Claire Irving

Twenty-year trends in prevalence and survival of Down syndrome

The aims of this study were (1) to determine trends in total prevalence and live birth prevalence of Down syndrome, (2) to analyse trends in factors likely to influence this prevalence and (3) to determine 1-year survival in Down syndrome. A retrospective review was made of prospectively collected data on all cases of Down syndrome within a malformation registry born in 1985–2004. Down syndrome affected 1188 pregnancies among 690 215 live births (1.72 per 1000 total births). The proportion increased over 20 years from 1.3 to 2.5 per 1000 total births (P<0.0001). There were 389 terminations for Down syndrome and 51 stillbirths. There were 748 live births with Down syndrome (1.08 per 1000 live births). The live birth prevalence declined in 1985–1994 and increased in 1995–2004 with no overall change. Total live births in the population declined by 20% over 20 years. Mothers delivering at 35 years of age or above increased from 6 to 15%. The uptake of maternal serum screening increased from zero in 1987 to 35% in 1993 but then plateaued. One-year survival of live births with Down syndrome increased, especially in babies with cardiovascular malformations, reaching almost 100%. The prevalence of pregnancies affected by Down syndrome has increased significantly, but there has been no overall change in live birth prevalence. Increasing maternal age and improved survival of children with Down syndrome have offset the effects of prenatal diagnosis followed by the termination of pregnancy and declining general birth rate.

Changes in fetal prevalence and outcome for trisomies 13 and 18: a population-based study over 23 years

Objective. Changes in prenatal diagnosis and maternal age are likely to have an impact on live born prevalence of trisomies 13 and 18. We investigated trends in diagnosis, prevalence, and survival in these conditions. Methods. A population-based study of one UK health region in 1985–2007 using a well-established congenital abnormality register. Individual records were reviewed and live birth and maternal age data obtained. Results. Pregnancies with trisomies 13 and 18 increased from 0.08 to 0.23 per 1000 registered births and 0.20 to 0.65 per 1000 registered births, respectively. Prenatal diagnosis increased and was associated with high termination rates. Live born prevalence with trisomy 13 decreased from 0.05 to 0.03 per 1000 live births and with trisomy 18 from 0.16 to 0.10 per 1000 live births. Postnatal survival remains poor: one baby (3%) with trisomy 13 and four (6%) with trisomy 18 survived the first year. The percentage of mothers over 35 years increased from 6 to 15%. Conclusions. Changes in prenatal screening and maternal age have had dramatic effects on the live born prevalence of trisomies 13 and 18. Infant survival remains largely unchanged with the majority dying in the neonatal period.

Cardiovascular abnormalities in Down's syndrome: spectrum, management and survival over 22 years

Background The prevalence of cardiovascular anomalies in Downs syndrome is well described, but there are few data on spectrum, management and outcome. The authors aimed to provide this information for infants with Downs syndrome in a defined population over a 22-year period. Methods The regional paediatric cardiology database in Newcastle upon Tyne provided information on all cardiovascular anomalies, surgical treatment and outcome. Data was subdivided into two eras, 1985–1995 and 1996–2006, and surgical results and outcomes compared. Data on live births with Downs syndrome were obtained from the Northern Congenital Abnormality Survey (NorCAS). Denominator data on all live births in the region were obtained from UK Statistics. Results In 1985–2006 there were 754,486 live births in the population. 821 infants were live-born with Downs syndrome (1.09 per 1000 live births). 342 (42%) infants with Downs syndrome had a cardiovascular anomaly. The commonest anomaly was complete atrioventricular septal defect in 125 (37%) infants. Three patients had univentricular physiology. In 1985–1995, 101/163 (62%) infants had surgery with 30% mortality; in 1996–2006, 129/180 (72%) had surgery with 5% mortality. One patient underwent Fontan completion. There were two cardiac transplants for cardiomyopathy. One-year survival in Downs syndrome with a cardiovascular anomaly improved from 82% in 1985–1995 to 94% in 1996–2006. Conclusions The incidence of cardiovascular anomalies in Downs syndrome was 42%. There has been a significant reduction in postoperative mortality and improvement in 1-year survival. Treatment modalities such as single ventricle palliation and cardiac transplantation are now considered in these patients.

