- Email: [email protected]
Long-term neurodevelopmental outcome after fetal arrhythmia
Research
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OBSTETRICS
Long-term neurodevelopmental outcome after fetal arrhythmia Enrico Lopriore, MD, PhD; Muhammed I. Aziz, MD; Helene T. Nagel, MD, PhD; Nico A. Blom, MD, PhD; Lieke Rozendaal, MD; Humphrey H. H. Kanhai, MD, PhD; Frank P. H. A. Vandenbussche, MD, PhD OBJECTIVE: The purpose of this study was to determine the long-term
neurodevelopmental outcome in fetuses with severe tachy- or bradyarrhythmia. STUDY DESIGN: This was a follow-up study to assess the neurologic, men-
tal, and psychomotor development in cases with fetal cardiac arrhythmia. RESULTS: A total of 44 fetuses were diagnosed with fetal tachy- or brady-
arrhythmia: 28 fetuses had supraventricular tachycardia (SVT); 7 fetuses had atrial flutter (AF), and 9 fetuses had atrioventricular block (AVB). The mortality rate was low (6%; 2/35 fetuses) in the SVT and AF groups and
high in the AVB group (78%; 7/9 fetuses). Six patients were lost to follow-up evaluation (14%). Neurodevelopmental outcome was normal in all survivors in the SVT and AF groups, except for 1 patient who experienced plexus brachialis injury because of shoulder dystocia. Two of the 3 survivors in the AVB group had severe developmental delay. CONCLUSION: The mortality rate and neurodevelopmental impairment
in infants with SVT and AF are low, but the mortality rate in infants with AVB is elevated. Key words: arrhythmia, mortality rate, neurodevelopment
Cite this article as: Lopriore E, Aziz MI, Nagel HT, et al. Long-term neurodevelopmental outcome after fetal arrhythmia. Am J Obstet Gynecol 2009;201:46.e1-5.
F
etal cardiac arrhythmias are common in clinical practice, with a frequency that ranges from 1-3% of all pregnancies. Most of these arrhythmias reflect transient, isolated ectopic beats. However, sustained episodes of tachy- or bradyarrhythmia may also occur and can lead, if not treated appropriately, to congestive heart failure, hydrops, fetal or
From the Division of Neonatology, Department of Pediatrics (Dr Lopriore); the Division of Fetal Medicine, Department of Obstetrics (Drs Aziz, Kanhai, and Vandenbussche); and the Department of Pediatric Cardiology (Drs Blom and Rozendaal), Leiden University Medical Center, Leiden, and the Department of Obstetrics and Gynecology, Bronovo Hospital, The Hague (Dr Nagel), The Netherlands. Received Aug. 20, 2008; revised Nov. 14, 2008; accepted Feb. 11, 2009. Reprints: E. Lopriore, MD, PhD, Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands. [email protected]. Authorship and contribution to the manuscript is limited to the 7 authors indicated. There was no outside funding or technical assistance with the production of this article. 0002-9378/$36.00 © 2009 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2009.02.002
46.e1
neonatal death, or severe neurologic morbidity in survivors.1-7 The most common forms of fetal tachycardias are supraventricular tachycardia (SVT), atrial flutter (AF), or sinus tachycardia. Most fetal SVTs are atrioventricular reentrant tachycardias that involve an accessory atrioventricular myocardial pathway. The most common form of fetal bradycardia is complete atrioventricular block (AVB). Structural heart defects are found in one-third of AVB cases. In the other two-thirds of cases, AVB often results from autoimmune-mediated injury to the fetal conduction system because of maternal anti–SS-A/SS-B antibodies. Complete AVB associated with complex congenital heart disease or fetal hydrops has a very poor prognosis.1-3 Severe fetal cardiac arrhythmia may lead to cerebral injury and neurologic morbidity because of dysfunction of cerebrovascular autoregulation.6-8 However, only few neurodevelopmental follow-up studies have been performed after fetal tachycardia or fetal bradycardia.8-10 The aim of this study was to evaluate the long-term neurodevelopmental outcome of fetuses with severe tachy- or bradyarrhythmia diagnosed at our center.
M ETHODS Patients We searched both our antenatal and neonatal databases for infants with in
American Journal of Obstetrics & Gynecology JULY 2009
utero cardiac arrhythmia that was diagnosed between January 1990 and December 2005 at our center. Leiden University Medical Center is a tertiary fetal referral center. In this time period, the management protocol included a complete work up with ultrasound examination and consultation of the pediatric cardiologist. Fetal ultrasound included detailed anatomic imaging of the fetal heart to diagnose or exclude cardiac defects. Routine karyotype was obtained in fetuses with suspected structural heart disease. SVT as a result of atrioventricular reentrant tachycardia was diagnosed if there was a 1:1 atrioventricular conduction observed at a rate of 200-300 beats/min. AF was diagnosed when the atrial rate was 300-450 beats/min. Ventricular rates in AF depended on the degree of atrioventricular conduction block, usually 200-300 beats/min. The highest (peak) fetal heart rate was noted to give an indication of the severity of the tachycardia. AVB was classified as second-degree or complete AVB based on M-mode registrations. Fetal hydrops was defined as a fluid collection that was visible on ultrasound in ⱖ 2 cavities of the fetal body (generalized edema, ascites, and pleural or pericardial effusions).11 Maternal serum antibody titers (anticardiolipin antibodies, anti-SS-A/Ro and anti-SS-
Obstetrics
www.AJOG.org B/La) were obtained in case of a heart block. Antiarrhythmic therapy was started when arrhythmias were sustained or associated with hemodynamic compromise at ⬍ 34 weeks of pregnancy. After 34 weeks gestation, such cases were delivered. A baseline electrocardiography of the mother was obtained before the treatment started, and maternal cardiac monitoring was conducted during the loading period to detect early signs of toxicity. During the study period, the following drugs were used: digoxin, sotalol, flecainide, amiodarone, and adenosine. Digoxin was administered to the mother in adjusted oral doses to maintain a maternal serum therapeutic level of 1-2 ng/mL (loading dose, 2 ⫻ 0.75 mg; maintenance, 0.25-0.5 mg; maximum, 0.75 mg/daily). Flecainide (oral dose, 200 mg-400 mg daily), and sotalol (oral dose, 2 times daily 80-160 mg) were used as secondary agents. Amiodarone was administered by combined direct fetal intravenous and maternal oral and intravenous route. Direct fetal amiodarone therapy consisted of amiodarone on the basis of estimated fetal weight (10 mg/ kg). In some cases, adenosine was given intravenously (0.1 mg/kg) as direct fetal therapy just before the amiodarone therapy. Drugs to treat AVB that were given to the mother included ritodrine (intravenously 9 mg/hr), dexamethasone (4 mg daily), and fenoterol (intravenously 150 g/hr).
