Isolated congenital complete heart block (CCHB) is a rare disease with significant associated morbidity and mortality. A diagnosis is often made in fetal life, but data regarding long-term outcomes are limited, and fetal therapy to improve prognosis is controversial. In our institution, 85 fetuses were diagnosed with CCHB from 1981 to 2013 in 80 mothers. There were 37 anti–Ro-positive pregnancies, 36 both anti-Ro and anti-La positive, 10 antibody negative, and 2 of unknown antibody status. Antenatal treatments were given in 14 fetuses, with 8 given fluorinated steroids, 4 beta sympathomimetics, and both in 2. Of the original 85, 74 babies survived to delivery. Fetal hydrops was the only risk factor found to be significantly associated with intrauterine death (p <0.001). Four babies died before pacemaker implantation, 56 have had pacemakers implanted, and 14 are pacemaker free. The Kaplan-Meier estimate for median time to pacemaker implantation was 2.6 years, with 15 implanted in the neonatal period. There have been 14 postnatal deaths, with a Kaplan-Meier estimate of survival at 30 years of 76.8% (95% confidence interval 65% to 90%). Dilated cardiomyopathy was uncommon, occurring in 6 patients. Prematurity and hydrops were associated with increased postnatal mortality (p = 0.02 and 0.005, respectively). In conclusion, we present the largest single-unit experience of prenatally diagnosed CCHB in the published literature. Our cohort was conservatively managed, with survival similar to those previously published. These data offer insight into the long-term natural history of CCHB.
Congenital complete heart block (CCHB) has been recognized as a clinical entity for a period of 100 years, with presentation before the era of fetal medicine with postnatal bradycardia and later Stokes-Adams attacks. The condition is rare, with an incidence placed at between 1 in 11,000 and 22,000 live births. Etiologically, the disease has been divided into subsets comprising those in association with structural heart disease, those with structurally normal hearts exposed to maternal anti-Ro or anti-La antibodies, and those with structurally normal hearts without maternal antibodies. The risk of mortality both prenatally and postnatally is significant and is highest in the population with structural abnormality. Several other variables have also been associated with increased mortality. Dilated cardiomyopathy (DCM) is well recognized as a complication of CCHB with a high associated mortality. Despite significant controversy, several fetal therapies have been proposed for isolated CCHB, including fluorinated steroids, beta sympathomimetics, intravenous immunoglobulins, and hydroxychloroquine. The aim of this study was to review long-term outcome data for prenatally diagnosed isolated complete heart block, and in this report, we present the largest, single-unit experience in the published literature.
Methods
This was a retrospective observational study of fetuses diagnosed with CCHB at a tertiary referral hospital (The Department of Fetal Cardiology at Evelina London Children’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust [Previously at Guy’s Hospital, London, United Kingdom]) from 1981 to 2013. The study population were fetuses with CCHB and their mothers. Cases were excluded if there was associated major structural congenital heart disease, such as left atrial isomerism or discordant atrioventricular connections.
Patients were identified from the fetal cardiology electronic database (Filemaker Pro; Filemaker Inc., Santa Clara) and records from previous publications. Data were collected from paper and electronic fetal records and postnatal patient casenotes. Where care was transferred elsewhere, external units were contacted to ascertain current status.
The cohort was divided into 2 equally sized groups, comprising earlier and later eras for further analysis, based on date of diagnosis. This yielded 2 groups, one comprising diagnoses made from January 1981 to August 1996 (early era) and a second from September 1996 to January 2013 (later era).
Data were analyzed in R (R, version 3.0.2; R Foundation for Statistical Computing, Vienna, Austria). Although a series of multivariate analyses had been planned, event rates were too low for this to be statistically viable. Analyses were, therefore, amended to individual analyses using the student’s t test with assumption of equal variances for continuous variables and Fisher’s exact test for categorical variables. Mortality and pacemaker insertion rates were expressed through the Kaplan-Meier method, with the log-rank test used to assess differences in mortality between groups. Two-sided tests were performed throughout, and a p value <0.05 was regarded as significant. Analyses were performed for a composite outcome of death or cardiac transplant.
The definition of DCM has varied among previous studies. In this work, we defined the condition as a left ventricular diastolic diameter z-score greater than +2 with fractional shortening <25% on echocardiography or description at postmortem. Institutional approval for the study was obtained.
Results
Ninety-five fetuses were identified with CCHB. After data collection, 10 were excluded, of which 2 had lesser degrees of heart block postnatally, 2 ended in termination of pregnancy, 1 had multiple structural congenital abnormalities across several systems and was considered not to be a representative of the cohort, and 5 had insufficient data available for analysis. This left 85 fetuses with CCHB, seen in our institution from 1981 to 2013, with outcomes summarized in Figure 1 . Of the 60 patients not known to have died or undergone transplant, we have confirmed status within the last 3 years for 51, with an overall median follow-up of 13.1 years.
Eighty-five fetuses from 80 mothers were analyzed, including 1 pair of twins. The antenatal findings are summarized in Table 1 . The median ventricular rate for all attendances was 58 (range = 24 to 110). One fetus had a ventricular rate recorded of 110 as its only documented fetal heart rate, which we have been unable to reconfirm as the study was recorded on a now-obsolete technology. This fetus was treated with digoxin and furosemide but later died. The next highest heart rate recorded during the study was 90, occurring in 2 fetuses on 1 occasion each. Hydrops developed in 16 fetuses, of whom 8 died in utero and 5 died in early postnatal life. The remaining 3 are alive with pacemakers and without evidence of DCM.
| Variable | Total | Earlier era | Later era |
|---|---|---|---|
| Fetuses | 85 | 43 | 42 |
| Mothers | 80 | 40 | 40 |
| Median Maternal Age ( n , range) | 30 (80, 17-42) | 30 (38, 17-41) | 29 (42, 18-42) |
| Median Gestation at referral ( n , range) | 24 (85, 18-37) | 24 (43, 19-37) | 24.5 (42, 18-34) |
| Antibody status | |||
| Anti-Ro positive | 73 (86%) | 37 (86%) | 36 (86%) |
| Anti-La positive | 36 (42%) | 15 (35%) | 21 (50%) |
| Anti-Ro/La negative | 10 (12%) | 4 (9%) | 6 (14%) |
| Unknown | 2 (2%) | 2 (5%) | 0 |
| Maternal autoimmune disease | |||
| Systemic Lupus Erythematosus | 12 (14%) | 3 (7%) | 9 (21%) |
| Sjogren’s | 12 (14%) | 5 (12%) | 7 (17%) |
| Systemic Lupus Erythematosus and Sjogren’s | 3 (4%) | 0 | 3 (7%) |
| Other | 6 (7%) | 1 (2%) | 5 (12%) |
| None/ Unknown | 52 (61%) | 34 (79%) | 18 (43%) |
| Median initial ventricular rate ( n , range) | 60 (84, 43- 110) | 60 (42, 19- 110) | 59 (42, 43-78) |
| Hydrops | 16 (19%) | 12 (28%) | 4 (10%) |
| Antenatal treatment ∗ | |||
| Fluorinated Steroids | 8 | 6 | 2 |
| Beta Sympathomimetics | 4 | 2 | 2 |
| Both | 2 | 0 | 2 |
∗ In addition, 3 mothers received Prednisolone and 1 was treated with Digoxin and Furosemide.
From the cohort of 85 fetuses, 74 babies were liveborn to 71 mothers, with 47 girls and 27 boys. Delivery details are summarized in Table 2 . Eighty-six percent survived to delivery in the first half of the study and 90% in the latter half. The associated Kaplan-Meier plots are shown in Figures 2 and 3 as an analysis for survival to term, with those born prematurely censored at delivery, giving overall study survival rate to delivery at term of 87%, with 95% confidence intervals by Kaplan-Meier of 80% to 94%. Univariable analyses of risk factors for antenatal mortality are summarized in Table 3 .
| Variable | Total | Earlier era | Later era |
|---|---|---|---|
| Patients | 74 | 36 | 38 |
| Mothers | 71 | 34 | 37 |
| Median Gestation ( n , range) | 37 (71, 29-40) | 37.5 (34, 29-40) | 37 (37, 30-39) |
| Median Birthweight, kg ( n , range) | 2.78 (66, 1.28- 3.80) | 2.71 (30, 1.50-3.60) | 2.84 (36, 1.28- 3.80) |
| Sex (M/F) | 27/47 | 15/21 | 12/26 |
| Delivery method | |||
| Lower Segment Cesarian Section | 54 | 19 | 35 |
| Spontaneous Vaginal Delivery | 13 | 11 | 2 |
| Other assisted | 2 | 2 | 0 |
| Unknown | 5 | 4 | 1 |
| Median Initial Ventricular Rate ( n , 95% CI) | 60 (67, 30-102) | 56 (31, 30- 80) | 60 (36, 40- 102) |
| Dilated Cardiomyopathy | 6 | 6 | 0 |
| Variable | Delivered | IUD | Odds ratio (95% CI) | p value |
|---|---|---|---|---|
| Initial Ventricular Rate | 59.7 | 61.5 | 0.75 | |
| Final Ventricular Rate | 57.8 | 54.2 | 0.6 | |
| Hydrops | 8/74 | 8/11 | 20.6 (4.0- 146) | <0.001 ∗ |
| Antenatal treatment | 13/74 | 1/11 | 0.47 (0.01- 3.89) | 0.68 |
| Antenatal fluorinated steroids | 9/74 | 1/11 | 0.72 (0.02- 6.34) | 1.0 |
| Anti-Ro antibodies | 64/72 | 9/11 | 0.57 (0.09- 6.3) | 0.62 |
| Anti-La antibodies | 32/72 | 4/11 | 0.72 (0.1- 3.1) | 0.75 |
Pacemakers have been implanted in most patients, with a Kaplan-Meier–estimated freedom from pacemaker implantation of 10.6% at 15 years (95% confidence interval [CI] 4.6% to 24.5%) ( Figure 4 ). The median age of pacemaker implantation was 2.6 years, with 15 implanted in the neonatal period. Dates of pacemaker implantation were unknown for 2 patients, and they were, therefore, excluded from this analysis. Assessment of indications for pacemaker implantation against the American Heart Association guidelines shows that 37 pacemakers were implanted for class I indications and 10 for class IIa indications. The indication was unknown in 9 cases, with all having their pacemaker implanted in other units.
Twenty-nine of the 74 delivered patients had additional cardiac diagnoses, which are listed in Table 4 . There have been a total of 14 postnatal events, comprising 12 deaths, 1 transplant, and 1 death after transplant, with 6 deaths within the neonatal period (all born prematurely). Three of these 6 had been paced through temporary pacing wires. Three more died inside the first year of life, of which 2 were born prematurely and 2 had been paced. One additional patient underwent cardiac transplant before 1 year of age. Of the 4 deaths or transplant after 1 year of age, all had been paced, and 3 had DCM.
| Lesion | Intervention | |
|---|---|---|
| Yes | No | |
| Structurally normal heart | – | 45 |
| Atrial Septal Defect | 3 | 0 |
| Atrial Septal Defect and Pulmonary stenosis | 1 | 1 |
| Patent Ductus Arteriosus | 17 | 3 |
| Patent Ductus Arteriosus and Atrial Septal Defect | 2 | 0 |
| Patent Ductus Arteriosus and Ventricular Septal Defect | 1 | 1 |
The associated Kaplan-Meier curve for postnatal death or transplant is shown in Figure 5 and separated by eras in Figure 6 . The Kaplan-Meier estimate of transplant-free survival at 15 years after live birth was 81% (95% CI 72.5% to 91.2%) and at 30 years 76.8% (95% CI 65% to 90%). Overall transplant-free survival at 15 years after a diagnosis during fetal life was 71% (95% CI 62% to 82%). Statistical analyses performed for risk factors for postnatal mortality are listed in Table 5 . DCM has developed in 6 patients, of whom 2 have died, 1 died after transplant, and 1 alive after transplant. The remaining 2 patients with DCM have biventricular pacemakers in situ.