Successful Bridge to Transplant With the Berlin Heart After Cavopulmonary Shunt

Mechanical cardiac assistance for infants and children may be accomplished using extracorporeal membrane oxygenation or ventricular assist device support, and are now well established as a bridge to cardiac transplantation or recovery in biventricular hearts, usually in the setting of low cardiac output states due to cardiomyopathy or acute myocarditis. Ventricular assist device support remains less well described in the setting of single ventricle physiology. We report the case of a 3-year-old girl who developed severe right ventricular failure 2 years after cavopulmonary shunt after an initial Stage I Norwood operation for hypoplastic left heart syndrome. She was successfully supported to cardiac transplantation using a single chamber Berlin Heart EXCOR ventricular assist device using right ventricular apex and aortic cannulation and is now well at home 10 months after transplant.

Donor-specific HLA antibodies in paediatric cardiac transplant recipients are associated with poor graft survival

Irving C, Carter V, Parry G, Hasan A, Kirk R. Donor‐specific HLA antibodies in paediatric cardiac transplant recipients are associated with poor graft survival.
Pediatr Transplantation 2011: 15:193–197.

Effect of persistent versus transient donor-specific HLA antibodies on graft outcomes in pediatric cardiac transplantation

BACKGROUND De novo donor-specific HLA antibodies (DSA) are a risk for poor graft outcomes, but there is little evidence of their long-term effect in pediatric cardiac transplantation or of the effect of transient versus persistent DSA found using newer antibody testing methods. METHODS Archived serum samples were obtained from patients <18 years of age who underwent primary cardiac transplantation during the period from 1996 to 2009. Luminex antibody testing was performed at 3 months, 6 months and 1 year post-transplant, and then annually. Outcomes including cardiac allograft vasculopathy (CAV), rejection and graft loss were correlated with the presence or absence of DSA or non-donor-specific HLA (non-DSA) antibodies. RESULTS Six hundred ninety-one samples from 108 patients, with mean age at transplant of 7.4 (0.1 to 15.9) years and mean follow-up 8.2 (1.9 to 15.7) years, were studied. Forty-three (40%) patients had DSA (which were persistent in 58%), 41 (38%) had non-DSA (persistent in 46%) and 24 (22%) had no antibodies. In those with DSA, 30% had Class I antibodies, 47% Class II and 23% both Class I and II, whereas, in the subgroup with persistent DSA, 88% had Class II antibodies. There were 14 cases of graft loss, 9 of these in patients with persistent DSA. All had Class II antibodies. There was an increased incidence of CAV, rejection and graft loss in those with persistent DSA. Outcomes were similar between the group with non-DSA antibodies and the group with no antibodies. CONCLUSIONS De novo HLA antibodies are detectable post-transplant in the majority of patients, but non-DSA and transient DSA do not appear to be associated with poor outcomes. Patients with persistent DSA, especially those with Class II DQ antibodies, have worse survival.

Outcomes following infant listing for cardiac transplantation: the impact of strategies introduced to counteract limited donor availability