Long-term follow-up evaluation After approval of the protocol by the institutional review board of the Leiden University Medical Center, family physicians were contacted by letter to explain the aims and nature of the study. After consultation with the family physician, the parents were sent an explanatory letter that requested their permission to review all medical records and their cooperation for testing the children. Parents were asked to fill out the Dutch translation of the Child Behavior Check List (CBCL), which is a validated questionnaire for the assessment of behavioral/ emotional problems. At the subsequent consultation, the child was examined by a pediatric cardiologist and a psycholo-
gist. Neurologic examination was performed by a pediatrician. Cerebral palsy was defined according to the European Cerebral Palsy Network and classified as diplegia, hemiplegia, quadriplegia, dyskinetic, or mixed.12 In children who were 6-30 months old, cognitive and neuromotor development was assessed by the Dutch version of the Bayley Scales of Infant Development, 2nd edition.13,14 Mental scales are converted to a mental developmental index, and motor scales are converted to a psychomotor developmental index. The mean score for both mental developmental index, and the psychomotor developmental index is 100. A score ⬍ 70 is ⬎ 2 standard deviations below the mean score and indicates severe developmental delay. In children 2.5-16 years old, the intelligence scores were assessed with the Snijders-Oomen Non-Verbal Intelligence Test-Revised (SON-R).15 Scores are calculated as performance scale and reasoning scale. Raw subtest scores are standardized with population, and agespecific scores are standardized with a mean value of 100 and a standard deviation of 15. The SON-R has been validated for Dutch and Belgian children. Total test scores are depicted as IQscores with confidence intervals. Neurodevelopmental impairment was defined as any of the following outcomes: neurologic injury (including cerebral palsy), deafness, blindness, or mental or psychomotor development index of the Bayley Scales of Infant Development, 2nd edition, or SON-R ⬎ 2 standard deviations below the normal mean.
R ESULTS Study population characteristics During the 16-year study period, 44 pregnancies were referred to our center because of sustained fetal tachy- or bradyarrhythmia. Derivation and outcome of the 44 fetuses with arrhythmias is shown in the Figure. Perinatal characteristics of the studied population are presented in Table 1. This study included no fetuses with ventricular tachycardia. The mechanism of SVT was atrioventricular reentrant tachycardia in all cases.
Research
Hydrops at the time of diagnosis was present in 39% (11/28) of SVT cases. There were no fetal deaths in the SVT group and 1 termination of pregnancy for trisomy 21 in the AF group. One infant in the SVT group with cardiomyopathy and encephalopathy because of hydroxyglutaric aciduria died at 5 months old. In the AVB group (n ⫽ 9), presence of fetal hydrops was identified in 44% (4/9) of the cases. Two children had autoimmune-associated AVB; 2 children had a severe form of long QT syndrome (LQTS 8 or Timothy syndrome), and 5 children had complex congenital heart malformations. Mortality rate in the AVB group was high (78%; 7/9). There were 3 fetal deaths and 4 postnatal deaths. The 3 fetal deaths were due to termination of pregnancy (n ⫽ 2); 1 intrauterine fetal death occurred with congenitally corrected transposition of the great arteries (cc-TGA). One infant with AVB because of maternal antibodies survived up to 1.5 years after birth. A pacemaker was placed, but she had cardiomyopathy and died during a period with fever and pneumonia. Another child received a pacemaker immediately after birth because of a third-grade AVB but died on day 2. Postmortem analysis showed endocardial fibroelastosis. One infant with a severe form of long QT syndrome received a pacemaker after birth but died at 4 weeks old because of persistent ventricular fibrillation. Another infant with a severe form of long QT syndrome died at 2 years of age, which was 1 month after the complete follow-up examination had been performed.
Long-term follow-up evaluation Neurodevelopmental outcome was assessed in 29 survivors. Six infants (14%) were lost to follow up. At the time of neurodevelopmental assessment, the median age of the children was 80 months (range, 6 months to 15 years). In the SVT group, 23 children were examined; 4 infants were lost to follow up. No cases still required drug therapy; no cases were treated with catheter ablation after the first year of life. Wolff Parkinson White syndrome was demonstrated on electrocardiography in 3 of 23 chil-
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dren. Neurodevelopmental assessment scores were within the normal range in 14 children (61%) and above average in 9 children (39%). Neurologic examination was normal in all children. The CBCL was indicative of behavioral problems in 3 children. These children were offered closer attention by the hospitals psychologist. In the AF group, 5 of the 6 children remained free of arrhythmia symptoms. Four of 5 children underwent neurodevelopmental examination. A 5-year-old child had a right-sided Erb’s palsy because of brachial plexus injury after shoulder dystocia. Neurodevelopmental assessment scores were all within the normal range. The CBCL was within normal range for all children. In the AVB group, 1 child was lost to follow up. This child had cc-TGA and received a pacemaker at the age of 6 years. Medical records showed that the child was in good condition at the age of 9 years. Two survivors in the AVB group had neurodevelopmental impairment. One infant had a severe form of long QT syndrome and received a pacemaker and an implantable cardioverter defibrillator afterwards. Neurodevelopmental assessment at 2 years old showed severe mental and motor retardation. The electrocardiogram showed extreme QT prolongation and T-wave alternans. He had recurrent implantable cardioverter defibrillator shocks for torsade des pointes and died at the age of 2 years 1 month of ventricular arrhythmia and cardiomyopathy after stellectomy of the left ganglion stellatum. The other infant had congenital cardiac anomalies (ventricular septal defect, left to right shunt and hypertrophic cardiomyopathy) and required pacemaker implantation. At 3 years old, the child had severe developmental delay. A summary of the results of long-term follow-up assessment is presented in Table 2.
