Prevalence of Congenital Heart Defects in Monochorionic/Diamniotic Twin Gestations A Systematic Literature Review

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1 Article Prevalence of Congenital Heart Defects in Monochorionic/Diamniotic Twin Gestations A Systematic Literature Review Mert Ozan Bahtiyar, MD, Antonette T. Dulay, MD, Bevin P. Weeks, MD, Alan H. Friedman, MD, Joshua A. Copel, MD Objective. Congenital heart defects (CHDs) affect approximately 0.5% of all neonates. Recent literature points to a possible increase in the CHD prevalence among monochorionic/diamniotic (MC/DA) twin gestations. We hypothesized that MC/DA twin pregnancy is a risk factor for CHD. Methods. A systematic review of all published English literature was conducted on MEDLINE (Ovid and PubMed) from January 2000 through April 2007 using the medical subject heading terms congenital heart defect and monozygotic twins. Four observational studies were included in the final analysis. Published historical data were used for the population background risk of CHD. Relative risk (RR) estimates with 95% confidence intervals (CIs) were calculated by fixed and random effect models. Results. We included a total of 40 fetuses with CHDs among 830 fetuses from MC/DA twin gestations. Compared with the population, CHDs were significantly more prevalent in MC/DA twins regardless of the presence of twin-twin transfusion syndrome (TTTS) (RR, 9.18; 95% CI, ; P <.001). Monochorionic/diamniotic twin gestations affected by TTTS were more likely to be complicated by CHDs than those that did not have TTTS (RR, 2.78; 95% CI, ; P =.04). Ventricular septal defects were the most frequent heart defects. Pulmonary stenosis and atrial septal defects were significantly more prevalent in pregnancies complicated with TTTS. Conclusions. Monochorionic/diamniotic twin gestation appears to be a risk factor for CHDs. Conditions that lead to abnormal placentation may also contribute to abnormal heart development, especially in MC/DA twin pregnancies complicated with TTTS. Fetal echocardiography may be considered for all MC/DA twin gestations because ventricular septal defects and pulmonary stenosis are the most common defects. Key words: congenital heart defect; monochorionic; twin pregnancy; twins; twin-twin transfusion syndrome. Abbreviations CHD, congenital heart defect; CI, confidence interval; MC/DA, monochorionic/diamniotic; RR, relative risk; TTTS, twin-twin transfusion syndrome; VEGF, vascular endothelial growth factor Received June 27, 2007, from the Departments of Obstetrics, Gynecology, and Reproductive Sciences (M.O.B., A.T.D., J.A.C.), and Pediatrics (B.P.W., A.H.F.), Yale University School of Medicine, New Haven, Connecticut USA. Revision requested July 22, Revised manuscript accepted for publication August 9, Address correspondence to Mert Ozan Bahtiyar, MD, Section of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, 333 Cedar St, PO Box , New Haven, CT USA. mert.bahtiyar@yale.edu C ongenital heart anomalies are among the most commonly identified congenital defects. Approximately 0.5% of all live-born fetuses have some type of congenital heart abnormality. 1,2 Advances in fetal sonography have revolutionized prenatal diagnosis and care of fetuses with congenital heart defects (CHDs). Fetal echocardiography has become a powerful tool in detecting fetal cardiac anomalies in the hands of expert centers. The association between congenital anomalies and multiple gestations has been reported previously. 3,4 Multiple gestations constitute approximately 3% of all pregnancies in the United States and are increasing in frequency. 5 Recent publications suggest that monochorionic/diamniotic (MC/DA) twins appear to be associated 2007 by the American Institute of Ultrasound in Medicine J Ultrasound Med 2007; 26: /07/$3.50