Background Survival following cardiac transplantation in infancy has improved substantially. There is a growing shortage of donors, the impact of which may be offset by increase in ABO-incompatible transplants, size-mismatching and mechanical support. The authors reviewed their results and outcomes following infant listing for cardiac transplantation over 22 years. Methods Children <12 months at time of listing for cardiac transplant in 1987–2008 were identified using the departmental cardiopulmonary transplant database. Details were obtained from databases and hospital medical records and subdivided into two eras, 1987–1997 and 1998–2008. Results In 1987–2008, 49 infants were listed, and 28 (57%) underwent cardiac transplantation (12 in 1987–1997 and 16 in 1998–2008). 15 patients (31%) died on the waiting list, 6 patients were delisted (5 of these because of recovery of cardiac function). There was a decrease in suitable donor offers from a mean of 36 per year in 1996–2000 to 11 per year in 2001–2006 (p=0.008). In 1998–2008, nine listed infants were on mechanical support; there were seven ABO-incompatible transplants, and all transplants were size-mismatched with donors on average 2.7 times heavier than recipients. Waiting times decreased from median 83 to 47 days. Six (21%) of the transplanted patients died, the majority in 1987–1997 and perioperatively. Conclusions There has been a fall in suitable donors for infant cardiac transplants over time despite increased demand. However, the introduction of size-mismatching, ABO-incompatible transplants and mechanical support has enabled an increase in the number of transplants to be carried out despite this fall in donor numbers. Outcomes following transplantation have improved over time.

Fatal presentation of congenital isolated left ventricular apical hypoplasia

Congenital isolated left ventricular apical hypoplasia has recently been recognised as a discrete clinical entity with well-defined diagnostic criteria on cardiac magnetic resonance imaging. This spectrum has been described in four previous cases, three of which presented with relatively mild symptoms and one with pulmonary oedema. All of these patients responded to standard medical management. We describe a sudden and fatal presentation of this anomaly in a previously well 19-year-old male, confirming the fact that this is not a benign condition but a spectrum with the potential for significant complications.

Pushing the boundaries: The current status of ABO-incompatible cardiac transplantation

Since the introduction of intentional ABO-incompatible (ABOi) cardiac transplantation in infants in the late 1990s, the number of patients listed for and undergoing ABOi transplants has increased. This practice has been shown to lead to a reduction in waiting list mortality and increased utilisation of donor organs with equivalent outcomes to ABO-compatible transplants. Differences in the infant immune system provide a window of opportunity for ABOi transplantation. However it is increasingly clear that older patients and those with significant amounts of blood group antibody specific isohaemagglutinins may also benefit. Newer research is now focussing on longer term outcomes of ABOi transplants - in particular the development of graft accommodation or tolerance. This review assesses the current status of ABO-incompatible cardiac transplantation both in infants and in sensitized and older patients.

ABO-incompatible cardiac transplantation in pediatric patients with high isohemagglutinin titers

BACKGROUND ABO-incompatible (ABOi) cardiac transplantation is now used widely in infants with isohemagglutinin titers <1:4, but there is increasing evidence that ABOi transplantation can also be used in children with significantly higher titers. We reviewed our high-titer ABOi transplants and report our results here. METHODS Patients who underwent ABOi cardiac transplantation from 2000 to 2013 with pre-existing isohemagglutinin titers of ≥1:16 were identified from departmental databases. Outcomes were reviewed using medical and laboratory records. RESULTS Thirty patients underwent ABOi cardiac transplantation between 2000 and 2013. Twelve (40%) had pre-transplant isohemagglutinin titers of ≥1:16 and were included for further study. Median age was 14.9 (range 9.8 to 107.3) months and median weight was 9.6 (range 7.6 to 25) kg. Five (42%) were male. Pre-transplant diagnosis was cardiomyopathy in 8 of 12 (67%) and congenital heart disease in 4 of 12 (33%). Highest pre-transplant isohemagglutinin titer was 1:256 in 2 patients. Four patients (33%) had early antibody-mediated rejection (AMR), all within 15 days post-transplant. Management included use of rituximab, bortezomib, immunoadsorption and eculizumab. Three patients died but no deaths were associated with high isohemagglutinin titers. CONCLUSIONS ABOi cardiac transplantation in patients with isohemagglutinin titers ≥1:16 is possible. AMR may occur early and immunoadsorption has proven effective at decreasing antibody titers.