The inheritance of congenital heart disease (CHD) has been analyzed in familial studies undertaken by Nora et al. [
A family history of CHD is a frequent reason for referring a patient for fetal echocardiography. Prenatal counseling in these patients is very difficult, because it is not always possible to exclude smaller or evolutive lesions in examined fetuses and the final prognosis of the affected cases may be sometimes completed only after birth. The recurrence rate in populations with familial risk referred for fetal echocardiography was first reported by Allan et al. [
1634 consecutive pregnancies from 1483 women referred for familial history of CHD were studied in our center by fetal echocardiography between January 1995 and June 2010. Patients’ families pedigree was collected for at least three generations and the patients were informed about the limits of the study.
The familial case with CHD who prompted the referral was defined as the index case: it was either an affected mother or father, or a sibling of the current pregnancy, or more distant relatives of the 2nd-3rd degree; 1477 cases were found to have a single familiar risk while 157 cases had multiple risks (2–5 relatives with CHD). One hundred thirty-nine women were examined in two, 12 in three and one in four consecutive, pregnancies, respectively. There were 21 twin pregnancies.
Only cases with a known followup were included while mothers with pregestational diabetes or those taking drugs during pregnancy were excluded, as were the index cases affected with Mendelian diagnosed syndromes or chromosomal anomalies, or cases of consanguineous parents.
Echocardiographic studies were performed using echocardiographic machines Acuson Sequoia 512, Siemens, Erlangen, Germany and Vivid 7, General Electrics, Healthcare Italy or Aloka Prosound Alpha 10, Tokyo, Japan, applying standard methodology with use of 2D, Doppler and Color Doppler techniques. These equipments had all a very good imaging standard. Studies were routinely recorded onto videotape or by digital storage of the echocardiographic machines. All studies were performed by one single experienced fetal cardiologist (V. Fesslova) and discussed with the team of perinatal medicine
Fetal cardiologic diagnosis of the cases was compared with the findings at autopsy, or postnatally, at follow-up examinations at 6 months of age or later. Regarding the differential diagnosis between a physiological patent foramen ovale and ASD secundum, we considered as a criterion the diameter >8 mm in the third trimester and >5 mm at 1 year of age.
All live-born infants either underwent a cardiologic examination in our centre or, if carried out elsewhere, the parents forwarded to us a follow-up questionnaire given to them at the last fetal examination, completed by the team that performed the examination. If necessary, the parents or cardiologists of other centres were contacted by one of our group in order to have a correct postnatal diagnosis.
The data regarding the index case and the echocardiographic findings of the examined fetus, with his subsequent outcomes, were analyzed by means of a computerized database (Filemaker Pro, VI, Claris Corp., Santa Clara, Calif, USA).
Cardiac defects were classified using the sequential segmental classification described by Tynan et al. [
Defects of the index case and of the examined fetus were analyzed for concordance and discordance. The defect in the examined fetus was described as exactly concordant if it was identical to that one seen in the index case and concordant for the group if the defect belonged to the same spectrum of CHD as seen in the index case, that is, group of shunts, conotruncal lesions, left and right heart obstructive lesions, and laterality defects/dextrocardia, according to the criteria used in previous studies [
The
Recurrence of congenital heart defects in cases with single- and multiple-familial risk.