2 Congenital Heart Defects in Monochorionic/Diamniotic Twin Gestations with an increased risk of all congenital defects and specifically carry a higher incidence of CHDs. 6 The association between MC/DA twin gestation and CHDs has important clinical implications because the number of twin gestations is steadily rising in the United States partly because of the increased use of assisted reproductive technologies, and this has increased the rate of both dichorionic and monochorionic twins. 7 We hypothesized that MC/DA twin pregnancy is a risk factor for CHDs. To estimate the magnitude of this effect, we systematically reviewed the published English literature. We also investigated the prevalence of specific defects in MC/DA twin gestations. Materials and Methods We conducted a systematic review of all published English literature on MEDLINE (Ovid and PubMed) from January 2000 through April 2007 using the medical subject heading terms congenital heart defect and monozygotic twins. Eligibility and exclusion criteria were predefined as a sample size of more than 10, a number of pregnancies and a number of fetuses affected by CHD that could be determined from the published data, a reported frequency of specific heart defects, inclusion of diagnostic criteria for twintwin transfusion syndrome (TTTS), staging based on that of Quintero et al 8 where applicable, and postnatal confirmation of the CHD. Data extraction was performed by 2 investigators (M.O.B. and J.A.C.). The population risk of CHDs was based on published historical data. 1,2 The search strategy identified 45 studies from January 2000 through April 2007 (Figure 1). Three of these were not in English. On the basis of inclusion criteria, 4 studies reporting the prevalence of CHD in MC/DA twin gestations were included in the final analysis. 6,9 11 Two studies were identified for the background population risk (Table 1). 1,2 Two study groups were defined: MC/DA twins with TTTS and MC/DA twins without this complication. Outcomes were analyzed between these study groups, and these were compared against the background population risk. Relative risk (RR) estimates with 95% confidence intervals (CIs) were made by both fixed and random effect models. Results were similar for both. We report the random effect model results. A difference in groups was considered statistically significant at P <.05. Results After reviewing the available literature, we identified 830 fetuses from MC/DA twin gestations. Of these, 40 fetuses were reported to have CHDs. All studies that are included were observational prospective cohorts. Details of the studies are presented in Table 1. Compared with singleton gestations, CHDs were significantly more prevalent in MC/DA twins regardless of the presence of TTTS (compared with Wren et al 1 : RR, 9.18; 95% CI, ; P <.001; compared with Ferencz et al 2 : RR, 13.89; 95% CI, ; P <.001). Monochorionic/diamniotic twin gestations that were not complicated by TTTS had a 6- to 10-fold increase in CHD prevalence (compared with Wren et al 1 : RR, 6.51; 95% CI, ; P <.001; compared with Ferencz et al 2 : RR, 15.04; 95% CI, ; P <.001). When an MC/DA twin gestation was affected by TTTS, the CHD prevalence Figure 1. Flow diagram depicting the identification and selection of the studies that were included in the final analysis J Ultrasound Med 2007; 26:

3 Bahtiyar et al was 15- to 23-fold higher than that of the population (compared with Wren et al 1 : RR, 9.67; 95% CI, ; P <.001; compared with Ferencz et al 2 : RR, 14.63; 95% CI, ; P <.001) (Figure 2). Furthermore, MC/DA twin gestations affected by TTTS were more likely to be complicated by CHDs than those did not have TTTS (RR, 2.78; 95% CI, ; P =.04) (Figure 3). The distribution of individual CHDs that were reported in each included study is presented in Table 2. Overall, ventricular septal defects were the most prevalent abnormalities among MC/DA twin gestations. However, pulmonary stenosis and atrial septal defects were significantly more prevalent in MC/DA twin pregnancies complicated with TTTS (Table 3). Table 1. Studies Included in the Systematic Review Study Postnatal Total CHD Source Year Design Population