PEDIATRICS Vol. 107 No. 6 June 2001, pp. 1277-1282

Impact of Prenatal Diagnosis on Survival and Early Neurologic Morbidity in Neonates With the Hypoplastic Left Heart Syndrome

William T. Mahle, MD^{*, §}, Robert R. Clancy, MD^{, §,} , Susan P. McGaurn, PharmD, James E. Goin, PhD^¶, and Bernard J. Clark, MD^{*, §}

From the Divisions of ^* Cardiology and  Neurology at the Children's Hospital of Philadelphia and the Departments of ^§ Pediatrics and  Neurology at the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and ^¶ DataMedix Corporation, Media, Pennsylvania.

	ABSTRACT

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Background.  Prenatal echocardiography can identify the fetus that has complex congenital heart disease and may improve early management and surgical outcome. Prenatal diagnosis may be particularly beneficial to patients who have hypoplastic left heart syndrome (HLHS) and who are at risk for hypoxic-ischemic insult at presentation.

Objectives.  We sought to determine whether prenatal diagnosis reduces neurologic morbidity and operative mortality in patients who undergo palliative surgery for the HLHS.

Methods.  Data from all patients who had HLHS, except for those with lethal genetic anomalies, and who were admitted to our institution between July 1992 and September 1997 were analyzed to assess the impact of prenatal diagnosis on preoperative management, neurologic morbidity, and surgical mortality. The primary outcome measures were hospital mortality and the incidence of adverse neurologic events (seizure or coma).

Results.  There were 216 patients who had HLHS and were referred for surgical palliation, 79 (36.6%) of whom had been diagnosed prenatally. All patients who had been diagnosed prenatally were delivered in an advanced nursery and were started on prostaglandin E₁ on the first day of life. Patients whose HLHS was diagnosed postnatally were begun on prostaglandin E₁ later in life (median = day 2 [range = 1-28 days]). There were 4 preoperative deaths and 53 operative or postoperative deaths. Overall hospital mortality was 26.4% and did not differ between patients whose HLHS had been diagnosed prenatally and those whose HLHS had been diagnosed postnatally. With the use of multivariable analysis, prenatal diagnosis was associated with fewer adverse perioperative neurologic events in the patients whose HLHS had been diagnosed prenatally than in those whose HLHS had been diagnosed postnatally (odds ratio = 0.46).

Conclusions.  These data suggest that prenatal diagnosis has a favorable impact on treatment of patients who have HLHS and are undergoing staged palliation and reduces early neurologic morbidity. Prenatal diagnosis was not associated with reduced hospital mortality. It is possible that prenatal diagnosis may improve long-term neurologic outcome.  Key words:  hypoplastic left heart syndrome, fetal echocardiography, neurologic outcome.

Prenatal echocardiography is being used with increasing frequency to identify complex congenital heart disease in the fetus.¹ It has been hypothesized that prenatal diagnosis of congenital heart disease might allow for optimal medical management in the newborn period, such as delivery in a high-risk neonatal center and prompt administration of prostaglandin for those who have ductal-dependent circulation.² Reducing the risk of preoperative hypoxic-ischemia may in turn improve surgical and neurologic outcome. Patients who have the hypoplastic left heart syndrome (HLHS) and its variants seem likely to benefit from prompt medical treatment. These infants often seem well at birth but may demonstrate rapid deterioration as the ductus arteriosus closes.³ Cardiovascular compromise may not occur until after the patient has been discharged to home from the nursery.

Reported mortality for those who undergo palliative surgery has ranged from 15% to 50%.^4-8 Previous studies suggested that delaying the palliative surgery may be associated with higher operative mortality.^4,8 Moreover, neurocognitive deficits in infancy, childhood, and adolescence are common in this patient population.^9-11 The occurrence of end-organ compromise related to cardiovascular impairment before surgical palliation also has been associated with later neurocognitive deficits.¹¹ We therefore hypothesized that prenatal diagnosis of HLHS may reduce the neurologic morbidity and mortality associated with delayed diagnosis in this patient population. The purpose of this study was to assess the impact of prenatal diagnosis on outcome in patients who have HLHS and are referred for staged palliation.