C OMMENT In this study we describe the neurologic and developmental outcomes in a cohort of infants with fetal arrhythmia. Overall outcome in the group of infants with SVT and AF was good. The 46.e3
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FIGURE
Flowchart Fetuses with arrhythmia n = 44
a
Supraventricular tachycardia n = 28
Atrial flutter n=7
Atrioventricular block n=9
Termination of pregnancy n=0
Termination of pregnancy n=1
Termination of pregnancy n=2
Intrauterine fetal death n=0
Intrauterine fetal death n=0
Intrauterine fetal death n=1
Neonatal death n=0
Neonatal death n=0
Neonatal death n=2
Infant death n=1
Infant death n=0
Infant death n = 2a
Long-term follow-up n = 23
Long-term follow-up n=4
Long-term follow-up n = 2a
1 infant died 1 month after long-term follow-up evaluation.
Lopriore. Neurodevelopmental outcome after arrhythmia. Am J Obstet Gynecol 2009.
mortality rate was low (3%) and was limited to a case with cardiomyopathy and encephalopathy because of hydroxyglutaric aciduria. Neurodevelopmental assessment was normal in all survivors, except for 1 patient (because of plexus brachialis injury after shoulder dystocia). In contrast, overall outcome in the group of infants with AVB was poor. Mortality rate was high (78%), and 2 of the 3 survivors had severe developmental delay.
American Journal of Obstetrics & Gynecology JULY 2009
According to Schade et al,6 fetuses with tachyarrhythmia and subsequent hydrops may be at increased risk for cerebral injury because of the circulatory disturbances and sudden changes in heart rate that may lead to fluctuations in cerebral perfusion. Immediate and complete control of the fetal heart rate in the treatment of tachyarrhythmia therefore may be of utmost importance. Transplacental or direct fetal therapy of the arrhythmia is probably preferable to pre-
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Research
TABLE 1
Characteristics of the study population (n ⴝ 44) by type of arrhythmia Supraventricular tachycardia (n ⴝ 28)
Variable
Atrioventricular block (n ⴝ 9)
Atrial flutter (n ⴝ 7)
Female (n)
11 (39%)
4 (57%)
5 (55%)
Gestational age at diagnosis of arrhythmia (wk)
29 (18-40)
30 (24-38)
23 (12-37)
247 (200-400)
237 (200-250)
55 (45-70)
................................................................................................................................................................................................................................................................................................................................................................................ a ................................................................................................................................................................................................................................................................................................................................................................................ a
Peak/slowest fetal heart rate (beats/min)
................................................................................................................................................................................................................................................................................................................................................................................
Fetal hydrops (n)
11 (39%)
0
4 (44%)
Antenatal maternal or fetal drug therapy (n)
16 (62%)
3 (43%)
3 (33%)
Duration of antenatal therapy (d)
56 (12-95)
49 (43-96)
33 (12-93)
Gestational age at birth (wk)
38 (30-42)
37 (36-38)
36 (30-40)
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ a ................................................................................................................................................................................................................................................................................................................................................................................ a ................................................................................................................................................................................................................................................................................................................................................................................ a
Birthweight (g)
2993 (1547-3965)
3282 (2530-4726)
2704 (2300-3470)
................................................................................................................................................................................................................................................................................................................................................................................ a
Value given as median (range).
Lopriore. Neurodevelopmental outcome after arrhythmia. Am J Obstet Gynecol 2009.
mature delivery because of the neonatal complications, especially in cases with hydrops.16 Only few follow-up studies have reported on the long-term neurodevelopmental outcome in children who are born after fetal arrhythmia. In 2003, Boldt et al1 reported on long-term outcome of fetuses with SVT (n ⫽ 21), AF (n ⫽ 13), and AVB (n ⫽ 36).1 In accordance with our results, the mortality rate in the group with SVT and AF was low (9%). However, in contrast with our study, the rate of neurologic injury in survivors was high (16%). The mortality rate in the AVB group was lower compared with our cohort (25% vs 78%), and only 1 of the 27 survivors (4%) had neurologic injury. However, special care must be taken when comparing the re-
sults, because discrepancy may partly be due to different methods, selection criteria, and definitions for neurodevelopmental impairment. In the study from Boldt et al, the methods that were used to determine neurologic outcome were not specified, and neurodevelopmental assessment was not performed, which are important limitations. Moreover, only 17% of infants (4/36) in the AVB group had complex congenital heart malformations, compared with 56% of infants (5/9) in our AVB cohort. In accordance with our results, the mortality rate in the 4 infants with AVB and complex congenital heart malformation was high (75%; 3/4).1 Jaeggi et al17 studied the outcome in a large series of AVB cases (n ⫽ 59) with and without associated major
structural congenital heart disease. In concordance with our results, 1-year survival rate in the AVB group with congenital heart disease was only 19%, compared with 75% in cases with isolated AVB (P ⬍ .0001).17 The authors conclude that AVB that is associated with major structural heart disease other than cc-TGA has an extremely poor outcome.17 Patients with LQTS 8 or Timothy syndrome with or without second-degree AVB have a poor postnatal outcome because of lethal ventricular arrhythmias, which was also demonstrated in our series. Long-term neurodevelopmental outcome in survivors after AVB was not evaluated in the report from Jaeggi et al.17 Besides complex congenital heart malformations, several other confounding vari-
TABLE 2
Long-term neurodevelopmental outcome and psychologic characteristics Variable
Supraventricular tachycardia (n ⴝ 23)
Atrial flutter (n ⴝ 4)
Atrioventricular Block (n ⴝ 2)
Total (n ⴝ 29)
Median follow-up time (mo)a
91 (6-186)
62 (21-96)
28 (25-32)
80 (6-186)
................................................................................................................................................................................................................................................................................................................................................................................