TTTS Follow-up Results Prevalence per Fetus Twins Karatza et al Cohort study All comers, 47 sets Included, Yes CHD prevalence: MC 3.8% (10/264) of MC/DA with no stage TTTS 6.9% (6/87), TTTS, 89 sets of reported recipient 11.9% (5/42), MC/DA without no TTTS 2.2% (4/177) TTTS Lopriore et al Cohort study All comers, 46 sets Quintero Yes CHD prevalence: MC 3.7% (6 /161) of MC/DA with staging: TTTS 5.4% (4/74), TTTS, 55 sets of stage I 17%, no TTTS 2.3% (2/87) MC/DA without stage II 37%, TTTS stage III 41%, stage IV 4% Manning and 2006 Cohort study All comers, 165 sets Quintero No At least 1 with CHD, MC 5.8% (19/330), Archer 6 of MC twins, 10 staging MC all 9.1% (15/165), MC/DA 4.4% (14/316), as part of triplets, MC/DA 7.0% (11/158) MC/MA 35.7% (5/14) subjects excluded (3 sets both affected), if heart anomaly MC/MA 57.1% (4/7) (1 secondary to TTTS set both affected), both affected 26.7% (4/15) Herberg et al Cohort study All comers, 89 Quintero Yes CHD prevalence: TTTS MC 11.2% (10/89) survivors from staging, 11.2% (10/89) 73 consecutive severe TTTS MC/DA pregnancies (146 fetuses) after prenatal S-LPC for severe TTTS Population Wren et al Retrospective Former Northern NA Yes CHD prevalence: 0.56% and prospective Health Region of (2671/477,960) ascertainment England (Cumbria, of all congenital Northumberland, cardiovascular Tyne and Wear, malformations Durham, and diagnosed in Cleveland counties) infancy from 1985 to 1997 Ferencz et al Prospective Baltimore-Washington NA Yes CHD prevalence: 0.37% observational Infant Study: cases (664/179,697) cohort during eligible if infant born 1981 and 1982 alive to a resident of the study area and diagnosis confirmed during the first year of life NA indicates not applicable; and S-LPC, selective laser photocoagulation. J Ultrasound Med 2007; 26:

4 Congenital Heart Defects in Monochorionic/Diamniotic Twin Gestations Figure 2. Statistical analysis of the studies that were included in the review. A, Risk of CHDs in MC/DA twin gestations relative to singleton gestations reported by Wren et al. 1 B, Risk of CHDs in MC/DA twin gestations relative to singleton gestations reported by Ferencz et al. 2 A B 1494 J Ultrasound Med 2007; 26:

5 Bahtiyar et al Figure 3. Risk of CHDs in MC/DA twin gestations affected by TTTS relative to MC/DA twin gestations that were not affected by TTTS. Relative risk estimates with 95% CIs were calculated by a random effect model. Table 2. Distribution of Specific Congenital Heart Defects in MC/DA Twin Pregnancies With or Without TTTS MC/DA Twin Gestation TTTS No TTTS Source All Donor Recipient All Twin 1 Twin 2 Karatza et al 9 n CHD PS PA-IVS 1 1 VSD Coarctation 1 1 Lopriore et al 10 n CHD 4 2 PS 1 ASD 1 VSD 2 2 Manning and Archer 6 n 316 CHD 14 PS 2 VSD 8 HLH 1 PA-VSD 1 PV stenosis 1 C-AVSD 1 Herberg et al 11 n CHD PS ASD VSD ASD indicates atrial septal defect; C-AVSD, complete atrioventricular septal defect; HLH, hypoplastic left heart syndrome; n, total number in the study; PA-IVS, pulmonary atresia with an intact interventricular septum; PA-VSD, pulmonary atresia with a ventricular septal defect; PS, pulmonary stenosis; PV pulmonary vein; and VSD, ventricular septal defect. J Ultrasound Med 2007; 26:

6 Congenital Heart Defects in Monochorionic/Diamniotic Twin Gestations Table 3. Prevalence of Individual CHDs in MC/DA Twin Pregnancies With or Without TTTS MC/DA Twin Gestation Population Prevalence TTTS No TTTS Total per 1000 Live Births Parameter n Prevalence 95% CI n Prevalence 95% CI n Prevalence 95% CI Wren et al 1 Ferencz et al 2 Fetuses CHD PS VSD ASD PA-IVS PA-VSD PV stenosis Coarctation HLH C-AVSD ASD indicates atrial septal defect; C-AVSD, complete atrioventricular septal defect; HLH, hypoplastic left heart syndrome; n, total number in the study; PA-IVS, pulmonary atresia with an intact interventricular septum; PA-VSD, pulmonary atresia with a VSD; PS, pulmonary stenosis; PV pulmonary vein; and VSD, ventricular septal defect. Discussion In this systematic literature review, we