Index case with CHD | Total cases | Affected cases | Recurrence rate % |
---|---|---|---|
Single risk—total | 1477 | 60 | 4.06 |
Previous child | 818 | 29 | 3.5 |
Mother alone | 250 | 13 | 5.2 |
Father alone | 93 | 7 | 7.5 |
One relative II°-III° | 316 | 11 | 3.5 |
Double cases risk | 137 | 4 | 2.9 |
2 previous children | 22 | 1 | 4.5 |
1 previous child + 1 relative | 23 | — | — |
| 26 | 2 | 7.7 |
+ 1 previous child | 8 | 1 | 11.1 |
+ father | 3 | 1 | 6.7 |
+ 1 relative | 15 | ||
| 19 | 1 | 5.3 |
+ prev. child | 12 | 1 | 8.3 |
+ 1 relative | 7 | — | — |
2 relatives II°-III° | 47 | — | — |
Multiple cases risk | 20 | 1 | 5 |
2 prev children + 1 relative | 2 | — | — |
Mother + prev. child or 2–4 relatives | 5 | 1 | 20.0 |
Father + 2 relatives | 3 | — | — |
3-4 relatives II°-III° | 10 | — | — |
Total double + multiple risk | 157 | 5 | 3.2 |
Total series | 1634 | 65 | 3.98 |
Recurrence of congenital heart defects in subgroups of CHD in index cases: total recurrence rate and recurrence rates in siblings, offspring, and distant relatives.
Index case diagnosis | Total index cases | Affected cases | Recurrence diagnosis | Recurrence rate Tot % | Recurrence rate in siblings % | Recurrence in offspring % | Recurrence rate in Relatives % |
---|---|---|---|---|---|---|---|
(i) UVH | 65 | 1 | 1 HLV | 1/65 = 1.5 | 1/52 = 1.9 | M 0/1, F 0/1 | 0/11 |
(ii) HLV | 81 | 1 | 1 HLV | 1/81 = 1.23 | 1/80 = 1.25 | — | 0/1 |
(iii) TrAtr | 37 | — | — | — | — | — | — |
(iv) AVSD | 64 | 5 | 1 VSD; 1 AVSD+ HLV | 5/64 = 7.8 | 3/46 = 6.5 | M 1/4 = 25.0, F 0/1 | 1/13 = 7.7 |
(v) Ebstein/Dyspl Tr | 21 | 2 | 1 LSVC; 1 CoA | 2/21 = 9.5 | 2/15 = 13.3 | M 0/1, F 0/5 | — |
(i) Tetralogy of Fallot | 151 | 9 | 1 DORV; 1 ASD+PS; | 8/151 = 5.3 | 2/73 = 2.7 | M 1/26 = 3.8, F 2/11 = 18.2 | 3/41 = 7.3 |
(ii) PAtr + VSD | 19 | 1 | 1 VSD | 1/19 = 5.3 | 1/11 = 9.1 | M 0/1 | 0/7 |
(iii) PAtr + IVS | 14 | 2 | 2 PS | 2/14 = 14.3 | 2/10 = 25 | — | 0/4 |
(iv) DORV | 15 | — | — | — | — | — | — |
(v) Truncus | 20 | 1 | 1 ASD | 1/20 = 5 | 1/20 = 5 | — | — |
(vi) TGA | 104 | 3 | 2 VSD; 1 PS | 3/104 = 2.88 | 2/66 = 3.03 | M 0/2 | 1/36 = 2.8 |
(vii) TGAc | 15 | 1 | 1 TGAc + VSD + PAtr | 1/15 = 6.7 | 1/10 = 10.0 | M 0/1, F 0/2 | 0/2 |
(i) VSD | 239 | 10 | 1 TrAtr +TGA+VSD; | 10/239 = 4.2 | 2/126 = 1.59 | M 5/66 = 7.5, F 1/14 = 7.1 | 2/33 = 6.1 |
(ii) VSD + ASD | 23 | 1 | 1 TGA | 1/23 = 4.35 | 1/18=6.3 | M 0/2, F 0/1 | 0/2 |
(iii) ASD | 194 | 8 | 2 ASD; 3 VSD; | 8/194 = 4.1. | 1/59 = 1.7 | M 5/88 = 5.7, F1/20 = 5–0 | 1/27 = 3.7 |
(iv) Ductus Arteriosus | 34 | 1 | 1 ASD | 1/34 = 2.94 | 0/10 | M 1/12 = 8.3, F 0/1 | 0/11 |
(i) CoA/Interr Ao arch | 134 | 3 | 1 HLV; 1 ASD;1CoA | 3/134 = 2.24 | 1/84 = 1.2 | M 1/17 = 5.9, F 1/7 = 14.3 | 0/26 |
(ii) AS | 115 | 5 | 1 VSD; 2 AS, | 5/115 = 4.3 | 0/28 | M 2/27 = 7.4, F 2/34 = 5.9 | 1/26 = 3.8 |
(iii) PS | 76 | 4 | 1 HLV; 1 PS; | 4/76 = 5.3 | 2/37 = 5.4 | M 0/18, F 1/6 = 16.7 | 1/15 = 6.6 |
(i) P/TAPVD | 22 | — | — | 0/22- | 0/12 | M 0/2, F 0/3 | 0/5 |
(ii) Heterotaxy syndrome | 22 | 1 | 1 AVSD + left isom; | 1/22 = 4.5 | 1/19 = 5.3 | — | 0/3 |
(iii) Dextrocardia + svi, s.sol | 23 | 2 | 1 HRV + PAtr; | 2/23 = 8.7 | 2/14 = 14.3 | M 0/5, F 0/2 | 0/2 |
41 | 1 | 1 VSD | 1/41 = 2.4 | 0/17 | M 0/7, F 0/6 | 1/11 = 9.1 | |
105 | 4 | 1 VSD; 2 CoA, 1 TGA | 4/105 = 3.8 | 3/30 = 10 | F 0/1 | 1/74 = 1.35 | |
Total | 1634 | 65 | 3.98 |
CHD was found in 65 infants with 2 being twins. Figure
Types of recurrent CHD. Dxc + Patr + HRV: dextrocardia + pulmonary atresia + hypoplastic right ventricle, PAIV: pulmonary atresia and intact septum, TGA-TGAc: transposition of great arteries, corrected transposition of great arteries, DORV: double outlet right ventricle, TF: Tetralogy of Fallot, PLSVC: persistent left superior vena cava, AS: aortic stenosis, ASD: atrial septal defect, VSD: ventricular septal defect, PAPVD: partial anomalous pulmonary venous drainage, HLV: hypoplastic left ventricle, CoA: coarctation of aorta, PS: pulmonary stenosis; AVSD: atrioventricular septal defect.
Twelve cases (18.4%) were diagnosed only after birth: one case with coarctation of the aorta who was examined in utero only in the 2nd trimester, 7 small VSDs, and 4 ASDs—confirmed at 12 months of age, after the fetal findings in the third trimester of a large foramen ovale (greater than 8 mm) and a large aneurysm of the foramen.
Total occurrence of CHD was 65/1634 (3,98%), 60/1477 (4.06%) in cases with single familiar risk, 2.9% (4/137) and 5% (1/20) in pregnancies having, respectively, double and multiple risk (Table
When excluding the cases that were not diagnosed in utero but found only after birth, the recurrence rate would be lower—of 3.2% (53/1634). As we stated in the Patients and Methods Section, the detailed analysis is based upon the total number of CHD in infants at 6 months of age.
The recurrence rate of CHD was 3.5% (29/818) when one previous child was affected, but increased to 4.5% (1/22) when 2 previous children had CHD.
When mother alone was affected, the recurrence was 5.2% (13/250); with additional 1-2 relatives the recurrence rate increased to 9.7% (3/31).
When father alone was affected, the recurrence rate was 7.5% (7/93) and 4.5% (1/22) with 1-2 other relatives affected. In cases of a single 2nd-3rd-degree relative affected, the recurrence was 3.5% (11/316).
Five fetuses of the 139 women who were followed in 2 pregnancies were affected (3.6%), with concordant recurrence of ASD in 2 infants of mothers affected with the same lesion; another mother with VSD had an infant with ASD and two siblings of index cases with TGA and AVSD had both a VSD.
Twelve women who were followed in their 3rd pregnancies had all normal infants: 2 were affected mothers and one affected father who have each had an affected child previously; 2 other affected mothers had normal children in both previous pregnancies, while in the remaining pregnancies normal infants were born after one previously affected child.