Neurologic injury (n)
0
1 (25%)
0
1 (3%)
Severe developmental delay (n)
0
0
2 (100%)
2 (7%)
Neurodevelopmental impairment (n)
0
1 (25%)
2 (100%)
3 (10%)
CBCL indicative of need for extra attention (n)
3 (13%)
0
1 (50%)
4 (14%)
................................................................................................................................................................................................................................................................................................................................................................................ b ................................................................................................................................................................................................................................................................................................................................................................................ c ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
CBCL, Child Behavior Check List. a
Data are given as median (range); b mental or psychomotor development index of the Bayley Scales of Infant Development, 2nd edition, with ⬍ 2 standard deviations, or Snijders-Oomen Non-Verbal Intelligence Test-Revised, with ⬍ 2 standard deviations; c neurologic injury, deafness, blindness, or severe developmental delay.
Lopriore. Neurodevelopmental outcome after arrhythmia. Am J Obstet Gynecol 2009.
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ables may be related to adverse longterm outcome, including prematurity and fetal hydrops. Breur et al9 recently assessed the longterm neurologic outcome in 10 fetuses with isolated congenital AVB and fetal hydrops. Mortality rate was 50% (5/10). Neurologic outcome in the 5 surviving AVB cases was normal. However, standardized neurocognitive testing was not performed, which is a limitation of the study. Favorable outcome could also be due to the selection of only isolated AVB cases. Brucato et al10 studied the long-term neurodevelopmental outcome in 13 infants with isolated AVB who were exposed to high-dose dexamethasone in utero, whose mothers were anti–Ro/SSA positive. The authors found no negative effects on the neuropsychologic development. Favorable outcome could be due to the fact that only 1 infant in this cohort had associated fetal hydrops. In conclusion, mortality rates in SVT and AF patients in our study were low, and long-term neurodevelopmental outcome was normal in all survivors. In contrast, mortality and morbidity rates in AVB patients were high, which warrants longterm follow-up evaluation. An important limitation of our study is the small size of our population, which is inherent to this disease. Given the low incidence of severe fetal tachy- or bradyarrhythmia, large multicenter studies with long-term follow-up
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www.AJOG.org evaluation are required to determine accurately the neurodevelopmental outcome in f this risk group. ACKNOWLEDGMENT We thank R.H. Meerman for managing our fetal data base.
REFERENCES 1. Boldt T, Eronen M, Andersson S. Long-term outcome in fetuses with cardiac arrhythmias. Obstet Gynecol 2003;102:1372-9. 2. Simpson JM, Sharland GK. Fetal tachycardias: management and outcome of 127 consecutive cases. Heart 1998;79:576-81. 3. Eronen M, Heikkila P, Teramo K. Congenital complete heart block in the fetus: hemodynamic features, antenatal treatment, and outcome in six cases. Pediatr Cardiol 2001; 22:385-92. 4. Vlagsma R, Hallensleben E, Meijboom EJ. [Supraventricular tachycardia and premature atrial contractions in fetus]. Ned Tijdschr Geneeskd 2001;145:295-9. 5. van Engelen AD, Weijtens O, Brenner JI, et al. Management outcome and follow-up of fetal tachycardia. J Am Coll Cardiol 1994;24: 1371-5. 6. Schade RP, Stoutenbeek P, de Vries LS, Meijboom EJ. Neurological morbidity after fetal supraventricular tachyarrhythmia. Ultrasound Obstet Gynecol 1999;13:43-7. 7. Sonesson SE, Winberg P, Lidegran M, Westgren M. Foetal supraventricular tachycardia and cerebral complications. Acta Paediatr 1996; 85:1249-52. 8. Oudijk MA, Gooskens RH, Stoutenbeek P, de Vries LS, Visser GH, Meijboom EJ. Neurological outcome of children who were treated for fetal tachycardia complicated by hydrops. Ultrasound Obstet Gynecol 2004;24:154-8.
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9. Breur JM, Gooskens RH, Kapusta L, et al. Neurological outcome in isolated congenital heart block and hydrops fetalis. Fetal Diagn Ther 2007;22:457-61. 10. Brucato A, Astori MG, Cimaz R, et al. Normal neuropsychological development in children with congenital complete heart block who may or may not be exposed to high-dose dexamethasone in utero. Ann Rheum Dis 2006; 65:1422-6. 11. Phibbs RH. Hydrops fetalis and other causes of neonatal edema and ascites. In: Polin RA. Fox WW, eds. Fetal and neonatal physiology. Philadelphia, PA: Saunders; 1992:131925. 12. Surveillance of Cerebral Palsy in Europe (SCPE). Surveillance of cerebral palsy in Europe: a collaboration of cerebral palsy surveys and registers. Dev Med Child Neurol 2000; 42:816-24. 13. Harris SR, Megens AM, Backman CL, Hayes VE. Stability of the Bayley II Scales of Infant Development in a sample of low-risk and high-risk infants. Dev Med Child Neurol 2005;47:820-3. 14. Voigt RG, Brown FR III, Fraley JK, et al. Concurrent and predictive validity of the cognitive adaptive test/clinical linguistic and auditory milestone scale (CAT/CLAMS) and the Mental Developmental Index of the Bayley Scales of Infant Development. Clin Pediatr (Phila) 2003;42:427-32. 15. Harris SH. An evaluation of the SnijdersOomen Nonverbal Intelligence Scale for Young Children. J Pediatr Psychol 1982;7:239-51. 16. Cuneo BF. Outcome of fetal cardiac defects. Curr Opin Pediatr 2006;18:490-6. 17. Jaeggi ET, Hornberger LK, Smallhorn JF, Fouron JC. Prenatal diagnosis of complete atrioventricular block associated with structural heart disease: combined experience of two tertiary care centers and review of the literature. Ultrasound Obstet Gynecol 2005; 26:16-21.
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OBSTETRICS
Long-term neurodevelopmental outcome after fetal arrhythmia Enrico Lopriore, MD, PhD; Muhammed I. Aziz, MD; Helene T. Nagel, MD, PhD; Nico A. Blom, MD, PhD; Lieke Rozendaal, MD; Humphrey H. H. Kanhai, MD, PhD; Frank P. H. A. Vandenbussche, MD, PhD OBJECTIVE: The purpose of this study was to determine the long-term
neurodevelopmental outcome in fetuses with severe tachy- or bradyarrhythmia. STUDY DESIGN: This was a follow-up study to assess the neurologic, men-
tal, and psychomotor development in cases with fetal cardiac arrhythmia. RESULTS: A total of 44 fetuses were diagnosed with fetal tachy- or brady-
arrhythmia: 28 fetuses had supraventricular tachycardia (SVT); 7 fetuses had atrial flutter (AF), and 9 fetuses had atrioventricular block (AVB). The mortality rate was low (6%; 2/35 fetuses) in the SVT and AF groups and
high in the AVB group (78%; 7/9 fetuses). Six patients were lost to follow-up evaluation (14%). Neurodevelopmental outcome was normal in all survivors in the SVT and AF groups, except for 1 patient who experienced plexus brachialis injury because of shoulder dystocia. Two of the 3 survivors in the AVB group had severe developmental delay. CONCLUSION: The mortality rate and neurodevelopmental impairment
in infants with SVT and AF are low, but the mortality rate in infants with AVB is elevated. Key words: arrhythmia, mortality rate, neurodevelopment
Cite this article as: Lopriore E, Aziz MI, Nagel HT, et al. Long-term neurodevelopmental outcome after fetal arrhythmia. Am J Obstet Gynecol 2009;201:46.e1-5.
F
etal cardiac arrhythmias are common in clinical practice, with a frequency that ranges from 1-3% of all pregnancies. Most of these arrhythmias reflect transient, isolated ectopic beats. However, sustained episodes of tachy- or bradyarrhythmia may also occur and can lead, if not treated appropriately, to congestive heart failure, hydrops, fetal or
From the Division of Neonatology, Department of Pediatrics (Dr Lopriore); the Division of Fetal Medicine, Department of Obstetrics (Drs Aziz, Kanhai, and Vandenbussche); and the Department of Pediatric Cardiology (Drs Blom and Rozendaal), Leiden University Medical Center, Leiden, and the Department of Obstetrics and Gynecology, Bronovo Hospital, The Hague (Dr Nagel), The Netherlands. Received Aug. 20, 2008; revised Nov. 14, 2008; accepted Feb. 11, 2009. Reprints: E. Lopriore, MD, PhD, Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands. [email protected]. Authorship and contribution to the manuscript is limited to the 7 authors indicated. There was no outside funding or technical assistance with the production of this article. 0002-9378/$36.00 © 2009 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2009.02.002
46.e1
neonatal death, or severe neurologic morbidity in survivors.1-7 The most common forms of fetal tachycardias are supraventricular tachycardia (SVT), atrial flutter (AF), or sinus tachycardia. Most fetal SVTs are atrioventricular reentrant tachycardias that involve an accessory atrioventricular myocardial pathway. The most common form of fetal bradycardia is complete atrioventricular block (AVB). Structural heart defects are found in one-third of AVB cases. In the other two-thirds of cases, AVB often results from autoimmune-mediated injury to the fetal conduction system because of maternal anti–SS-A/SS-B antibodies. Complete AVB associated with complex congenital heart disease or fetal hydrops has a very poor prognosis.1-3 Severe fetal cardiac arrhythmia may lead to cerebral injury and neurologic morbidity because of dysfunction of cerebrovascular autoregulation.6-8 However, only few neurodevelopmental follow-up studies have been performed after fetal tachycardia or fetal bradycardia.8-10 The aim of this study was to evaluate the long-term neurodevelopmental outcome of fetuses with severe tachy- or bradyarrhythmia diagnosed at our center.
M ETHODS Patients We searched both our antenatal and neonatal databases for infants with in
American Journal of Obstetrics & Gynecology JULY 2009
utero cardiac arrhythmia that was diagnosed between January 1990 and December 2005 at our center. Leiden University Medical Center is a tertiary fetal referral center. In this time period, the management protocol included a complete work up with ultrasound examination and consultation of the pediatric cardiologist. Fetal ultrasound included detailed anatomic imaging of the fetal heart to diagnose or exclude cardiac defects. Routine karyotype was obtained in fetuses with suspected structural heart disease. SVT as a result of atrioventricular reentrant tachycardia was diagnosed if there was a 1:1 atrioventricular conduction observed at a rate of 200-300 beats/min. AF was diagnosed when the atrial rate was 300-450 beats/min. Ventricular rates in AF depended on the degree of atrioventricular conduction block, usually 200-300 beats/min. The highest (peak) fetal heart rate was noted to give an indication of the severity of the tachycardia. AVB was classified as second-degree or complete AVB based on M-mode registrations. Fetal hydrops was defined as a fluid collection that was visible on ultrasound in ⱖ 2 cavities of the fetal body (generalized edema, ascites, and pleural or pericardial effusions).11 Maternal serum antibody titers (anticardiolipin antibodies, anti-SS-A/Ro and anti-SS-
Obstetrics
www.AJOG.org B/La) were obtained in case of a heart block. Antiarrhythmic therapy was started when arrhythmias were sustained or associated with hemodynamic compromise at ⬍ 34 weeks of pregnancy. After 34 weeks gestation, such cases were delivered. A baseline electrocardiography of the mother was obtained before the treatment started, and maternal cardiac monitoring was conducted during the loading period to detect early signs of toxicity. During the study period, the following drugs were used: digoxin, sotalol, flecainide, amiodarone, and adenosine. Digoxin was administered to the mother in adjusted oral doses to maintain a maternal serum therapeutic level of 1-2 ng/mL (loading dose, 2 ⫻ 0.75 mg; maintenance, 0.25-0.5 mg; maximum, 0.75 mg/daily). Flecainide (oral dose, 200 mg-400 mg daily), and sotalol (oral dose, 2 times daily 80-160 mg) were used as secondary agents. Amiodarone was administered by combined direct fetal intravenous and maternal oral and intravenous route. Direct fetal amiodarone therapy consisted of amiodarone on the basis of estimated fetal weight (10 mg/ kg). In some cases, adenosine was given intravenously (0.1 mg/kg) as direct fetal therapy just before the amiodarone therapy. Drugs to treat AVB that were given to the mother included ritodrine (intravenously 9 mg/hr), dexamethasone (4 mg daily), and fenoterol (intravenously 150 g/hr).
Long-term follow-up evaluation After approval of the protocol by the institutional review board of the Leiden University Medical Center, family physicians were contacted by letter to explain the aims and nature of the study. After consultation with the family physician, the parents were sent an explanatory letter that requested their permission to review all medical records and their cooperation for testing the children. Parents were asked to fill out the Dutch translation of the Child Behavior Check List (CBCL), which is a validated questionnaire for the assessment of behavioral/ emotional problems. At the subsequent consultation, the child was examined by a pediatric cardiologist and a psycholo-
gist. Neurologic examination was performed by a pediatrician. Cerebral palsy was defined according to the European Cerebral Palsy Network and classified as diplegia, hemiplegia, quadriplegia, dyskinetic, or mixed.12 In children who were 6-30 months old, cognitive and neuromotor development was assessed by the Dutch version of the Bayley Scales of Infant Development, 2nd edition.13,14 Mental scales are converted to a mental developmental index, and motor scales are converted to a psychomotor developmental index. The mean score for both mental developmental index, and the psychomotor developmental index is 100. A score ⬍ 70 is ⬎ 2 standard deviations below the mean score and indicates severe developmental delay. In children 2.5-16 years old, the intelligence scores were assessed with the Snijders-Oomen Non-Verbal Intelligence Test-Revised (SON-R).15 Scores are calculated as performance scale and reasoning scale. Raw subtest scores are standardized with population, and agespecific scores are standardized with a mean value of 100 and a standard deviation of 15. The SON-R has been validated for Dutch and Belgian children. Total test scores are depicted as IQscores with confidence intervals. Neurodevelopmental impairment was defined as any of the following outcomes: neurologic injury (including cerebral palsy), deafness, blindness, or mental or psychomotor development index of the Bayley Scales of Infant Development, 2nd edition, or SON-R ⬎ 2 standard deviations below the normal mean.
R ESULTS Study population characteristics During the 16-year study period, 44 pregnancies were referred to our center because of sustained fetal tachy- or bradyarrhythmia. Derivation and outcome of the 44 fetuses with arrhythmias is shown in the Figure. Perinatal characteristics of the studied population are presented in Table 1. This study included no fetuses with ventricular tachycardia. The mechanism of SVT was atrioventricular reentrant tachycardia in all cases.
Research
Hydrops at the time of diagnosis was present in 39% (11/28) of SVT cases. There were no fetal deaths in the SVT group and 1 termination of pregnancy for trisomy 21 in the AF group. One infant in the SVT group with cardiomyopathy and encephalopathy because of hydroxyglutaric aciduria died at 5 months old. In the AVB group (n ⫽ 9), presence of fetal hydrops was identified in 44% (4/9) of the cases. Two children had autoimmune-associated AVB; 2 children had a severe form of long QT syndrome (LQTS 8 or Timothy syndrome), and 5 children had complex congenital heart malformations. Mortality rate in the AVB group was high (78%; 7/9). There were 3 fetal deaths and 4 postnatal deaths. The 3 fetal deaths were due to termination of pregnancy (n ⫽ 2); 1 intrauterine fetal death occurred with congenitally corrected transposition of the great arteries (cc-TGA). One infant with AVB because of maternal antibodies survived up to 1.5 years after birth. A pacemaker was placed, but she had cardiomyopathy and died during a period with fever and pneumonia. Another child received a pacemaker immediately after birth because of a third-grade AVB but died on day 2. Postmortem analysis showed endocardial fibroelastosis. One infant with a severe form of long QT syndrome received a pacemaker after birth but died at 4 weeks old because of persistent ventricular fibrillation. Another infant with a severe form of long QT syndrome died at 2 years of age, which was 1 month after the complete follow-up examination had been performed.
Long-term follow-up evaluation Neurodevelopmental outcome was assessed in 29 survivors. Six infants (14%) were lost to follow up. At the time of neurodevelopmental assessment, the median age of the children was 80 months (range, 6 months to 15 years). In the SVT group, 23 children were examined; 4 infants were lost to follow up. No cases still required drug therapy; no cases were treated with catheter ablation after the first year of life. Wolff Parkinson White syndrome was demonstrated on electrocardiography in 3 of 23 chil-
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dren. Neurodevelopmental assessment scores were within the normal range in 14 children (61%) and above average in 9 children (39%). Neurologic examination was normal in all children. The CBCL was indicative of behavioral problems in 3 children. These children were offered closer attention by the hospitals psychologist. In the AF group, 5 of the 6 children remained free of arrhythmia symptoms. Four of 5 children underwent neurodevelopmental examination. A 5-year-old child had a right-sided Erb’s palsy because of brachial plexus injury after shoulder dystocia. Neurodevelopmental assessment scores were all within the normal range. The CBCL was within normal range for all children. In the AVB group, 1 child was lost to follow up. This child had cc-TGA and received a pacemaker at the age of 6 years. Medical records showed that the child was in good condition at the age of 9 years. Two survivors in the AVB group had neurodevelopmental impairment. One infant had a severe form of long QT syndrome and received a pacemaker and an implantable cardioverter defibrillator afterwards. Neurodevelopmental assessment at 2 years old showed severe mental and motor retardation. The electrocardiogram showed extreme QT prolongation and T-wave alternans. He had recurrent implantable cardioverter defibrillator shocks for torsade des pointes and died at the age of 2 years 1 month of ventricular arrhythmia and cardiomyopathy after stellectomy of the left ganglion stellatum. The other infant had congenital cardiac anomalies (ventricular septal defect, left to right shunt and hypertrophic cardiomyopathy) and required pacemaker implantation. At 3 years old, the child had severe developmental delay. A summary of the results of long-term follow-up assessment is presented in Table 2.
C OMMENT In this study we describe the neurologic and developmental outcomes in a cohort of infants with fetal arrhythmia. Overall outcome in the group of infants with SVT and AF was good. The 46.e3
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FIGURE
Flowchart Fetuses with arrhythmia n = 44
a
Supraventricular tachycardia n = 28
Atrial flutter n=7
Atrioventricular block n=9
Termination of pregnancy n=0
Termination of pregnancy n=1
Termination of pregnancy n=2
Intrauterine fetal death n=0
Intrauterine fetal death n=0
Intrauterine fetal death n=1
Neonatal death n=0
Neonatal death n=0
Neonatal death n=2
Infant death n=1
Infant death n=0
Infant death n = 2a
Long-term follow-up n = 23
Long-term follow-up n=4
Long-term follow-up n = 2a
1 infant died 1 month after long-term follow-up evaluation.
Lopriore. Neurodevelopmental outcome after arrhythmia. Am J Obstet Gynecol 2009.
mortality rate was low (3%) and was limited to a case with cardiomyopathy and encephalopathy because of hydroxyglutaric aciduria. Neurodevelopmental assessment was normal in all survivors, except for 1 patient (because of plexus brachialis injury after shoulder dystocia). In contrast, overall outcome in the group of infants with AVB was poor. Mortality rate was high (78%), and 2 of the 3 survivors had severe developmental delay.
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According to Schade et al,6 fetuses with tachyarrhythmia and subsequent hydrops may be at increased risk for cerebral injury because of the circulatory disturbances and sudden changes in heart rate that may lead to fluctuations in cerebral perfusion. Immediate and complete control of the fetal heart rate in the treatment of tachyarrhythmia therefore may be of utmost importance. Transplacental or direct fetal therapy of the arrhythmia is probably preferable to pre-
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TABLE 1
Characteristics of the study population (n ⴝ 44) by type of arrhythmia Supraventricular tachycardia (n ⴝ 28)
Variable
Atrioventricular block (n ⴝ 9)
Atrial flutter (n ⴝ 7)
Female (n)
11 (39%)
4 (57%)
5 (55%)
Gestational age at diagnosis of arrhythmia (wk)
29 (18-40)
30 (24-38)
23 (12-37)
247 (200-400)
237 (200-250)
55 (45-70)
................................................................................................................................................................................................................................................................................................................................................................................ a ................................................................................................................................................................................................................................................................................................................................................................................ a
Peak/slowest fetal heart rate (beats/min)
................................................................................................................................................................................................................................................................................................................................................................................
Fetal hydrops (n)
11 (39%)
0
4 (44%)
Antenatal maternal or fetal drug therapy (n)
16 (62%)
3 (43%)
3 (33%)
Duration of antenatal therapy (d)
56 (12-95)
49 (43-96)
33 (12-93)
Gestational age at birth (wk)
38 (30-42)
37 (36-38)
36 (30-40)
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ a ................................................................................................................................................................................................................................................................................................................................................................................ a ................................................................................................................................................................................................................................................................................................................................................................................ a
Birthweight (g)
2993 (1547-3965)
3282 (2530-4726)
2704 (2300-3470)
................................................................................................................................................................................................................................................................................................................................................................................ a
Value given as median (range).
Lopriore. Neurodevelopmental outcome after arrhythmia. Am J Obstet Gynecol 2009.
mature delivery because of the neonatal complications, especially in cases with hydrops.16 Only few follow-up studies have reported on the long-term neurodevelopmental outcome in children who are born after fetal arrhythmia. In 2003, Boldt et al1 reported on long-term outcome of fetuses with SVT (n ⫽ 21), AF (n ⫽ 13), and AVB (n ⫽ 36).1 In accordance with our results, the mortality rate in the group with SVT and AF was low (9%). However, in contrast with our study, the rate of neurologic injury in survivors was high (16%). The mortality rate in the AVB group was lower compared with our cohort (25% vs 78%), and only 1 of the 27 survivors (4%) had neurologic injury. However, special care must be taken when comparing the re-
sults, because discrepancy may partly be due to different methods, selection criteria, and definitions for neurodevelopmental impairment. In the study from Boldt et al, the methods that were used to determine neurologic outcome were not specified, and neurodevelopmental assessment was not performed, which are important limitations. Moreover, only 17% of infants (4/36) in the AVB group had complex congenital heart malformations, compared with 56% of infants (5/9) in our AVB cohort. In accordance with our results, the mortality rate in the 4 infants with AVB and complex congenital heart malformation was high (75%; 3/4).1 Jaeggi et al17 studied the outcome in a large series of AVB cases (n ⫽ 59) with and without associated major
structural congenital heart disease. In concordance with our results, 1-year survival rate in the AVB group with congenital heart disease was only 19%, compared with 75% in cases with isolated AVB (P ⬍ .0001).17 The authors conclude that AVB that is associated with major structural heart disease other than cc-TGA has an extremely poor outcome.17 Patients with LQTS 8 or Timothy syndrome with or without second-degree AVB have a poor postnatal outcome because of lethal ventricular arrhythmias, which was also demonstrated in our series. Long-term neurodevelopmental outcome in survivors after AVB was not evaluated in the report from Jaeggi et al.17 Besides complex congenital heart malformations, several other confounding vari-
TABLE 2
Long-term neurodevelopmental outcome and psychologic characteristics Variable
Supraventricular tachycardia (n ⴝ 23)
Atrial flutter (n ⴝ 4)
Atrioventricular Block (n ⴝ 2)
Total (n ⴝ 29)
Median follow-up time (mo)a
91 (6-186)
62 (21-96)
28 (25-32)
80 (6-186)
................................................................................................................................................................................................................................................................................................................................................................................
Neurologic injury (n)
0
1 (25%)
0
1 (3%)
Severe developmental delay (n)
0
0
2 (100%)
2 (7%)
Neurodevelopmental impairment (n)
0
1 (25%)
2 (100%)
3 (10%)
CBCL indicative of need for extra attention (n)
3 (13%)
0
1 (50%)
4 (14%)
................................................................................................................................................................................................................................................................................................................................................................................ b ................................................................................................................................................................................................................................................................................................................................................................................ c ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
CBCL, Child Behavior Check List. a
Data are given as median (range); b mental or psychomotor development index of the Bayley Scales of Infant Development, 2nd edition, with ⬍ 2 standard deviations, or Snijders-Oomen Non-Verbal Intelligence Test-Revised, with ⬍ 2 standard deviations; c neurologic injury, deafness, blindness, or severe developmental delay.
Lopriore. Neurodevelopmental outcome after arrhythmia. Am J Obstet Gynecol 2009.
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ables may be related to adverse longterm outcome, including prematurity and fetal hydrops. Breur et al9 recently assessed the longterm neurologic outcome in 10 fetuses with isolated congenital AVB and fetal hydrops. Mortality rate was 50% (5/10). Neurologic outcome in the 5 surviving AVB cases was normal. However, standardized neurocognitive testing was not performed, which is a limitation of the study. Favorable outcome could also be due to the selection of only isolated AVB cases. Brucato et al10 studied the long-term neurodevelopmental outcome in 13 infants with isolated AVB who were exposed to high-dose dexamethasone in utero, whose mothers were anti–Ro/SSA positive. The authors found no negative effects on the neuropsychologic development. Favorable outcome could be due to the fact that only 1 infant in this cohort had associated fetal hydrops. In conclusion, mortality rates in SVT and AF patients in our study were low, and long-term neurodevelopmental outcome was normal in all survivors. In contrast, mortality and morbidity rates in AVB patients were high, which warrants longterm follow-up evaluation. An important limitation of our study is the small size of our population, which is inherent to this disease. Given the low incidence of severe fetal tachy- or bradyarrhythmia, large multicenter studies with long-term follow-up
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www.AJOG.org evaluation are required to determine accurately the neurodevelopmental outcome in f this risk group. ACKNOWLEDGMENT We thank R.H. Meerman for managing our fetal data base.
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9. Breur JM, Gooskens RH, Kapusta L, et al. Neurological outcome in isolated congenital heart block and hydrops fetalis. Fetal Diagn Ther 2007;22:457-61. 10. Brucato A, Astori MG, Cimaz R, et al. Normal neuropsychological development in children with congenital complete heart block who may or may not be exposed to high-dose dexamethasone in utero. Ann Rheum Dis 2006; 65:1422-6. 11. Phibbs RH. Hydrops fetalis and other causes of neonatal edema and ascites. In: Polin RA. Fox WW, eds. Fetal and neonatal physiology. Philadelphia, PA: Saunders; 1992:131925. 12. Surveillance of Cerebral Palsy in Europe (SCPE). Surveillance of cerebral palsy in Europe: a collaboration of cerebral palsy surveys and registers. Dev Med Child Neurol 2000; 42:816-24. 13. Harris SR, Megens AM, Backman CL, Hayes VE. Stability of the Bayley II Scales of Infant Development in a sample of low-risk and high-risk infants. Dev Med Child Neurol 2005;47:820-3. 14. Voigt RG, Brown FR III, Fraley JK, et al. Concurrent and predictive validity of the cognitive adaptive test/clinical linguistic and auditory milestone scale (CAT/CLAMS) and the Mental Developmental Index of the Bayley Scales of Infant Development. Clin Pediatr (Phila) 2003;42:427-32. 15. Harris SH. An evaluation of the SnijdersOomen Nonverbal Intelligence Scale for Young Children. J Pediatr Psychol 1982;7:239-51. 16. Cuneo BF. Outcome of fetal cardiac defects. Curr Opin Pediatr 2006;18:490-6. 17. Jaeggi ET, Hornberger LK, Smallhorn JF, Fouron JC. Prenatal diagnosis of complete atrioventricular block associated with structural heart disease: combined experience of two tertiary care centers and review of the literature. Ultrasound Obstet Gynecol 2005; 26:16-21.