have summarized available literature and have shown that there is approximately a 9-fold increase in the CHD risk in MC/DA twin pregnancies. In addition, MC/DA twin pregnancies complicated by TTTS confer a 13- to 14-fold increase in CHD risk compared with the population. The pathophysiologic mechanisms behind this significant increase in CHD risk have not yet been completely explored. It appears that the interplay of abnormal placentation in conjunction with a genetic predisposition may play some part in this increased CHD risk. 12 It is noteworthy that MC/DA twin gestations affected by TTTS are associated with a higher CHD prevalence. Recent studies speculate that the etiology of CHDs in general may be partly due to aberrant angiogenic factors such as vascular endothelial growth factor (VEGF). Elevated systemic VEGF levels have been documented in children with cyanotic heart disease. 13 During normal heart development, VEGF is specifically upregulated in the atrioventricular field of the heart soon after the onset of endocardial cushion formation. Premature induction of myocardial VEGF prevents formation of endocardial cushions in animal models. Furthermore, VEGF also inhibits the transformation of the endocardium to the mesenchyma. Transformation can be restored when inhibitory soluble VEGF receptor 1 (soluble fms-like tyrosine kinase 1) is added to the environment. 14 Placental anomalies (ie, vascular anastomosis) that are seen in MC/DA twin gestations leading to TTTS may also be a manifestation of abnormal angiogenic factor regulation. Indeed, higher levels of VEGF have been documented in twin pregnancies compared with singleton pregnancies. 15 So far, there have been no studies investigating the potential role of angiogenic factors in the setting of an atrial septal defect or pulmonary stenosis. In addition to possible alterations in the angiogenic factors in MC/DA twin gestations complicated with TTTS, changes in fetal hemodynamics may also play a part in the development of these defects. Further studies are needed to investigate these relationships. In unselected populations, CHD detection rates may vary between 8.5% to 25% However, detection rates as high as 80% to 90% can be achieved with targeted fetal echocardiography in the hands of expert centers. 20,21 Because of the complexity and cost of fetal echocardiography, proper identification of risk factors contributing to the development of CHDs is crucial for determining appropriate candidates. Our systematic review based on available literature indicates that approximately 12 sets (24 fetuses) of MC/DA twin gestations would need to undergo fetal echocardiography to identify 1 fetus with a CHD J Ultrasound Med 2007; 26:

7 Bahtiyar et al Although universal performance of fetal echocardiography in all MC/DA twins may present logistical difficulties, centers that have this capability may consider its use in the care of MC/DA twin pregnancies. Finding fetal cardiac abnormalities allows patients to make more informed decisions regarding the extent of care desired in their current pregnancies. Moreover, care providers can prepare for immediate postnatal management, thereby conferring a survival advantage for those neonates with critical heart defects. 22 Data used in this systematic review were extracted from prospective observational studies from referral centers. Certainly, this may have increased the prevalence of reported CHDs because of inherent biases in the data; for example, fetuses with cardiac anomalies found elsewhere may have been referred to the centers that reported their experiences. From the available data, it was not possible to determine whether a difference in the incidence of monocohorionic twin gestations varied among the study centers. However, statistically there was no variation among the centers. Although the etiology is not yet well understood, current evidence supports the idea that monochorionic placentation is indeed a risk factor for CHDs. Certainly, the presence