One woman, followed up in 4 pregnancies, after the first child with TGA and who had another distant relative affected with an undefined CHD, delivered normal offspring in the subsequent pregnancies.
Table
When the father alone was affected, an exact concordance occurred in 1/7 cases and a partial one in another case.
When one previous child was affected, the complete concordance was 8/29 (27.6%) and a partial one in 2/29 (6.9%).
In 34 cases (51.5%), there was a Lesions of a similar gravity in 5 cases. Milder lesions in 19 cases. More complex CHD in 10 cases.
The type of recurrence could not be defined in 4 cases because of a nonspecific diagnosis of the cardiac anomaly in the index case.
Out of 5 affected fetuses with double/multiple familiar risk there was one case with
Table
Relative risks ratios—comparison between our series and normal population (Moons et al.).
CHD | Our series (‰) | Moons et al. (‰) | RR | Confidence limits (95%) | |
---|---|---|---|---|---|
HLV | 1/1634 (.6 ) | 10/111225 (.09) | 6.8 | 0.9–53.2 | 0.067 |
UHV | 1/1634 (.6) | 9/111225 (.08) | 7.6 | 0.96–59.8 | 0.055 |
TF | 9/1634 (5.5) | 52/111225 (.5) | 11.8 | 5.8–24.1 | 0.0001 |
PA + VSD | 1/1634 (.6) | 6/111225 (.05) | 11.4 | 1.4–94.3 | 0.024 |
PAIVS | 2/1634 (1.2) | 6/111225 (.05) | 29.7 | 4.6–112.6 | 0.0001 |
Truncus | 1/1634 (.6) | 7/111225 (.06) | 13.7 | 1.7–111.1 | 0.0145 |
TGA | 3/1634 (1.8) | 29/111225 (.3) | 7.05 | 2.1–23.2 | 0.0013 |
TGAc | 1/1634 (.6 ) | 3/111225 (.03) | 22.7 | 24–218 | 0.007 |
CoA | 3/1634 (1.8) | 46/111225 (.4) | 4.5 | 1.4–14.3 | 0.0123 |
AVSD | 5/1634 (3.1) | 37/111225 (.3) | 9.2 | 3.6–23.5 | 0.38 |
Ebstein | 2/1634 (1.2) | 3/111225 (.03) | 63.8 | 10.7–382.4 | <0.0001 |
PS | 3/1634 (1.8) | 88/111225 (.8) | 2.3 | 0.7–7.3 | 0.007 |
As | 5/1634 (3.1) | 26/111225 (.2) | 18.5 | 7.1–48.1 | <0.0001 |
ASD | 8/1634 (4.9) | 162/111225 (1.5) | 4.7 | 2.3–9.7 | <0.0001 |
VSD | 10/1634 (6.1) | 303/111225 (2.7) | 2.3 | 1.9–4.2 | 0.0008 |
T/PAPVD | 1/1634 (.6) | 28/111225 (.3) | 3.4 | 0.46–25.1 | 0.2277 |
CHD: congenital heart disease, HLV: hypoplastic left ventricle, UVH: univentricular heart, TF: Tetralogy of Fallot, PAtr: pulmonary atresia, PAIVS: pulmonary atresia + intact ventricular septum, TGA: transposition of great arteries, TGAc: corrected transposition of great arteries, CoA: coarctation of aorta, AVSD: atrioventricular septal defect, PS: pulmonary stenosis, AS: aortic stenosis, ASD: atrial septal defect ostium secundum, VSD: ventricular septal defect, T/PAPVD: total/partial anomalous pulmonary venous drainage.
Epidemiology and genetics of cardiac malformations have been an object of several studies over several last decades. The large epidemiological Baltimore Washington Infants Study [
Nora [
Subsequent studies of Burn et al. [
Higher recurrence rates in the offspring of mothers with CHD with and without surgical treatment (of 16.1%) were reported by Whittemore et al. [
A positive family history of CHD is a frequent cause for the referral for prenatal cardiac investigation which led to the first study of the recurrence of CHD in the population of mothers referred for fetal echocardiography for a family history [
The present study included also the cases studied by fetal echocardiography because of a family history of CHD in either first degree or more distant relatives. We insisted on a final cardiologic examination of the child at least at 6 months of age or later, in order to detect even those smaller anomalies, that are difficult to visualize in the fetus [
The recurrence rate would have been lower if we have had considered only cases diagnosed during fetal life (3.2%), more similar to the results of Gill et al. [
As for the single categories of familial risk, the recurrence rate in our study was 3.8% (30/784) when one previous child was affected increasing to 4.8% (1/21) with 2 previous children with CHD, in agreement with several other reports [
Our recurrence rates for siblings and offspring correspond to those reported by Nora and Nora [
We found a difference between the recurrences in offspring of affected mothers and fathers. The preponderance of affected offsprings of mothers with CHD may be at least partly explained by cytoplasmatic inheritance, that is, transmission of maternal cytopathy, while the paternal transmission is of about 2% lower than the maternal one [
High relative risk recurrence ratios both of a specific and discordant CHD in first-degree relatives compared with the normal population prevalence were reported also by Øyen et al. [
Lower ratios were found for the 2nd- and 3rd-degree relatives. Their study includes, however, also cases with associated chromosomal or extracardiac anomalies.
Our results confirm a large variability in the recurrence of cardiac lesions, both in cases with multiple familial risk factors and in consecutive pregnancies, in agreement with other reports [
Among discordant pairs of lesions, some occur more frequently and mainly within the group of septal defects (ASD, VSD, AVSD) or between TF, TGA, and VSD. We found also a case of recurrence of PS after the previous pulmonary atresia. Equally, the variability between different types of the left ventricular obstructive lesions has been reported in several studies [
Familial occurrence of AVSD is reported both in the presence of euploidy and aneuploidy (trisomy 21), with a rate in siblings about 3-4% [
Familial recurrence of CHD among patients with nonsyndromic TF was reported of 2.5–3% [
J. J. Nora and A. H. Nora [
Obstructive lesions of the left outflow tract are presumed to be due to an altered embryonic blood flow and may occur in families with variable degrees of severity starting with bicuspid aortic valve, AS, coarctation of the aorta, and HLHS suggesting a genetic predisposition to the flow alterations [
Recurrence for the laterality defects have been reported to be between 2 and 4.75% [
In our series, we have found a total recurrence of 1/22 (4.5%) in index cases with left and right isomerism and a concordant recurrence in siblings of 1/19 (5.3%) with left isomerism and AVSD, but with different associated intracardiac lesions.
High relative risk ratio for heterotaxy was reported by Pradat and Øyen et al. [
Out of 22 cases with dextrocardia, either with situs solitus and or inversus, recurrent lesions occurred in 2 cases (total recurrence 8.7% and rate in siblings 2/14–14.3%).
Our data demonstrate a higher recurrence rate of CHD than in previously published data, mainly thanks to an improved detection of even milder forms of CHD both in utero and after birth, and confirm the specific transmission of certain types of CHD in some families indicating a genetic component. Ongoing genetic and molecular studies suggest intriguing links between certain specific cardiac lesions in some familial pedigrees. The clinical significance of data regarding the recurrence of CHF is evident, particularly for preconception and prenatal counseling.
The couple receiving prenatal counseling and surveillance should be informed of the impossibility of a total exclusion of the occurrence of some small defects and evolutive lesions as coarctation and that the global prognosis of the infant can be sometimes completed only after birth.
No funding was received for the manuscript.
Congenital heart disease
Hypoplastic left heart syndrome, hypoplastic left ventricle
Atrioventricular septal defect
Ventricular septal defect
Atrial septal defect ostium secundum
Transposition of great arteries
Pulmonary stenosis
Aortic stenosis
Coarctation of the aorta
Tetralogy of Fallot
Transposition of great arteries
Corrected transposition.