	METHODS

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Study Design

Between July 1992 and September 1997, all infants who had congenital heart defects that required surgery in the newborn period and deep hypothermic circulatory arrest and who were admitted were screened for enrollment in a single-center neuroprotection trial. Inclusion and exclusion criteria have been published elsewhere.¹² The present study included all patients who had HLHSpatients who were enrolled in the neuroprotection trial and patients who were not enrolledwith the exception of patients who had lethal genetic disorders.

Data from these patients were used to address the impact of prenatal diagnosis on early neurologic events and survival for neonates who require staged palliation for HLHS. The palliative surgery consisted of the stage I procedure as originally described by Norwood et al.¹³ The aortic arch was augmented with pulmonary homograft in all patients. A modified Blalock-Taussig shunt or central shunt was placed to provide pulmonary blood flow. No patient in this series underwent primary heart transplantation. For the purposes of this study, HLHS was defined as diminutive left ventricle and aortic hypoplasia.

The patient data included the prenatal diagnosis of congenital heart disease. In addition, we recorded characteristics of the labor and delivery, including Apgar scores and level of nursery where the patient was born (Table 1). A nursery was classified as advanced if it routinely provided mechanical ventilation for ill neonates. All other nurseries were deemed basic. Because the presence of genetic anomalies is a known risk factor for mortality at stage I surgery, all patients were evaluated for the presence of potential genetic defects. Genetic anomalies were classified as either dysmorphism or specific named genetic disorders.

Outcome Variables

The primary outcome variables in this study were mortality and the occurrence of adverse neurologic events before or within 6 weeks of palliative surgery. Outcome variables were recorded prospectively for all patients, regardless of enrollment status in the neuroprotection trial. A neurologic event was defined as either seizure or coma. Seizures were identified clinically with the use of established criteria of tonic, clonic, or myoclonic activity of a limb, trunk, or cranial muscle that could not be aborted by holding or repositioning of the involved body part. All intensive care nurses were certified in neonatal seizure identification with the use of instructional videotapes. Coma was identified by examination by a child neurologist: comatose infants exhibited no spontaneous or responsive eye opening on repeated observations. Therapeutically paralyzed infants were not evaluable for this endpoint. Interobserver reliability of mental status examinations was demonstrated serially during the study. The neurologic examination was performed without knowledge of the patient's status with regard to prenatal diagnosis. We also examined preoperative measures of hypoxic-ischemic injury such as the degree of acidosis and the occurrence of hepatic dysfunction, defined as an elevation of serum transaminase levels >3 times normal (aspartate aminotransferase >420 u/L, alanine aminotransferase >150 u/L). Last, we examined the relationship of prenatal diagnosis to length of hospital stay at our institution for survivors of palliative surgery.

Statistical Analysis

Data are characterized by sample size (N), proportion, mean, standard deviation, median, interquartile range (IQ), and range, where appropriate. Comparison of demographic and preoperative clinical data between the prenatally diagnosed and postnatally diagnosed groups was performed with ² test for categorical variables and a Wilcoxon rank sum test for continuous variables. Outcome data were analyzed with the use of Fisher's exact test, and missing Apgar scores (n = 26) were replaced by the mean of the available Apgar scores. Logistic regression models with and without the imputed Apgar scores are presented. Besides the prenatal/postnatal variable, only variables that demonstrated significant effect (P  .05) were included in the logistic models. Treatment assignment in the neuroprotection randomized trial and enrollment status were included as stratification variables in the logistic model. SAS (SAS Institute, Cary, NC) and SatXact (Cytel Software, Cambridge, MA) were used for analysis. All P values are 2-sided, and confidence intervals are 95%.

	RESULTS

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Patient Population

Between July 1992 and September 1997, 218 infants who had HLHS were admitted to the cardiac or neonatal intensive care units at our institution. Two infants initially were discharged to home from other institutions after their guardians chose nonintervention, but later were admitted to our hospital after the caregivers decided to pursue surgical palliation. These patients are not included in the analysis. The remaining 216 patients make up the study group. A prenatal diagnosis of HLHS was made in 79 patients (36.6%).

Preoperative Variables

All 79 patients (100.0%) whose HLHS had been diagnosed prenatally were delivered in an advanced obstetric setting. Only 58.9% of patients whose HLHS had been diagnosed postnatally were similarly delivered (P < .001; Table 2). Of the patients whose HLHS had been diagnosed postnatally, 13 (10.1%) were discharged to home from the nursery before diagnosis. The median Apgar scores at 1 minute were not significantly different between the 2 groups; however, the 5-minute Apgar scores were slightly lower in patients whose HLHS had been diagnosed prenatally. All of the patients whose HLHS had been diagnosed prenatally were started on prostaglandin E₁ (PGE₁) on the first day of life. The majority (77.9%) of patients whose HLHS had been diagnosed postnatally were started on PGE₁ within the first 3 days of life. There were, however, 11 patients (8.1%) who were not started on PGE₁ until after 7 days of life. For the patients whose HLHS had been diagnosed prenatally, the median age at admission to the Children's Hospital of Philadelphia was <24 hours as compared with 4 days for the patients whose HLHS had been diagnosed postnatally (P = .001; Table 3).

Complete blood gas data were available for 148 of the 216 patients (68.5%; Table 3). The group whose HLHS had been diagnosed postnatally demonstrated a more significant degree of metabolic acidosis. The mean value of the highest recorded base deficit in the group whose HLHS had been diagnosed postnatally was 7.6 mmol/dL as compared with 3.6 mmol/dL in the group whose HLHS had been diagnosed prenatally (P < .001). Dysmorphism was noted in 25 patients (11.6%), and named genetic syndromes were present in 11 (5.1%). There was no difference between the groups whose HLHS had been diagnosed prenatally and postnatally with respect to either dysmorphisms or named genetic syndromes. There also was no significant difference between the 2 groups with respect to intraoperative variables such as surgeon, duration of deep hypothermic circulatory arrest, or use of modified ultrafiltration. The median age at stage I surgery, however, was less for patients whose HLHS had been diagnosed prenatally (4 days vs 8 days; P < .0001).

Mortality and Neurologic Events

Four patients died before surgical intervention, 2 of whose HLHS had been diagnosed prenatally. The causes of death for these patients included necrotizing enterocolitis in 2 patients and sepsis in 1 patient; 1 patient was found to have significant ischemic neurologic injury. Because of the poor prognosis, the family elected to withdraw support. Overall operative mortality in the remaining 212 patients was 24.1%. Prenatal diagnosis was not associated with preoperative, operative, or overall mortality (Table 4). Factors that were associated with higher mortality in multivariable analysis included the presence of a named genetic syndrome and low Apgar scores at 5 minutes (Table 5). The incidence of seizures and coma in preoperative and postoperative periods for the patient subgroups are shown in Table 4. Forty-eight of 216 patients (22%) in this study had at least 1 neurologic event (seizure or coma). Multivariable analysis demonstrated fewer neurologic events (seizure or coma) in the patients whose HLHS had been diagnosed prenatally (P = .05; Table 6).

The median length of hospitalization for the study cohort was 21 days, and the median duration from surgery to discharge was 16.5 days. In the 2 study groups, there was no significant difference in the overall length of hospital stay or time from surgery to discharge (P = .65 and P = .51, respectively).

	DISCUSSION

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In the present study, prenatal diagnosis was associated with a reduction in adverse neurologic events in the perioperative period for neonates who had HLHS and were undergoing palliative surgery. Although a relatively small study group limits additional analysis, there seems to be a trend toward decreased preoperative and postoperative neurologic morbidity. A reduction in preoperative neurologic insult seems related to reduced hypoxic-ischemic insult at presentation. How prenatal diagnosis might reduce postoperative neurologic morbidity is less clear. One could hypothesize that some patients experience hypoxic-ischemic insult to the brain that lowers the threshold for postoperative neurologic injury. Preoperative electroencephalography and neuroimaging would corroborate this hypothesis.

Previous studies suggested that perioperative neurologic events, such as seizures, are predictive of long-term cognitive dysfunction. Several investigators found that postoperative seizures were associated with lower scores on standardized tests of cognitive function in patients who had transposition of the great arteries (TGA) and who underwent the arterial switch procedure in the newborn period.^14,15 In a retrospective analysis of school-aged and adolescent survivors who had HLHS, we found that the occurrence of seizures before stage I surgery was associated with lower scores on all IQ subtests.¹¹ Although the association of perioperative coma with neurologic outcome has not been studied in the congenital heart disease population, there is substantial literature linking coma and depressed neurologic status after neonatal asphyxia to later neurologic impairment.^16,17

The importance of reducing early neurologic injury cannot be overstated in the HLHS population. Several studies suggested that patients who have HLHS are at risk for scoring lower on standardized cognitive tests and developing long-term neurologic deficits. Rogers et al⁹ described major developmental sequelae in 7 of 11 patients (64%) who had HLHS. We found a median full scale IQ of 86 in an early cohort of patients who had HLHS and underwent staged surgical palliation.¹¹ Kern et al¹⁰ reported very similar findings in a more contemporary cohort. The cause of cognitive impairment in patients who have HLHS seems to be multifactorial with both developmental and acquired abnormalities detected. Neuropathologic studies have demonstrated acquired brain injury before surgery.¹⁸ Prenatal diagnosis may be most valuable in reducing this preoperative acquired insult.

Despite the association between prenatal diagnosis and acute neurologic events, prenatal diagnosis did not have a significant impact on operative survival. There are several possible explanations for this finding. These include the potential to improve hemodynamics and organ function with medical intervention in patients who have experienced a preoperative ischemic insult before proceeding to surgery. In addition, the stage I procedure involves technically complex arch reconstruction and is associated with a relatively long period of circulatory arrest even in patients who have optimal preoperative status.¹⁹ Last, the postoperative circulation requires a balance of systemic and pulmonary blood. Failure to maintain this balance can result in rapid hemodynamic deterioration.²⁰ Together, these factors may have a much greater impact on operative survival than the occurrence of preoperative ischemia. It is interesting to note that previous retrospective analyses failed to demonstrate a correlation between preoperative condition and survival after stage I palliation.^8,21 It must be recognized that although some of the patients whose HLHS had been diagnosed postnatally were discharged to home and presented in shock, the great majority of patients whose HLHS had been diagnosed postnatally were started on prostaglandin therapy within the first 3 days of life. This may represent an increased awareness of ductal-dependent lesions among nursery personnel.

Several previous studies examined the relationship between prenatal diagnosis and outcome for neonates who undergo open-heart surgery. Chang et al² demonstrated that prenatal diagnosis was associated with earlier transport of the neonate with critical left heart obstruction to a referral center and speculated that prenatal diagnosis might improve survival by reducing preoperative morbidity. Subsequent reports demonstrated that fetal diagnosis was associated with less preoperative acidosis and earlier age at surgery in patients who had obstructive left-sided lesions.^22,23 However, these smaller studies failed to demonstrate an improved outcome in patients whose HLHS had been diagnosed prenatally. Bonnet et al²⁴ recently demonstrated improved survival in patients whose TGA had been diagnosed prenatally. Although the findings of this European study are important to our study, they may not be generalizable to other geographic regions, such as North America. The median age at diagnosis in the postnatal group was 73 hours. This is later than what has been reported in North American referral centers in which most neonates who have TGA are admitted within 24 hours.^25,26 In addition, the preoperative mortality of 8% in the postnatal group is higher than the 3.7% to 4.1% reported in other contemporary series.^24,25 This difference may reflect variations in obstetric and neonatal management in these different geographic regions.

It has been suggested that prenatal diagnosis might have a favorable impact on length of stay in the hospital and perhaps justify fetal echocardiography on a cost-benefit basis. Copel et al²⁷ noted a trend toward lower costs and shorter length of stay in neonates whose HLHS had been diagnosed prenatally and who underwent 2-ventricle surgical repair. Although a detailed cost-benefit analysis was beyond the scope of this study, we did examine the relationship of prenatal diagnosis to length of hospitalization in the survivors of staged palliation for HLHS. There was no statistically significant difference between the 2 groups with respect to length of stay.

Although the aim of this study was to investigate the impact of prenatal diagnosis on mortality and neurologic events, the multivariable analysis demonstrated that several additional variables seem to have an impact on survival and neurologic morbidity. Interestingly, low Apgar scores at 5 minutes were associated with an increased mortality. Interpretation of these data are difficult because we and others have shown that there is a likely bias in determining Apgar scores among patients who have received a prenatal diagnosis of HLHS.²² Nonetheless, there are a small number of patients who demonstrate significant instability at the time of delivery (Apgar scores 5). This instability occurs even among patients whose HLHS is diagnosed prenatally and who are delivered in an advanced nursery. Last, genetic factors are an important risk factor for both mortality and neurologic events. It is worth noting that the incidence of genetic syndromes or dysmorphisms was no different between the groups whose HLHS had been diagnosed prenatally and postnatally.

Study Limitations

The major limitation to this study is that it is not population-based. The study patients were referred to our intensive care unit for surgery from a broad geographic area. We do not know the number of neonates who had HLHS and who may have died before diagnosis or the number who were not referred for palliative surgery for other reasons. Data from the Baltimore-Washington Infant Study suggest that the number of patients who have congenital heart disease and die before diagnosis is significant. These investigators estimated that between 1981 and 1989, 14% of patients who had HLHS died before diagnosis,²⁸ although data from a more recent population-based study in Quebec suggests that <2% of patients who had complex congenital heart disease died before diagnosis.²⁹ In addition, the identification of adverse neurologic events may have been influenced by several factors, including the use of paralyzing agents and the hemodynamic status of the patientwith critically ill patients being observed more closely. The identification of clinical seizures can be difficult. Using electroencephalography, previous investigators found a relatively high incidence of clinically silent seizures in neonates after open-heart surgery.³⁰ Last, there are other potential benefits of prenatal diagnosis that are not addressed in this article, such as the opportunity for elective termination or the emotional value of allowing a family to prepare for the challenges of caring for a child who has a complex heart disease.

Study Strengths

Data in this study were obtained prospectively. Patients were not excluded on the basis of comorbidities such as nonlethal genetic anomalies and low birth weight. Unlike a previous study in which the mortality for stage I surgery approached 50%,²² the 25% mortality in this series is comparable to results from several of the larger centers in the current era. The study design also will allow for neurocognitive evaluation of these patients as they reach school age. This is important because many children who had no obvious neurologic event in the perioperative period have been found to have neurologic and cognitive deficits at later follow-up.

	CONCLUSION

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Prenatal diagnosis is associated with favorable changes in preoperative management and fewer perioperative neurologic events in neonates who have HLHS and are undergoing stage I palliation. Operative mortality and hospital stay were not affected by prenatal diagnosis. Additional follow-up will be necessary to determine whether prenatal diagnosis affects later cognitive function.

	ACKNOWLEDGMENT

This work was supported in part by a grant from the National Institutes of Health (NIH-N01-NS-1-2315).

	FOOTNOTES

Received for publication Jun 1, 2000; accepted Sep 27, 2000.

Reprint requests to (W.T.M.) Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA 19072. E-mail: mahle{at}email.chop.edu

	ABBREVIATIONS

HLHS, hypoplastic left heart syndrome; IQ, interquartile range; PGE₁, prostaglandin E₁; TGA, transposition of the great arteries.

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