of TTTS warrants referral for a detailed sonographic evaluation. These findings may prompt centers that have the capability of providing a formal fetal echocardiographic examination to offer this test to all patients with MC/DA twin pregnancies. References 1. Wren C, Richmond S, Donaldson L. Temporal variability in birth prevalence of cardiovascular malformations. Heart 2000; 83: Ferencz C, Rubin JD, McCarter RJ, et al. Congenital heart disease: prevalence at live birth. The Baltimore-Washington Infant Study. Am J Epidemiol 1985; 121: Layde PM, Erickson JD, Falek A, McCarthy BJ. Congenital malformation in twins. Am J Hum Genet 1980; 32: Kallen B. Congenital malformations in twins: a population study. Acta Genet Med Gemellol (Roma) 1986; 35: Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Kirmeyer S. Births: final data for Natl Vital Stat Rep 2006; 55: Manning N, Archer N. A study to determine the incidence of structural congenital heart disease in monochorionic twins. Prenat Diagn 2006; 26: Toledo MG. Is there increased monozygotic twinning after assisted reproductive technology? Aust NZ J Obstet Gynaecol 2005; 45: Quintero RA, Morales WJ, Allen MH, Bornick PW, Johnson PK, Kruger M. Staging of twin-twin transfusion syndrome. J Perinatol 1999; 19: Karatza AA, Wolfenden JL, Taylor MJO, Wee L, Fisk NM, Gardiner HM. Influence of twin-twin transfusion syndrome on fetal cardiovascular structure and function: prospective case-control study of 136 monochorionic twin pregnancies. Heart 2002; 88: Lopriore E, Bokenkamp R, Rijlaarsdam M, Sueter M, Vandenbussche FP, Walther FJ. Congenital heart disease in Twin-to-twin transfusion syndrome treated with fetoscopic laser surgery. Congenit Heart Dis 2007; 2: Herberg U, Gross W, Bartmann P, Banek CS, Hecher K, Breuer J. Long-term cardiac follow-up of severe twin-totwin transfusion syndrome after intrauterine laser coagulation. Heart 2006; 92: Bjarnegard M, Enge M, Norlin J, et al. Endothelium-specific ablation of PDGFB leads to pericyte loss and glomerular, cardiac and placental abnormalities. Development 2004; 131: Ootaki Y, Yamaguchi M, Yoshimura N, Oka S, Yoshida M, Hasegawa T. Vascular endothelial growth factor in children with congenital heart disease. Ann Thorac Surg 2003; 75: Dor Y, Camenisch TD, Itin A, et al. A novel role for VEGF in endocardial cushion formation and its potential contribution to congenital heart defects. Development 2001; 128: Evans PW, Wheeler T, Anthony FW, Osmond C. A longitudinal study of maternal serum vascular endothelial growth factor in early pregnancy. Hum Reprod 1998; 13: Jaeggi ET, Sholler GF, Jones OD, Cooper SG. Comparative analysis of pattern, management and outcome of pre- versus postnatally diagnosed major congenital heart disease: a population-based study. Ultrasound Obstet Gynecol 2001; 17: Garne E, Stoll C, Clementi M, Euroscan Group. Evaluation of prenatal diagnosis of congenital heart diseases by ultrasound: experience from 20 European registries. Ultrasound Obstet Gynecol 2001; 17: Randall P, Brealey S, Hahn S, Khan KS, Parsons JM. Accuracy of fetal echocardiography in the routine detection of congenital heart disease among unselected and low risk populations: a systematic review. BJOG 2005; 112: Todros T, Faggiano F, Chiappa E, Gaglioti P, Mitola B, Sciarrone A. Accuracy of routine ultrasonography in screening heart disease prenatally. Gruppo Piemontese for Prenatal Screening of Congenital Heart Disease. Prenat Diagn 1997; 17: J Ultrasound Med 2007; 26:

8 Congenital Heart Defects in Monochorionic/Diamniotic Twin Gestations 20. Paladini D, Vassallo M, Sglavo G, Russo MG, Martinelli P. Diagnosis and outcome of congenital heart disease in fetuses from multiple pregnancies. Prenat Diagn 2005; 25: Ozkutlu S, Saraclar M. The accuracy of antenatal fetal echocardiography. Turk J Pediatr 1999; 41: Copel JA, Tan AS, Kleinman CS. Does a prenatal diagnosis of congenital heart disease alter short-term outcome? Ultrasound Obstet Gynecol 1997; 10: J Ultrasound Med 2007; 26: