Relationship Between Isolated Mild Tricuspid Valve Regurgitation in Second-Trimester Fetuses and Postnatal Congenital Cardiac Disorders

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1 ORIGINAL RESEARCH Relationship Between Isolated Mild Tricuspid Valve Regurgitation in Second-Trimester Fetuses and Postnatal Congenital Cardiac Disorders Jizi Zhou, MD, PhD, Yun Zhang, MD, Yonghao Gui, MD, PhD, Chen Chu, MD, PhD, Congcong Zhang, MD, Qiongjie Zhou, MD, Ying Zhang, MD, PhD, Xiaotian Li, MD, PhD, Yingliu Yan, MD Article includes CME test Received August 16, 2013, from the Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China (J.Z., Yu.Z., Q.Z., Yi.Z., X.L., Y.Y.); Children s Hospital, Fudan University, Shanghai, China (Y.G., C.C., C.Z.); and Shanghai Key Laboratory of Female Reproductive Endocrine- Related Diseases, Shanghai, China (X.L.). Revision requested October 17, Revised manuscript accepted for publication January 6, This study was supported by National High Technology Research and Development Program 863 under grant 2007AA02Z442. Drs Jizi Zhou and Yun Zhang are co-first authors. Address correspondence to Xiaotian Li, MD, PhD, or Yingliu Yan, MD, Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Rd, Shanghai, China. xiaotianli555@163.com, yan_ying_liu@hotmail.com doi: /ultra Objectives In most cases, the clinical importance of fetal isolated mild tricuspid valve regurgitation is not known. This study evaluated the relationship between fetal isolated mild tricuspid regurgitation in the general obstetric population and postnatal congenital cardiac disorders. Methods Detailed fetal echocardiography was done between 18 and 24 weeks gestation to detect tricuspid regurgitation and to exclude complicated cardiac defects. Routine second-trimester targeted organ scans were also performed to exclude extracardiac defects. Follow-up was done until birth. After birth, the cardiac anatomy of the neonates was examined by echocardiography. The association between fetal isolated mild tricuspid regurgitation and postnatal congenital cardiac disorders was assessed by logistic regression analysis. Results No major cardiac disorders were found postnatally. Some minor disorders were found, including a patent foramen ovale, atrial septal defects, a patent ductus arteriosus, and small ventricular septal defects. Fetuses with isolated mild tricuspid regurgitation had a significantly higher likelihood of having ventricular septal defects (odds ratio, 5.80; P =.027) or a patent foramen ovale with atrial septal defects and a patent ductus arteriosus (odds ratio, 11.61; P =.007). There was no significant association between tricuspid regurgitation and an isolated patent foramen ovale or a patent foramen ovale with atrial septal defects in neonates. Conclusions Fetuses with isolated mild tricuspid regurgitation in the second trimester did not have a higher incidence of major cardiac disorders after birth. The presence of isolated mild tricuspid regurgitation may be an indication of minor postnatal congenital cardiac disorders. Key Words congenital cardiac disorders; echocardiography; fetal; isolated mild tricuspid regurgitation; pediatric ultrasound; postnatal F etal tricuspid valve regurgitation occurs when the right ventricular pressure exceeds the right atrial pressure during systole and results from imperfect coaptation of the tricuspid valve. The development of color Doppler sonographic techniques has enabled relatively frequent detection of tricuspid regurgitation. To date, the evidence has been contradictory as to whether fetal tricuspid regurgitation is predictive of other disorders. In some studies, fetal tricuspid regurgitation during the first trimester was reported to be predictive of chromosomal abnormalities 1 3 or cardiac defects by the American Institute of Ultrasound in Medicine J Ultrasound Med 2014; 33:

2 Similarly, Anuwutnavin et al 5 found that in women with high-risk pregnancies, fetal tricuspid regurgitation during the second trimester was a sonographic marker that identified fetuses with Down syndrome and was associated with cardiac defects in fetuses with normal chromosomes. In addition, tricuspid regurgitation has been reported to be one of the strongest predictors of adverse neonatal outcomes in fetuses with intrauterine growth restriction. 6 However, another study 7 found that fetal tricuspid regurgitation that occurred during the second trimester was benign in fetuses with normal cardiac anatomy. Gembruch and Smrcek 8 reported that tricuspid regurgitation was a frequent finding during Doppler echocardiography, and in most cases, it was an isolated, transient finding with little progression in the severity and breadth of the tricuspid regurgitation jet. However, few studies have been done in the general obstetric population in which the postnatal cardiac anatomy of fetuses with isolated tricuspid regurgitation has been examined in detail. It is not known whether the presence of fetal isolated tricuspid regurgitation alone during the second trimester is a valuable predictor of postnatal cardiac anatomy in the general obstetric population. The purpose of this study was to determine whether there is an association between fetal isolated mild tricuspid regurgitation and postnatal congenital cardiac disorders within the general obstetric population. The clinical importance of fetal isolated mild tricuspid regurgitation was also assessed. Materials and Methods Participants This prospective cohort study was conducted between November 2008 and October 2010 at the Obstetrics and Gynecology Hospital affiliated with Fudan University. Target organ sonographic examinations are routinely performed on all pregnant women between 18 and 24 gestational weeks in the Ultrasound Department of the hospital. The gestational age was calculated on the basis of the date of the last menstrual period and corrected by using the crown-rump length at the first-trimester sonographic examination. During this visit, the maternal and gestational ages were recorded. The inclusion criteria for this study were singleton pregnancies with viable fetuses and planned deliveries at our hospital. The exclusion criteria were pregnancies with multiple gestations, major fetal malformations, fetal aneuploidy, and preterm delivery. Follow-up was conducted in all enrolled pregnant women until birth. The neonates underwent echocardiography for examination of cardiac anatomy. In addition, the gestational age at birth and birth weight were recorded. The study cohort was categorized into two groups according to the presence or absence of prenatal tricuspid regurgitation: a tricuspid regurgitation group and control group. This study was approved by the Ethics Committee of the Children s Hospital of Fudan University. Written informed consent was obtained from all study participants. Fetal and Neonatal Echocardiography A single operator, with more than 20 years of prenatal diagnostic ultrasound experience, performed fetal echocardiography. A Voluson E8 ultrasound machine (GE Healthcare, Milwaukee, WI) with a 3 6-MHz abdominal probe was used. Efforts were made to minimize excessive fetal movement during image acquisition. The images obtained included a 4-chamber view, views of the left and right ventricular outflow tracts, a 3-vessel and trachea view, a short-axis view, and a view of the abdominal circumference level to localize the aorta and inferior vena cava. Tricuspid regurgitation was recorded during ventricular contraction in the apical or basal 4-chamber view using color Doppler imaging with an angle of 0 to 30 (Figure 1). The size of the color box was set to 60 cm/s when possible. The degree of tricuspid regurgitation was based on the length of the jet into the atrium (ie, the distance from the Figure 1. Sonogram from a fetus with normal heart anatomy at 21.6 weeks gestation. The image shows reversed flow (arrow) across the tricuspid valve at the level of the 4-chamber view. LA indicates left atrium; LV, left ventricle; RA, right atrium; and RV, right ventricle J Ultrasound Med 2014; 33:

3 tricuspid valve to the opposite atrial wall) as follows: mild, less than 1/3; moderate, 1/3 to 2/3; and severe, greater than 2/3. 7 Neonates underwent postnatal echocardiography, done by 2 professional pediatric cardiologists, within 5 days of birth. In this study, ventricular septal defects were defined by visualization of a left-right shunt at the level of the interventricular septum. Deficient areas in the interatrial septum that were 3 mm or greater in size were defined as atrial septal defects. Atrial septal defects that are less than 3 mm in size are reported to close naturally and need not be followed. 9 A patent foramen ovale was defined by visualization of an area of an unclosed foramen ovale of 5 mm or greater with blood flow across it. Two shunts occurring across the interatrial septum was defined as a patent foramen ovale with concomitant atrial septal defects. A patent ductus arteriosus was defined by left-right shunting that passed from the descending aorta through the ductus arteriosus and to the pulmonary artery. Statistical Analysis SPSS version 17.0 software (IBM Corporation, Armonk, NY) was used for statistical analysis. A t test was used to compare the maternal age, gestational age at diagnosis and birth, and fetal birth weight between the tricuspid regurgitation and control groups. The percentages of neonates with congenital cardiac defects in the tricuspid regurgitation and control groups were compared by a χ 2 test or Fisher exact test. Fetuses with tricuspid regurgitation were compared to those without tricuspid regurgitation, and univariate logistic regression analysis was used to determine odds ratios for various congenital cardiac disorders. P <.05 was considered statistically significant. ages at diagnosis were similar between the tricuspid regurgitation and control groups. Fetal isolated mild tricuspid regurgitation during the second trimester was not associated with gestational age at birth or birth weight. Fetal isolated mild tricuspid regurgitation during the second trimester was identified in 6.71% of fetuses examined (86 of 1281). Only 2 and 8 cases of muscular ventricular septal defects were detected in the tricuspid regurgitation and control groups, respectively. Only 1 case of inlet ventricular septal defects was identified in the tricuspid regurgitation group. The proportion of neonates with ventricular septal defects was significantly higher in the tricuspid regurgitation group than in the control group (3.49% versus 0.67%; P =.027). The deficient area was significantly larger in ventricular septal defect cases in the tricuspid regurgitation group compared to ventricular septal defect cases in the Figure 2. Flowchart of the study population. Results Initially, 1435 singleton pregnancies were enrolled in our study. Of these, 143 cases (9.96%) were excluded because the deliveries took place in other hospitals; 4 cases were eliminated for complex cardiac defects; 2 cases were excluded for extracardiac defects; and 5 cases were excluded for preterm labor. A total of 1281 neonates, including 86 cases in the tricuspid regurgitation group and 1195 cases in the control group, with normal healthy appearances and no obvious abnormalities or chromosomal disorders underwent echocardiography. The acquisition process for the study population is shown in Figure 2. General information regarding the two groups is listed in Table 1. The mean age at which postnatal echocardiography was done was similar between the groups (2.88 versus 2.67 days; P =.62). The mean maternal age and gestational Table 1. General Maternal and Obstetric Characteristics of the Study Population Tricuspid Regurgitation Present Absent Characteristic (n = 86) (n = 1195) P Maternal age, y ± ± Gestational age at diagnosis, wk ± ± Gestational age at birth, wk ± ± Birth weight, kg 3.3 ± ± Age at postnatal examination, d 2.88 ± ± Values were compared by an independent-samples t test and are presented as mean ± SD. J Ultrasound Med 2014; 33:

4 control group (mean ± SD, 2.50 ± 0.29 versus 1.69 ± 0.13 mm; P =.0142; Table 2). The proportion of patent foramen ovale cases that coexisted with atrial septal defects and a patent ductus arteriosus was significantly higher in the tricuspid regurgitation group than the control group (3.49% versus 0.33%; P=.007); however, there was no significant difference between the tricuspid regurgitation and control groups in the proportion of cases of an isolated patent foramen ovale or a patent foramen ovale that coexisted with atrial septal defects (5.81% versus 2.76%; P =.085; and 1.16% versus 0.42%; P =.316; Table 3 and Figure 3). The deficient area was slightly larger in atrial septal defect cases in the tricuspid regurgitation group compared with atrial septal defect cases in the control group, but the difference was not statistically significant (3.95 ± 0.24 versus 3.49 ± 0.10 mm; P =.053; Table 2). Discussion Isolated mild tricuspid regurgitation was observed during the second trimester in 6.71% of the healthy fetuses examined in this cohort study. Postnatal data indicated that isolated mild tricuspid regurgitation during the second trimester was not associated with pregnancy outcomes and was not predictive of major cardiac disorders. However, Table 2. Comparison of Deficient Area Diameters in Atrial and Ventricular Septal Defects Between the Tricuspid Regurgitation and Control Groups Deficient Area Tricuspid Regurgitation Diameter, mm Present Absent P ASD 3.95 ± 0.24 (n = 4) 3.49 ± 0.10 (n = 9).053 VSD 2.50 ± 0.29 (n = 3) 1.69 ± 0.13 (n = 8).0142 Values were compared by an independent-samples t test and are presented as mean ± SD. ASD indicates atrial septal defects; and VSD, ventricular septal defects. isolated mild tricuspid regurgitation was found to be associated with some minor cardiac disorders, including a patent foramen ovale, atrial septal defects, a patent ductus arteriosus, and ventricular septal defects and, moreover, the sizes of the deficient areas of atrial and ventricular septal defects. A patent foramen ovale, atrial septal defects, a patent ductus arteriosus, and ventricular septal defects are congenital cardiac disorders that are often hemodynamically insignificant and not considered cardiac malformations in light of their natural evolution. Most cases of a patent foramen ovale, atrial septal defects, a patent ductus arteriosus, and ventricular septal defects spontaneously close during childhood, although there is evidence that these defects may be linked to secondary diseases if they persist into adulthood Therefore, although an association between the occurrence of fetal isolated mild tricuspid regurgitation during the second trimester and postnatal cases of a patent foramen ovale, atrial septal defects, a patent ductus arteriosus, and ventricular septal defects was found in this study, it is of limited clinical importance, since the tricuspid regurgitation was found to be associated with only minor postnatal congenital cardiac disorders. These findings, however, are contrary to results reported in some other studies of cardiac disorders. Pereira et al 4 and Volpe et al 14 found that tricuspid regurgitation was one of the sonographic markers for some major cardiac defects, mainly atrioventricular septal defects. The differing results may be due to the fact that tricuspid regurgitation was detected during the second trimester in our study, and most major cardiac disorders are identified by secondtrimester echocardiography. 15 Furthermore, the severity of the tricuspid regurgitation detected may also have contributed to the differences in results. Table 3. Cardiac Disorders in Neonates in the Tricuspid Regurgitation and Control Groups Tricuspid Regurgitation Present Absent Characteristic (n = 86) (n = 1195) P OR (95%CI) Normal heart anatomy 74 (86) 1145 (95.8) PFO Isolated PFO 5 (5.81) 33 (2.76) ( ) PFO and ASD 1 (1.16) 5 (0.42) ( ) PFO, ASD, and PDA 3 (3.49) 4 (0.33) ( ) VSD 3 (3.49) 8 (0.67) ( ) Values are presented as number (percent) where applicable. P values were analyzed by a Fisher exact test or a χ 2 test, and odds ratios were analyzed by univariate logistic regression analysis. ASD indicates atrial septal defects; CI, confidence interval; OR, odds ratio; PDA, patent ductus arteriosus; PFO, patent foramen ovale; and VSD, ventricular septal defects J Ultrasound Med 2014; 33:

5 The underlying mechanism for the association between fetal isolated mild tricuspid regurgitation and a patent foramen ovale, atrial septal defects, a patent ductus arteriosus, and ventricular septal defects in neonates is unclear. These benign cardiac disorders represent examples of congenital lesions that are characterized by an abnormal hemodynamic exchange. The abnormal exchange is caused by incomplete closure of the cardiac septum, thus allowing ejection from the right side of the heart into the left side of the heart. We speculate that the presence of fetal isolated mild tricuspid regurgitation may alter the flow dynamics in the right atrium, resulting in delayed closure of the interatrial septum, leading to a patent foramen ovale or atrial septal defects. In cases of ventricular septal defects, we infer that the lack of an interventricular septum might disturb the detachment of the tricuspid valve septum or anterior leaflet, which in turn would increase the chance of tricuspid valve regurgitation. 16 Apart from this situation, it is possible that undiagnosed maternal disease, maternal pharmacologic treatment, and fetal infections at any time during pregnancy could be responsible for the concomitant presence of fetal isolated mild tricuspid regurgitation and postnatal findings of minor cardiac disorders. 17 Although our data were derived from a single center, a relatively large sample size was used. A multicenter study could be conducted in the future to eliminate bias. Other limitations of this study were the relatively early time at which postnatal echocardiography was conducted and the Figure 3. Comparisons of the percentages of various cardiac disorders between the tricuspid regurgitation (TR) and control groups. ASD indicates atrial septal defects; PDA, patent ductus arteriosus; PFO, patent foramen ovale; and VSD, ventricular septal defects. *P <.05. lack of postnatal follow-up. There was still the likelihood of spontaneous closure of many of the minor cardiac disorders that were identified in our study. In conclusion, isolated mild tricuspid regurgitation during the second trimester is common in fetuses with normal heart anatomy, although tricuspid regurgitation may be useful as a prenatal sonographic marker for minor postnatal congenital cardiac disorders. Once a cardiac disorder, such as an atrial or ventricular septal defect, is identified, the necessary follow-up, if any, can be determined according to the type and size of the defect. References 1. Huggon IC, DeFigueiredo DB, Allan LD. Tricuspid regurgitation in the diagnosis of chromosomal anomalies in the fetus at weeks of gestation. Heart 2003; 89: Faiola S, Tsoi E, Huggon IC, Allan LD, Nicolaides KH. Likelihood ratio for trisomy 21 in fetuses with tricuspid regurgitation at the 11 to week scan. Ultrasound Obstet Gynecol 2005; 26: Falcon O, Faiola S, Huggon I, Allan L, Nicolaides KH. Fetal tricuspid regurgitation at the to week scan: association with chromosomal defects and reproducibility of the method. Ultrasound Obstet Gynecol 2006; 27: Pereira S, Ganapathy R, Syngelaki A, Maiz N, Nicolaides KH. Contribution of fetal tricuspid regurgitation in first-trimester screening for major cardiac defects. Obstet Gynecol 2011; 117: Anuwutnavin S, Wanitpongpan P, Chanprapaph P. Specificity of fetal tricuspid regurgitation in prediction of Down syndrome in Thai fetuses at weeks of gestation. J Med Assoc Thai 2009; 92: Makikallio K, Rasanen J, Makikallio T, Vuolteenaho O, Huhta JC. Human fetal cardiovascular profile score and neonatal outcome in intrauterine growth restriction. Ultrasound Obstet Gynecol2008; 31: Messing B, Porat S, Imbar T, Valsky DV, Anteby EY, Yagel S. Mild tricuspid regurgitation: a benign fetal finding at various stages of pregnancy. Ultrasound Obstet Gynecol 2005; 26: Gembruch U, Smrcek JM. The prevalence and clinical significance of tricuspid valve regurgitation in normally grown fetuses and those with intrauterine growth retardation. Ultrasound Obstet Gynecol 1997; 9: Radzik D, Davignon A, van Doesburg N, Fournier A, Marchand T, Ducharme G. Predictive factors for spontaneous closure of atrial septal defects diagnosed in the first 3 months of life. J Am Coll Cardiol 1993; 22: Chang JK, Jien WY, Chen HL, Hsieh KS. Color Doppler echocardiographic study on the incidence and natural history of early-infancy muscular ventricular septal defect. Pediatr Neonatol 2011; 52: Ammash NM, Warnes CA. Ventricular septal defects in adults. Ann Intern Med 2001; 135: Schneider DJ. The patent ductus arteriosus in term infants, children, and adults. Semin Perinatol 2012; 36: J Ultrasound Med 2014; 33:

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