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​Cihat Şen, ​Nicola Volpe

Cecilia Villalain, Daniel Rolnik, M. Mar Gil

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Prenatal diagnosis and pregnancy outcomes of 149 fetuses with tetralogy of Fallot accompanied by concomitant cardiac and extra cardiac anomalies

Gökhan Bolluk, Özge Özdemir, Helen Bornaun

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Prenatal diagnosis and pregnancy outcomes of 149 fetuses with tetralogy of Fallot accompanied by concomitant cardiac and extra cardiac anomalies. Perinatal Journal 2022;30(3):- DOI: 10.2399/prn.22.0303008

Author(s) Information

Gökhan Bolluk1,
Özge Özdemir2,
Helen Bornaun3

  1. Health Sciences University, Hamidiye School of Medicine, İstanbul Kanuni Sultan Süleyman Education and Research Hospital Department of Perinatal Medicine İstanbul Turkiye
  2. Health Sciences University, Hamidiye School of Medicine, Başaksehir Çam and Sakura City Hospital Department of Perinatal Medicine İstanbul Turkiye
  3. Health Sciences University, Hamidiye School of Medicine, İstanbul Kanuni Sultan Süleyman Education and Research Hospital Department of Pediatric Cardiology İstanbul Turkiye

Gökhan Bolluk, Health Sciences University, Hamidiye School of Medicine, İstanbul Kanuni Sultan Süleyman Education and Research Hospital Department of Perinatal Medicine İstanbul Turkiye, [email protected]

Publication History

Manuscript Received: April 06, 2022

Manuscript Accepted: August 03, 2022

Earlyview Date: August 03, 2022

Conflicts of Interest

No conflicts declared.

We aimed to analyze the pregnancy outcomes of cases that were diagnosed prenatally with Tetralogy of Fallot (TOF) and to investigate its prenatal diagnosis, treatment conditions, and postnatal outcomes. 
The clinical information data of a total of 149 fetuses diagnosed with TOF (145 cases were singleton and 4 cases were twins) were collected and reviewed retrospectively between January 2016 and January 2022 in İstanbul Kanuni Sultan Süleyman Research and Training Hospital. 
Among completely 61034 pregnancies between these years, 149 fetuses were diagnosed with TOF by fetal prenatal ultrasound imaging with the occurrence rate of about 0.24% (149/61034), and the average gestational age was 26.13 weeks. Among these cases, 22 cases (14,76%, 22/149) opted for termination of pregnancy. Of these 149 fetuses, a total of 60 cases (46,30%, 60/149) accepted genetic testing and 11 cases (7,38%, 11/149) revealed chromosomal disorders with trisomy 21 in 5 cases, trisomy 18 in 1 case, 22q11.2 microdeletion syndrome in 4 cases and abnormality of the short arm of 8th chromosome in 1 case. After delivery, 4 cases were diagnosed with trisomy 21. Pregnancy was continued in a total of 127 fetuses, of which 114 cases resulted in delivery. While 36 cases were delivered by cesarean section and the other 78 cases were delivered vaginally. Thirteen fetuses died during the pregnancy period. Newborns who survived the postpartum period were followed up to 5 years of age for surgery. Among 114 cases, 28 cases died during the postnatal period at different times. 
The diagnosis of TOF is mainly made with the help of fetal ultrasound in the second trimester. A genetic examination is also necessary after prenatal diagnosis and multidisciplinary work is also important between departments. TOF without genetic disorder can be successfully corrected with surgery after birth. 

Tetralogy of Fallot, Genetic diagnosis, Outcomes

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease, which consists of 5-7% of all congenital heart diseases [1]. It is a conotruncal cardiac anomaly in which four classic cardiac anomalies are seen together: right ventricular outflow tract obstruction, malalignment-type ventricular septal defect, overriding aorta, and right ventricular hypertrophy [2]. Right ventricular hypertrophy is not usually seen in utero with the help of patency of the foramen ovale and ductus arteriosus, which balance the pressure load in the right ventricle. It occurs with a prevalence of 3.68 per 10000 live births [3]. Only 10% of the untreated newborn can live into their 20s [4]. About a quarter of fetuses with this condition also have genetic diseases, which increases morbidity and mortality [5]. Three main subtypes of TOF were respectively; pulmonary stenosis, pulmonary atresia, and absent pulmonary valve subtype, and the last two subtypes represent the severe forms of this syndrome [6].
The outcome of fetuses with TOF mainly depends on the severity of the disease, its subtype, concurrent cardiac or extracardiac anomalies, and postnatal treatment. Today, prenatally the diagnosis of TOF is made with fetal echocardiography. For the treatment of a child with TOF, the complete repair is made within the first year after birth but palliative and multistage surgeries can be also performed when necessary [7]. Prenatally reported detection rates for TOF have been known to range from 30% to 60% [8]. The 10-year survival rate after successful surgery for cases with TOF ranges between 87% and 97% [9]. These patients can have quality living conditions and long lifespans, even with residual lesions and long-term complications with one or more-stage treatment approaches. While the palliation-based approach was applied in the early periods, correction surgeries have come to the fore today.
In the present study, we examined the pregnancy outcomes of cases diagnosed with tetralogy of Fallot prenatally and investigated the diagnosis, treatment conditions, and postpartum outcomes. 
The clinical information and results of 149 cases diagnosed as TOF (145 cases were singleton and 4 cases were twins) were obtained retrospectively between January 2016 and January 2022 in İstanbul Kanuni Sultan Süleyman research and training hospital. The total number of deliveries during this period was 61,034. Information was collected about the course of pregnancy, the gestational week at which the diagnosis was made, genetic results, presence of additional cardiac and other extra-cardiac anomalies. Informed consent was taken from all patients for prenatal images of fetuses, as well as for the collection of pregnancy courses and outcomes.
This study was carried out solely on human fetuses with a confirmed prenatal diagnosis of TOF. While some cases with TOF were diagnosed in our clinic, other cases were referred from an external center. The reason for a referral from an external center is suspicion of a cardiac anomaly or detection of an extra-cardiac anomaly. This study contained information about the clinical outcomes and genetic testing results of cases (either prenatal or postnatal). In this study, three major subtypes of fetal TOF were enrolled including TOF with pulmonary stenosis, pulmonary atresia, and absent pulmonary valve syndrome.
In each case, intracardiac anatomy and extracardiac structures were examined in detail by ultrasound. Karyotyping and fluorescent in situ hybridization (FISH) procedures were performed when accepted. This study was reviewed and approved by the ethics committee of the institution (2022.03.57). The inclusion criteria were confirmed definite postnatal cardiac TOF diagnosis and infant delivery in our clinic. Fetal growth restriction was defined as estimated fetal weight < 3rd centile according to the sonographic examination of fetal Hadlock formula [10]. The decision regarding the mode of delivery depended on obstetrics indications [11]. Infant survival was assessed 5 years after delivery. Postnatal echocardiography was obtained in all cases.
Statistical analysis
The statistical analysis was performed using IBM SPSS Statistics for Windows, Version 21.0 (IBM Corp., Armonk, NY, USA). A descriptive statistical analysis was performed. Continuous variables were expressed as mean±std, and categorical variables were presented as numbers and percentages.
A total of 149 cases out of a total of 61,034 births in this period were diagnosed as fetal TOF with fetal heart ultrasound examination with about 0.24% (149/61,034) occurrence rate, and the mean gestational 26.13±5.40 weeks gestation. The earliest diagnosis was at 17 gestational weeks of a case diagnosed with TOF with pulmonary stenosis subtype. The average maternal age was 30.24±5.42. While 145 (97.31%) of the cases were singleton, 4 (2.69%) were twins (Table 1). The most common reason for external referral to our clinic was the suspicion of a cardiac anomaly during a routine obstetric ultrasound examination. Extracardiac anomalies diagnosed prenatally were observed in different organ systems on 24 cases (16.1%) (Table 2). Coexisting cardiac anomalies other than TOF were observed among 48 cases (32.21%) and Table 3 summarizes the type and number of these anomalies.
Totally 22 cases (14.76%, 22/149) out of 149 cases were terminated by induced labor. The total number of cases who were offered genetic examination and accepted the procedure was 60 (46.30%, 60/149) and chromosomal abnormality was detected in 11 cases (7.38%, 11/149) of them, and these chromosomal abnormalities including trisomy 21 in 5 cases, trisomy 18 in 1 case, 22q11.2 microdeletion syndrome in 4 cases and abnormality of the short arm of chromosome 8 in 1 case. After delivery, 4 cases were diagnosed with trisomy 21. A total of 127 cases decided to continue the pregnancy and a total of 114 cases (76.51%) underwent delivery with 36 cases cesarean section delivery and 78 cases vaginal delivery. Intrauterine fetal death occurred in 13 cases (8.72%). Neonatal survival and outcomes were followed from 1 month to 5 years postpartum period in terms of Tetralogy of Fallot surgery. During this postnatal period, death was observed in a total of 28 cases (18,79%) at different periods.
Overall, 149 cases constituting this study were analyzed according to the subtype of TOF, of which 117 (78.52%) were TOF with pulmonary stenosis, 19 (12.75%) were with pulmonary atresia, and 13 (8.72%) were with an absent pulmonary valve. Absent ductus arteriosus were seen in a total of 13 cases among the cases of TOF with an absent pulmonary valve or pulmonary atresia. Additional intracardiac defects (Table 3), such as right aortic arch, persistent left vena cava superior, and aberrant right subclavian artery were seen in a total of 46 cases (30.87%).
TOF is one of the most common cyanotic congenital heart diseases seen in approximately one in 3600 live births [12]. The clinical course of TOF in newborns depends on the severity of the disease and associated chromosomal and other extracardiac abnormalities. Mild TOF may be asymptomatic and therefore undiagnosed. TOF with severe stenosis in the right ventricular outflow tract usually presents cyanosis. When severe right ventricular outflow obstruction is suspected before birth, postpartum prostaglandin should be administered to ensure the patency of ductus arteriosus. Among the three subtypes of TOF, the classical form of TOF with pulmonary stenosis accounts for about 80% of all newborns with TOF [13]. In our study, 78% of cases with pulmonary stenosis subtype are close to previous publications according to rate.
It has been stated in previous case series that approximately 30% of patients with TOF may have chromosomal disorders. Moreover, chromosome 22q11.2 deletion syndrome, also called DiGeorge syndrome, can be seen in 16% of TOF patients, especially in cases with TOF diagnosed postnatally [14,15]. In another study, the incidence of chromosomal disorders in TOF cases was reported as 10% [16]. Zhao et al. reported that 34.4% of TOF cases diagnosed prenatally were accompanied by chromosomal abnormalities, of which 17.4% were 22q11 deletion and 17% were the other abnormalities. The slightly higher incidence of chromosomal anomalies was because pregnancies complicated by chromosomal abnormalities are more probably to be terminated [7]. Previous studies indicated that the rates of chromosome 22q11.2 deletion syndrome were varying from 0% to 18% in TOF cases. Also, 22q11 deletion was more frequent in TOF cases with pulmonary atresia or absent pulmonary valve [15,17,18]. Our results indicate that 7.38% of TOF cases were complicated by chromosomal anomalies. DiGeorge syndrome was seen only in 2.68% of all our cases. We attribute the low rate of a chromosomal anomaly in our study compared to the literature, to the low rate of patients accepting karyotype analysis and low frequency of pulmonary atresia and absent pulmonary valve in our study group.
The etiology of TOF is so complex that in most cases, the cause is unknown and both environmental factors and genetic disorders may be associated with TOF. Postoperative TOF usually has a good prognosis unless there is a genetic disease. It is very important prenatally to role out the association between genetic disorders and unfavorable prognosis. Cardiac anomalies associated with TOF are common. Right aortic arch can be seen in 25% of cases prenatally. In our study, the right aortic arch was seen in 14.09% of the cases. Atrioventricular septal defect with TOF is associated with a high risk of chromosomal abnormalities. Patent foramen ovale or atrial septal defect was reported in 83% of newborns with TOF, and persistent left superior vena cava in 11% [19]. An absent ductus arteriosus can be seen as a common sonographic feature, especially in TOF patients with pulmonary atresia and absent pulmonary valve subtype. Our result indicates that 40.62% of cases have an absent ductus arteriosus among cases with pulmonary atresia and absent pulmonary valve subtype.
The earliest prenatal diagnosis was at 13 weeks, with a range of 12-15 weeks of gestation in case series of TOF [20]. The earliest prenatal diagnosis in our series was at 17 weeks of gestation in case of TOF with pulmonary stenosis. Overall, suspected TOF is the most common reason for referral to our clinic. Also, non-cardiac malformations or known chromosomal disorders are other reasons for referral. In our study, the main reason for fetal echocardiography was to suspect a cardiac anomaly or to detect a non-cardiac anomaly during the screening examination. Prenatally diagnosed fetuses with TOF can be delivered vaginally, but it is important to have a pediatric cardiology team for postnatal care in the birth center. Our vaginal delivery rate is 68.42%.
A substantial percentage of TOF cases were observed with extracardiac abnormalities [21,22,23]. Several previous reports found that the incidence of TOF cases with one or more congenital extracardiac abnormalities was 17-28%. The most common extracardiac anomalies were detected to be genitourinary, musculoskeletal, and gastrointestinal abnormalities [18,24]. In our study, one or more extracardiac abnormalities were detected to be 16.1% in TOF cases. TOF cases coexisting with extracardiac abnormality markedly increased the risk for genetic abnormalities [21]. Therefore, guidelines recommended a detailed ultrasound examination to rule out extracardiac abnormalities, particularly rule out soft markers and thymus hypoplasia, and suggested genetic testing with chromosomal microarray analysis when coexisting with extracardiac anomalies [25].  
The definite treatment of TOF is mainly a full correction surgery that is electively usually performed between 3 and 6 months of the postpartum period. The timing of surgical repair is dependent on the degree of cyanosis and the presence of non-cardiac abnormalities after birth. Complete surgical repair can be made primary or after a palliative procedure. It is stated that the short- and long-term survival rates of newborns with TOF reach 90% [26]. In our study, newborns with TOF who underwent surgery were followed up for their clinical status between 1 month and 5 years after birth, and during this period survival ratio was 78%. The risk of recurrence is approximately 3%. Sometimes, TOF may not be diagnosed properly and is missed during the second trimester. Generally, these cases are the mild form of TOF where the discrepancy in the vessel size is not very obvious and VSD is not easily seen.
Studies on the results and prognosis of TOF reveal excellent outcomes [26]. Herein, we aimed to define our patient group with the presence of some features like genotype anomalies, and extracardiac abnormalities and explore early intervention predictors and outcomes. In our study, the overall mortality during the follow-up period was 8.72% and 18.79% postnatally respectively. TOF is a lifelong follow-up disease that may require careful additional surgical and interventional procedures later in life. In recent years, the use of subchromosomal microarray analyses, which can show the presence of conditions such as deletion or duplication has increased especially in patients with complex cardiac anomalies. 
This study summarizes prenatal genetic, sonographic features, and postnatal outcomes of cases diagnosed with TOF. The diagnosis of TOF is mainly made with the help of fetal ultrasound in the second trimester. A genetic examination is also necessary after prenatal diagnosis and multidisciplinary work is also important between departments. TOF without genetic disorder can be successfully corrected with surgery after birth. After the diagnosis, treatment plan and long-term follow-up should be done by experts. 
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Table 1.
Demographic characteristics of fetuses diagnosed with prenatally TOF.
Table 2.
Associated extracardiac defects in fetuses with TOF.
Table 3
Characteristics of concomitant cardiac anomalies in fetuses diagnosed with TOF