The cerebroplacental Doppler ratio predicts postnatal outcome in fetuses with congenital heart block

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1 ORIGINAL ARTICLE The cerebroplacental Doppler ratio predicts postnatal outcome in fetuses with congenital heart block GA Fleming 1, A Bircher 2, A Kavanaugh-McHugh 1 and MR Liske 1 (2008) 28, r 2008 Nature Publishing Group All rights reserved /08 $ Division of Pediatric Cardiology, Department of Pediatrics, Monroe Carell Jr Children s Hospital, Vanderbilt University, Nashville, TN, USA and 2 Division of Medical Genetics, Department of Pediatrics, Monroe Carell Jr Children s Hospital, Vanderbilt University, Nashville, TN, USA Objective: Autoimmune-mediated congenital complete heart block (CCHB) is associated with significant perinatal morbidity and mortality, and prenatal monitoring of these fetuses is a significant challenge. The cerebroplacental Doppler ratio (CPR), defined as the ratio of the middle cerebral artery pulsatility index (MCA-PI) to the umbilical artery pulsatility index (UA-PI), is predictive of perinatal outcome in growth-restricted fetuses. This study tests the hypothesis that the CPR would be useful in monitoring fetal well-being in fetuses with CCHB. Study Design: We reviewed data on all patients diagnosed prenatally with autoimmune-mediated CCHB at our institution over the past 2 years. The fetal echocardiograms from each patient were analyzed for: CPR, UA-PI, MCA-PI, cardiothoracic ratio, degree of tricuspid regurgitation, ventricular function and presence of effusions. We compared hemodynamic data from the fetal echocardiogram before delivery in patients who required urgent pacemaker placement postnatally to those patients that did not require an urgent pacemaker. Result: Five patients with autoimmune-mediated CCHB were identified, and two patients required urgent pacemaker placement. The CPR before delivery was significantly lower in the patients who required urgent pacemaker placement (0.97±0.06 versus 1.45±0.03; P ¼ 0.003), but there was no difference in other fetal echocardiographic markers between groups. Both patients requiring urgent pacemaker placement had a CPR less than Conclusion: The CPR is predictive of postnatal outcome in fetuses with CCHB and is useful in prenatal monitoring of these patients. (2008) 28, ; doi: /jp ; published online 14 August 2008 Keywords: cerebroplacental Doppler ratio; congenital heart block; fetal echocardiography Correspondence: Dr MR Liske, Division of Pediatric Cardiology, Department of Pediatrics, Monroe Carell Jr Children s Hospital, Vanderbilt University, 2200 Children s Way, Suite 5230, Nashville, TN , USA. michael.liske@vanderbilt.edu Received 20 November 2007; revised 27 May 2008; accepted 16 June 2008; published online 14 August 2008 Introduction Congenital complete heart block (CCHB) is an uncommon disorder with an incidence of about 1 per live births, 1 and in fetuses with structurally normal hearts, it is commonly associated with the maternal autoantibodies Ro and La. 2 Fetuses diagnosed with autoimmune-mediated complete congenital heart block are at risk for developing heart failure, hydrops or fetal demise due to inadequate cardiac output. Many fetuses ultimately require ventricular pacing for poor cardiac output shortly after delivery. 2 5 Low ventricular rate, hydrops fetalis, low birth weight, male sex, endocardial fibroelastosis (EFE) of the ventricle and gestational age less than 34 weeks are risk factors for a poor fetal outcome. 2,4,5 Prenatal monitoring of fetuses with CCHB remains a significant challenge. Fetuses with deteriorating cardiac function may not always exhibit the lowest heart rate, 6 and other ultrasonographic markers of poor cardiac output, including standard Doppler indices, can be unreliable in the face of substantial bradycardia. 7,8 The cerebroplacental Doppler ratio (CPR), defined as the ratio of the middle cerebral artery pulsatility index (MCA-PI) to the umbilical artery pulsatility index (UA-PI), is a measure of redistribution of cardiac output, and it is predictive of adverse perinatal outcome in growth-restricted fetuses where there is altered umbilical artery resistance and fetal hypoxia. 9 We hypothesize that the CPR will also be predictive of fetal outcome in cases where there is the potential for diminished cardiac output secondary to complete heart block. We present a case series of patients diagnosed prenatally with autoimmune-mediated CCHB in which the CPR was assessed, and propose that this index be used to help identify those at risk of cardiovascular compromise before the onset of overt ventricular failure, hydrops, fetal distress or death. Methods This study was approved by the Vanderbilt University Institutional Review Board for Research. We conducted a comprehensive review

2 Fetal monitoring of congenital heart block 792 of the fetal echocardiography database at our institution, identifying patients diagnosed prenatally with CCHB between the years 2006 and We reviewed all fetal echocardiograms of each identified patient for the following data: ventricular rate, atrial rate, cardiothoracic ratio, degree of tricuspid regurgitation, ventricular function, presence of effusions, UA-PI, MCA-PI and CPR. The pulsatility index was calculated according to Gosling and King as follows: (peak systolic velocity end diastolic velocity)/ mean velocity. 10 The CPR was computed as the ratio of the MCA-PI to the UA-PI. 9 We reviewed the prenatal and postnatal clinical course of each patient. All fetuses had middle cerebral artery Doppler interrogations available from the fetal echocardiogram performed before their delivery, and two fetuses had serial data from the time of diagnosis. We compared the hemodynamic data, from the fetal echocardiogram closest to delivery between patients who required urgent pacemaker placement postnatally due to hemodynamic compromise to that of patients that did not require urgent pacemaker placement. Statistical analyses were performed using Student s t-test or Mann Whitney U-test for continuous variables, and w 2 -test or Fisher s exact test for categorical variables. Data are presented as mean±standard error of the mean (s.e.m.). Data were analyzed using SPSS (Version 16; SPSS, Chicago, IL, USA). Results Five patients were identified. The gestational age at diagnosis of complete heart block varied from 20 to 33 weeks. All cases were associated with maternal autoantibodies to SSA/Ro and/or SSB/La. All patients were monitored routinely by fetal echocardiography from the time of diagnosis to delivery. Our institution follows a transplacental fetal treatment protocol for autoimmune-mediated CCHB as described by Jaeggi et al., 11 in which dexamethasone is initiated at the time of diagnosis at an initial dose of 8 mg orally once a day for 2 weeks, then 4 mg orally per day for 2 weeks, then 2 mg per day until delivery. The b-sympathomimetic agent terbutaline is added for ventricular rates less than 55 b.p.m. at an initial dose of 5 mg orally every 6 h and titrated upward as tolerated. There are minor variations in this dosing regimen on occasion. All five mothers were treated with dexamethasone, and the mothers in cases 2, 3 and 4 were also treated with terbutaline. The course of each patient is briefly described below. Patient 1 CCHB was diagnosed at 20 weeks estimated gestational age (EGA) in this female fetus. Dexamethasone therapy was initiated at diagnosis, and terbutaline was added at 23 weeks EGA and continued through delivery with improvement in the ventricular rate to greater than 55 b.p.m. Mother delivered a female infant prematurely at 34 weeks by Caesarean section due to a nonreassuring biophysical profile, maternal preeclampsia and persistent fetal ventricular rate less than 55 b.p.m. The infant required mechanical ventilation and initiation of an isoproterenol infusion in the delivery room. A temporary transvenous pacemaker was urgently placed on her first day of life due to persistent metabolic acidosis and inadequate cardiac output. A permanent single ventricular lead epicardial pacemaker was placed the following day. Patient 2 CCHB was diagnosed at 25 weeks EGA in this female fetus. Dexamethasone and terbutaline were initiated at presentation. The patient was delivered by Caesarean section at 36 weeks EGA due to persistent, severe fetal bradycardia with heart rates less than 50 b.p.m. She did not require significant resuscitation in the delivery room, but an isoproterenol infusion was initiated for ventricular heart rates less than 50 b.p.m. Over the following 24 h, she developed worsening metabolic acidosis, and a single ventricular lead epicardial pacemaker was placed due to inadequate cardiac output. Patient 3 CCHB was diagnosed at 33 weeks EGA in this female fetus, at which time dexamethasone was prescribed. The patient was delivered by elective Caesarean section at 38 weeks EGA, was vigorous, and was transferred to the newborn nursery. She was discharged at 3 days of life. A permanent pacemaker was placed at 13 months of age for persistent nocturnal heart rates of 35 b.p.m. Patient 4 CCHB was diagnosed at 29 weeks EGA in this male fetus. Dexamethasone was started at the time of diagnosis, and terbutaline was added at 31 weeks EGA. The patient was born by elective Caesarean section at 39 weeks EGA, and had an initial ventricular heart rate of 60 b.p.m. However, over the course of the next few hours, his ventricular rate dropped below 50 b.p.m. in spite of isoproterenol therapy. During that time, he remained vigorous, with normal perfusion, and was free of lactic acidosis. A single ventricular lead epicardial pacemaker was electively placed on the first day of life due to persistently low heart rates less than 50 b.p.m. Patient 5 CCHB was diagnosed at 21 weeks EGA in this male fetus. Pharmacologic therapy with dexamethasone was utilized during this pregnancy. The patient was born at 32 weeks EGA by Caesarean section after mother presented with premature rupture of membranes. Delivery was uncomplicated, and he remained hemodynamically stable throughout his hospital stay. Ventricular rates remained stable, and he was discharged home from the hospital at 2 weeks of age without a pacemaker.

3 Fetal monitoring of congenital heart block 793 Table 1 presents data from the fetal echocardiogram performed before delivery, and Table 2 presents postnatal data for each patient. Patient 4 was included in the group that did not require urgent pacemaker placement as he did not have any evidence of hemodynamic compromise and had elective placement of a pacemaker for persistence of low ventricular rates. The CPR before delivery was significantly lower in the patients who required urgent pacemaker placement (0.97±0.06 versus 1.45±0.03; P ¼ 0.003), whereas there was no significant difference in other fetal echocardiographic measurements between groups (Table 3). Both patients requiring urgent pacemaker placement had a CPR less than Longitudinal CPR data was available for patients 4 and 5 and is depicted in Figure 1. The birth weight percentile was significantly lower in patients requiring urgent pacemaker placement (12.5±2.5 versus 55±5; P ¼ 0.008), but there was no difference between groups in other postnatal measures (Table 3). Discussion Autoimmune-mediated CCHB is associated with significant morbidity and mortality in the perinatal period. The authors of one study reported a total mortality rate of 19%, with 27% of those dying in utero and a further 45% dying within the first 3 months after delivery. 2 This condition also results in significant morbidity with one group reporting 27% of fetuses developing fetal hydrops, 21% developing cardiac failure without hydrops and 53% requiring pacemaker therapy in the newborn period. 4 Premature delivery is one of the most important risk factors for mortality, with one large series showing 52% mortality in infants born at less than 34 weeks gestational age compared to 8% mortality in infants born at or after 34 weeks gestational age. 2 Other risk factors of poor fetal outcome are low ventricular rate, hydrops fetalis, low birth weight, male sex and EFE of the ventricle. 4,5 Fetuses exposed to the maternal autoantibodies Ro and La can develop EFE, and its presence is associated with ventricular dysfunction, independent of bradycardia. 12 Over the past several years, there have been significant advances in the prenatal diagnosis and management of fetuses with autoimmune-mediated CCHB. Fetal echocardiography has become the method of choice for detection, analysis and follow-up of fetal arrhythmias; however, prenatal monitoring of fetuses with CCHB remains a significant challenge. 3,7,8,13,14 Huhta 15 proposed a cardiovascular profile score based on fetal echocardiographic characteristics as a method for evaluation of a fetus with suspected congestive heart failure of any etiology. Donofrio et al. 14 incorporated a fetal management protocol that used Huhta s cardiovascular profile score along with the biophysical profile to monitor fetal well-being in two fetuses with autoimmune-mediated CCHB. Huhta s five-item profile score, which assesses hydrops, venous Doppler patterns, heart size, cardiac function and arterial Doppler traces, is intrinsically limited in fetuses with CCHB by the fact that many of these items are usually abnormal even in the absence of cardiovascular compromise. For example, in CCHB the ductus venosus typically shows flow reversal, and the umbilical vein exhibits notching during atrial contractions that occur while the tricuspid valve is closed (canon A waves), which led Huhta to appropriately conclude that only venous pulsations occurring at the atrial rate are significant. 15 Cardiomegaly is to be expected in this Table 1 Data from fetal echocardiogram closest to delivery Pt EGA Atrial rate Ventricular rate Effusions TR CT area LV function MCA-PI UA-PI CPR Trivial pericardial None 0.30 Mildly depressed None Trivial 0.38 Normal None None 0.33 Normal None None 0.40 Normal None Trivial 0.33 Normal Abbreviations: CPR, cerebroplacental Doppler ratio; CT area, cardiothoracic area; EGA, estimated gestational age at last fetal echocardiogram; LV function, subjective evaluation of left ventricular function; MCA-PI, middle cerebral artery pulsatility index; Pt, patient number; TR, presence of tricuspid regurgitation; UA-PI, umbilical artery pulsatility index. Table 2 Postnatal characteristics Pt EGA Birth weight percentile Cord ph Apgar score Ventricular rate Isoproterenol in delivery room Urgent pacemaker th /0/5 40s Yes Yes th /8 40 Yes Yes th NP 8/9 50s No No th NP 7/8 60 No No th /8 100 No No Abbreviations: EGA, estimated gestational age at delivery; NP, not performed; Pt, patient number.

4 794 Fetal monitoring of congenital heart block Table 3 Fetal echocardiographic data and birth characteristics Variable No pacemaker Pacemaker P-value Ventricular rate (b.p.m.) 69± ± Atrial rate (b.p.m.) 135.7± ± Cardiothoracic area 0.35± ± Umbilical artery pulsatility index 1.51± ± Middle cerebral artery pulsatility index 2.20± ± Cerebroplacental ratio 1.45± ± Birth weight 2.2± ± Gestational age at birth 36.3±2.2 35± Birth weight percentile 55±5 12.5± Abbreviation: b.p.m., beats per minute. Figure 1 Trend of cerebroplacental Doppler ratio (CPR) at advancing gestational ages in patients 4 and 5. condition as a compensatory mechanism. 8 Finally, altered umbilical arterial indices that would seem to indicate an elevation of placental resistance may only reflect a prolonged diastolic time related to the underlying bradycardia. And so this profile score, when strictly applied, may lead some physicians to inappropriately diagnose fetal distress. Due to the difficulty in monitoring these fetuses, some practitioners have resorted to invasive techniques by serial amniotic erythropoietin assay 7 or scalp electrode determination of fetal atrial rates. 16 Doppler investigation of regional fetal circulation can provide information regarding fetal well-being and has been evaluated in a number of conditions including intrauterine growth retardation and preeclampsia, where the particular focus has been on relative changes in cerebral and umbilical blood flow resistances. 9,17,18 A beneficial, autoregulatory brain sparing effect from a decrease in middle cerebral arterial resistance improves oxygen delivery to the brain in the presence of increased umbilical artery resistance. This effect is likely due to two potential mechanisms: forced centralization from elevated placental resistance; and a decrement in cerebral arterial resistance. 19,20 The CPR offers the advantage of detecting redistribution of flow and has been shown to be more predictive of adverse perinatal outcome in growth-restricted fetuses than UA or MCA Doppler values alone. 9,21 Baschat and Gembruch have published a gestational age-based CPR nomogram which was validated in a study by Odibo et al., who furthermore confirmed that a categorical CPR value of less than 1.08 was predictive of adverse perinatal outcome in infants with intrauterine growth retardation We hypothesized that this assessment of fetal wellbeing, currently used in cases of elevated placental resistance, could also be applied to situations of diminished cardiac output secondary to bradycardia. In our case series, standard fetal echocardiographic markers did not identify the high risk fetuses; however, lower CPR was predictive of an adverse outcome, which was defined as persistent metabolic acidosis due to inadequate cardiac output that required urgent placement of a pacemaker. Furthermore, a CPR less than 1.08, which is predictive of adverse outcome in growth-retarded fetuses, was also predictive of adverse outcome in our patients. Figures 2a and b, the Doppler traces of patient 3 whose CPR was 1.45, demonstrates relatively lower velocity diastolic flow in the middle cerebral artery compared to the umbilical artery, consistent with normal resistance relationships and the absence of cerebral autoregulation in this nonstressed fetus. Figures 3a and b from patient 1, whose CPR was 1.02, shows a middle cerebral artery diastolic flow pattern similar to that of the umbilical artery, compatible with autoregulation in this fetus who later was born with Apgar scores of 1, 0, and 5 and required an urgent pacemaker. Patient 4, whose CPR was 1.5, is particularly instructive, as this neonate, whose heart rates later fell to less than 50 b.p.m. following delivery, remained vigorous and free of acidosis in spite of very low heart rates. The CPR may also be useful in monitoring the effect of treatment. Unfortunately longitudinal CPR data were only available in two of our patients, depicted in Figure 1. It is conceivable that the improvement in CPR in these two fetuses reflects successful treatment, however, it should also be noted that Baschat and Gembuch s normative study demonstrated occasional fetuses with CPR values less than 1.08 at gestational ages less than 30 weeks, 20 and that isolated low values may reflect transient fetal hypoxia due to extracardiac etiologies. On the basis of our case series of five patients, we feel that the CPR is helpful in detecting early evidence of fetal cardiac failure before the onset of ominous echocardiographic signs such as hydrops fetalis and ventricular dysfunction, and that it could prove to be an adjunct to the biophysical profile and Huhta s cardiovascular profile score in monitoring these high risk fetuses. Perhaps the Arterial Doppler component of Huhta s score could be modified for fetuses with heart block such that a CPR of greater than or equal to 1.08 would be assigned 2 points, a CPR of less than 1.08 assigned 1 point, and umbilical artery reversed end

5 Fetal monitoring of congenital heart block 795 Figure 2 (a, b) Middle cerebral artery (MCA) (a) and umbilical artery (UA) (b) Doppler traces in patient 3 whose cerebroplacental Doppler ratio (CPR) was calculated to be There is relatively less flow in the MCA at end diastole suggesting a higher resistance in this vessel, a feature seen in the unstressed fetus. diastolic flow be assigned 0 points. Certainly, it is imperative to note the caveat raised by Akalin-Sel et al. 24 and Sepulveda et al., 25 that in growth-retarded fetuses suffering severe hypoxia, the MCA- PI normalizes as the fetus loses his ability for cerebral autoregulation. We predict that this pseudonormalization would also hold true in the premorbid fetus with severe bradycardia, and so would caution that the CPR should not be considered as the sole index of fetal well-being in this vulnerable population, but rather as an adjunct to the previously mentioned modalities of monitoring. This study carries all the limitations of a case series, and it is difficult to confirm our hypothesis with such a small number of patients. CCHB is a rare disease, and therefore a multi-institutional, prospective study is needed to determine the validity of this test in monitoring fetuses with CCHB, and to determine if certain levels of the CPR predict various states such as growth arrest, metabolic acidosis or impending demise. In conclusion, autoimmune-mediated CCHB causes significant morbidity and mortality, particularly in the perinatal period. Fetuses with CCHB require close monitoring, and our case series Figure 3 (a, b) Middle cerebral artery (MCA) (a) and umbilical artery (UA) (b) Doppler traces from patient 1. The velocity at end diastole is increased in the MCA and is similar to that of the UA suggesting the presence of cerebral autoregulation in this stressed fetus. suggests that the CPR can be an adjunct to other echocardiographic parameters in monitoring fetal well-being. We suggest an approach to prenatal monitoring of these patients that uses the CPR in addition to other previously described methods of assessing congestive heart failure and fetal well-being. A prospective study with a larger number of patients is required to further clarify the role of the CPR in monitoring fetuses with CCHB. Acknowledgments We thank Angela J Liske, MD, for her editorial assistance. No grants or other financial support were received for this publication.

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