in Ireland and in Switzerland there is no higher limit of data collection time [6].
The prevalence of visible CAs (e.g.abdominal wall defects, oro-facial clefts, limb abnormalities) and severe congenital heart defects in Estonia was comparable with the prevalence of other European countries [11][12][13] and United States [14].The prevalence of CAs that are detectable by ultrasound scan exceeded European average up to 2 times (e.g.urinary tract abnormalities, especially hydronephrosis and congenital heart defects, especially ventricular septal defects).
It may be explaned by the fact that Estonia has national policy regarding fetal ultrasound scanning during the pregnancy and coverage of prenatal screening and diagnosis in our pregnant population at 2020 was high, 98.2% [15].We can speculate that many of otherwise undetected cases have been picked up already antenatally and confirmed during the first month of life.Diagnostic differences of CAs might also play a role of variations in prevalence.We collected data of all ventricular septal defects diagnosed during the first month of age, some of them may not be hemodynamically relevant and/or resolve spontanously during the first year.
Not all of CAs are visible or diagnosed at birth or after termination of pregnancy, and accurate diagnosis frequently requires additional examinations and health care resources.In our report, approximately in half of terminations of pregnancies or spontaneous losses after 12 weeks (n ¼ 151 out of 308) neither autopsy nor genetic testing were done, possibly causing underestimation of certain CAs.However in these cases no fetal abnormality were detected as a result of prenatal screening.
There was predominant prevalence of chromosomal abnormalities, especially Down and Edwards syndrome in Estonia.The prevalence of Down syndrome was 39.9 and Edwards syndrome 12.2 per 10,000 births, compared to EUROCAT average of 26.4 and 7.4 per 10,000 births.Respective data from Finland in 2019 were similar to our study, 36 and 10 per 10,000 births for Down and Edwards syndrome [12].In Belgium where 81.2% of pregnant women were screened by using noninvasive cell-free DNA test, the total prevalence of Down and Edwards syndrome was reported as 32.2 and 7.4 cases per 10,000 births [16].Estonia's prevalence rate is in concordance with high prenatal detection rate of chromosomal aneuploidies.Prenatal detection rate in Estonia for Trisomy 21 is 94%, for Trisomy 18 and trisomy 13 it was 100% [17].
In addition, cultural and social preferences may affect the prevalence of CAs among births.In Estonia there were no or very few live births with aneuploidies, nervous system anomalies and abdominal wall defects.Prenatal detection and counseling about prognosis of severe CAs enables pregnant women and their families have an option to opt to terminate the pregnancy before 22 gestational weeks.

Conclusions
This one year study gives reference for the prevalence of CAs, chromosomal abnormalities and monogenic diseases among neonates and TOPFA in Estonia in 2020.Collected data elucidated the high prevalence of CA, and chromosomal abnormalities and genetic diseases indicating high population coverage with prenatal diagnostics, good detection rate of chromosomal abnormalities and different cultural preferences compared to many European regions.

0 -
Atresia or stenosis of other parts of small intestine Q41.1-

0 -
Other osteochondrodysplasia with defects of growth of tubular bones and spine Q77.8; Q78.cases that have not coded by ICD-10 Q00-Q99 codes, e.g.cystic hygroma, fetal hydrops, severe growth restriction and fetal tumors.b genetic disorders include syndromes, hereditary skin disorders and skeletal dysplasias.CI: confidence interval; TOPFA: termination of pregnancy due to fetal anomaly(ies).

Table 1 .
Prevalence of congenital anomalies, chromosomal anomalies and monogenic diseases among neonates and terminated pregnancies due to fetal anomalies from 12 gestational weeks to 21 gestational weeks and 6 days in Estonia during year 2020.