We have demonstrated that prenatal echocardiographic diagnosis of atrial septal restriction is associated with a significant survival disadvantage, with increased early and late mortality in these patients in comparison with prenatally diagnosed patients without evidence of left atrial hypertension. In terms of overall mortality, early mortality (prior to stage 1 palliation (S1P)) accounted for most of the observed difference; however for patients who were live born and survived to undergo S1P there was still proportionately lower survival at 2 years in those diagnosed with atrial restriction prenatally (60% vs. 83%), and though this difference did not achieve statistical significance this may have been due to the relatively small numbers of patients in the cohort. Additionally, there were a disproportionate number of interstage deaths in the patients identified in fetal life with any degree of restriction. The majority of the early and late deaths in our cohort were in the severely restrictive by prenatal echocardiographic criteria; fetuses with mild-moderate atrial septal restriction in utero had similar postoperative courses and 2 year survival to the group with no restriction, though there was proportionately more deaths prior to completion of superior cavopulmonary anastamoses in the restrictive group as a whole including 2/7 of the mild/moderately restrictive patients. On a descriptive basis, of those who lived to undergo S1P, 5/7(71%) mild/moderate restriction patients, and 1/3(33%) severe restriction patients survived to 2 years, versus 29/35(83%) survival for non-restrictive patients; our study did not have sufficient power to analyze the apparent difference in proportions from a statistical standpoint. However if larger studies can demonstrate a difference between mild/moderate restriction and no restriction in these patients it would suggest that there are factors other than relief of the atrial obstruction alone, that continue to confer disadvantage to these patients after they have undergone S1P.
Our early results with exclusively prenatally diagnosed patients with severe restriction are similar to those presented by Glatz et al.5
in 2007. This retrospective study of both prenatal and postnatal presentation showed that prenatal diagnosis versus postnatal diagnosis, did not improve initial hospital survival or cumulative survival for any degree of atrial restriction. In this single-center series, all seven patients diagnosed prenatally with severe restriction underwent immediate (surgical or catheter based) intervention with an overall survival to hospital discharge of 28%. Although the study did not evaluate longer term outcome, the estimated two year cumulative survival of all patients with severe restriction postnatally indicated only ~20% survival at two years. Interestingly, and similar to our experience, they also reported an unusually high late mortality in those with moderate restriction, with a three-year cumulative survival of 60%. However, they included preterm infants and infants with known or suspected genetic syndromes, factors that have previously been shown to independently affect outcome in HLHS14
, thus this may influence their analysis of morbidity and mortality. In contrast, in a study by Vlahos et al.,
the postnatal courses of 33 babies born with HLHS and a restrictive or intact septum that needed immediate postnatal intervention were described12
. They reported that those who survived the neonatal period had late survival, pulmonary artery pressure, and pulmonary vascular resistance similar to those of control subjects. However only 16 (48%) of the patients in that study had prenatal diagnosis of HLHS, and those who did not require postnatal urgent atrial decompression were not included, making their results difficult to compare directly with ours.
Additional somewhat better short-term survival for neonates who require left atrial decompression prior to S1P was described in 2007 by Vida et al.6
in a group of patients with HLHS and severely restrictive or intact atrial septum undergoing prenatal or postnatal atrial decompression followed by S1P. They reported an overall survival of 69% to hospital discharge. In this cohort, prenatal diagnosis alone was not associated with improved survival versus historical controls, but infants who had undergone prenatal intervention (some of whom also required postnatal atrial decompression) had improved hospital survival of 79% compared with 61% of infants treated only postnatally. Interstage mortality was reported at 23% and Kaplan-Meier survival estimate at 6 months of age was 49%. Importantly, fetuses and neonates with moderate restriction who did not undergo atrial decompression were not included in this report. This again limits comparison of this prior study with our cohort with diagnosis of restriction based on fetal echocardiographic characteristics but decision to intervene based on criteria related to severity of clinical presentation at birth.
Therefore, our patients' early outcomes in the face of severe restriction are in keeping with what has previously been published; further supporting that prenatal echocardiographic diagnosis of atrial septal restriction in the setting of HLHS is associated with a significant survival disadvantage5,6,15
. Indeed, there was no observed difference in the perioperative morbidity and mortality between their cohorts and ours5,6,15
. Our data additionally identify a new group of at-risk patients, however-- those diagnosed prenatally with some degree of restriction but who do not require atrial decompression on an urgent basis postnatally. ROC analysis for forward:reverse VTI ratio suggested a cutoff value of 5.1:1 was associated with the best positive predictive value for need for immediate intervention, similar to the previously published work by Michfelder et al10
. Unfortunately pulmonary venous Doppler forward to reverse VTI ratio was less useful in predicting 2 year survival in our cohort.
It is well known that severe restriction at the atrial level in fetuses with HLHS causes increased arterial medial thickness with muscular extension to the smaller respiratory arterioles4,16
leading to lymphangiectasia, poor pulmonary mechanics and poor outcomes in the immediate postnatal period. We speculate that there may be differences in pulmonary vasculature at birth, which may in some cases be clinically important beyond the immediate perinatal period, and suggest further study. Whether prenatal intervention could potentially reduce the pathological pulmonary process and thus improve both neonatal and longer-term outcomes in patients with restrictive atrial septum diagnosed in-utero remains unknown. Recently, fetal intervention for HLHS with an intact septum or a highly restrictive septum 17
has been preliminarily investigated by the group at Boston Children's Hospital with a hope that prenatal decompression of the left atrium will mitigate the development of adverse pulmonary venous remodeling4
. In 2008, Marshall et al.
reported results of a highly select group of patients with prenatal detection of intact or severely restrictive atrial septum and HLHS undergoing intervention at a median gestational age of 29 weeks (range, 23–34 weeks)17
. Though a high rate of technical success was achieved, there were 2 fetal deaths associated with the procedure and a substantial number of patients needed additional atrial decompression at birth prior to S1P. Further, there was no overall improvement in survival associated with a prenatal procedure. Ongoing research in this area is suggested given the uniformly poor outcomes with postnatal intervention.
Our study has a number of limitations. We chose to analyze the two groups' S1P surgical variables and outcomes in an as-treated manner, excluding those that were intended to, but did not actually undergo S1P. An intent-to-treat analysis would have however only exaggerated the difference in “surgical” survival, while not contributing to the operative or postoperative variables analyzed (i.e. bypass times, ventilator days, length of stay). Low survival to the BDG precluded meaningful analysis of preoperative and postoperative characteristics in this cohort, which might have shed some light on the etiology of poorer survival. The retrospective design led to limited availability of echocardiographic information in some patients. There was however no clear difference in ascertainment of restriction on fetal echocardiograms related to era. In addition this single-center experience with a relatively rare disease was underpowered to detect differences in survival within sub-classifications of restriction, limiting this analysis to a descriptive one; furthermore, the 10-year span may have confounded morbidity and mortality data given improvements in operative and postoperative care during this time period. Larger multicenter studies will be necessary to determine whether the decreased survival in patients with left atrial hypertension in utero who are hemodynamically stable after birth (without urgent atrial decompression) truly have decreased long-term survival as suggested by our results. If the observation holds true, additional investigation may be warranted to determine whether prenatal intervention to decompress the left atrium with the intention of mitigating or reversing pulmonary vascular changes during fetal life will improve long-term prognosis.