- Email: [email protected]
The influence of twinning on cardiac development
Early Human Development (2008) 84, 173–179
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / e a r l h u m d e v
BEST PRACTICE GUIDELINE ARTICLE
The influence of twinning on cardiac development Nicky Manning ⁎ Department of Paediatric Cardiology (Fetal Cardiology), Oxford Children's Hospital, The John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
KEYWORDS Twins; Congenital heart disease; Monozygotic; Monochorionic; Dichorionic; Twin-to-twin transfusion syndrome
Abstract The risk for a cardiac anomaly in a twin pregnancy is increased, particularly in monochorionic twins. This is relevant in terms of fetal diagnosis as well as for the management of the pregnancy; there are also implications for the neonatal period and possibly beyond. The risk for a cardiac abnormality depends on the type of monochorionic twin as determined by the timing of embryonic division. Prenatal identification of twin type and the relative risks for a cardiac anomaly are discussed along with theories for the aetiology of the different cardiac lesions. © 2008 Elsevier Ireland Ltd. All rights reserved.
Contents 1.
Primary structural cardiac anomalies . . . . . . . . . . 1.1. Aetiology of primary structural cardiac anomalies 2. Acquired cardiac anomalies . . . . . . . . . . . . . . . . 2.1. Aetiology of acquired cardiac anomalies . . . . 2.1.1. Implications for adult health . . . . . . 3. ‘Iatrogenic’ cardiac complications in twins . . . . . . . 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . 5. Key guidelines . . . . . . . . . . . . . . . . . . . . . . . 6. Research directions . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The risk of complications and adverse outcome is greater in twin pregnancies compared to singletons, mainly due to the increased risk of prematurity. However a significant contribu⁎ Tel.: +44 01865 231313; fax: +44 01865 234211. E-mail address: [email protected].
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
175 175 175 176 177 178 178 178 178 178 178
tion to this higher morbidity and mortality is made by the cardiac complications of being a twin. This includes an increased risk of structural congenital heart disease (CHD) [1] and also of acquired cardiac complications associated with the twinning process. The incidence of heart disease is higher in monochorionic twins [2] and a proportion of these anomalies
0378-3782/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2008.01.009
174
N. Manning
are acquired as a result of altered haemodynamics, particularly in the recipient twin affected by twin-to-twin transfusion syndrome (TTTS). This review will focus on abnormalities of cardiac development associated with twinning. Twins account for around 2% of all pregnancies; approximately two thirds of these are dizygotic (DZ), resulting from fertilisation of two oocytes and are as genetically different as singleton siblings (non identical). The remaining third are monozygotic (MZ) following the division of a single embryonic cell mass after fertilisation and are identical. Monozygotic twins are at an increased risk of CHD [3] and this risk varies according to the type of MZ twin, as determined by the timing of division of the single fertilised embryo (Fig. 1). Chorionicity refers to the type of placentation and it is chorionicity rather than zygosity that determines the risk to the pregnancy and so defines the appropriate level of surveillance. Zygosity cannot be diagnosed by ultrasound other than by the observation of different sexes in some sets of dizygotic twins. However chorionicity can be established prenatally by ultrasound, most accurately during the 1st trimester, by the demonstration of a ‘lambda sign’ — a structure consisting of 2 layers of chorion within 2 layers of amnion (Fig. 2). In approximately one third of MZ twins the lambda sign is present and the twins are dichorionic (and thus also diamniotic). In the remaining two thirds the lambda sign is absent and the twins are therefore monochorionic. For monochorionic twins it is then possible to define amniocity; the presence of a thin dividing membrane (2 layers of amnion without a chorion) indicates that the twins are monochorionic and diamniotic (MC/DA). Absence of a dividing membrane and the presence of umbilical cord entanglement confirm that the twins are monochorionic and monoamniotic (MC/MA). The later the division of the cell mass, the higher the risk for the pregnancy for all complications including cardiac anomalies. In the case of conjoined twins, division is incomplete. This rare condition can be diagnosed by ultrasound, increasingly during the first trimester [4]. Monochorionic twins are at an increased risk for complications during pregnancy, in particular for developing twinto-twin transfusion syndrome (TTTS); approximately 15% of MC twin pregnancies develop TTTS [5]. Assessment of nuchal translucency can be particularly helpful in twin pregnancies. Although the incidence of
Figure 1
Figure 2 Ultrasound image demonstrating the lambda sign seen with dichorionic twins.
aneuploidy is lower in MC twins [6], discordant nuchal measurements suggest that the risk for developing TTTS in that pregnancy is increased as well as the risk for a structural cardiac anomaly in that fetus. A dichorionic diamniotic twin (DC/DA), whether DZ or MZ, is not considered to be at an increased risk of structural congenital heart disease (CHD) except perhaps when conceived by in vitro fertilisation [7]. A dichorionic diamniotic twin pregnancy with no other risk factors for CHD will still have twice the risk of at least one of the fetuses having CHD compared to a singleton pregnancy. For the purposes of this review abnormal cardiac development in twin pregnancies will be divided into: A) ‘primary’ structural cardiac lesions B) ‘acquired’ cardiac lesions: functional heart disease acquired as a result of TTTS C) ‘iatrogenic’ cardiac disease: influence of non steroidal anti-inflammatory drugs (NSAIDs) Aetiologies, both speculative and evidence based, will be discussed.
Timing of embryonic division and subsequent type of monozygotic twin pregnancy.
The influence of twinning on cardiac development
175
1. Primary structural cardiac anomalies
proposed that the differences could be at molecular level [17] or be due to the occurrence of a de novo mutation in one twin [2]. Disturbance of laterality in MZ twins has been better explored. Heterotaxy results from failure to establish left– right asymmetry during embryological development and one theory suggests that if MC/MA twinning occurs around the time that the left–right axis is defined, this process could be impaired in one twin. The relatively late division of the embryonic mass in both MA and conjoined twins may thus explain the higher incidence of laterality defects in this context. The left side of the body is thought to determine laterality and it is proposed that late division could cause the right half to become separated from its point of reference thus interfering with the heart looping sequence [3]. The fact that it is usually the right twin in a conjoined pair with heterotaxy supports this theory. It has been suggested that abnormalities of laterality in singleton pregnancies may result from the loss of an undiagnosed MZ twin very early in pregnancy [18].
The population risk for structural congenital heart disease is 8:1000 live births [8] and various factors are known to increase this risk, including the presence of MC twins. 1. monochorionic diamniotic twins The risk for at least 1 of a MC/DA twin pair having some form of CHD is approximately 7% and if one twin is affected, the risk to the other twin is increased up to 25% [1]. Although the lesion most frequently seen is a VSD, all types of CHD are represented in this group; when present in both fetuses concordancy for the lesion has been variably reported between 25% and 46% [9]. 2. monochorionic monoamniotic twins For MC/MA twins the risk is higher than for MC/DA twins [1] for all types of cardiac anomaly but with a significant increase in disturbance of laterality; heterotaxy is an unusual diagnosis (1:24,000 births [10]) but was reported to be increased (with an odds ratio of 4.8 for an affected twin compared to a singleton) in a series of MZ twins in which amnionicity was not defined [11]. In a small series of MC/MA twins, heterotaxy was present in at least one twin in 3/10 sets [12]. 3. conjoined twins Twins joined at thoracic level (thoracopagus) are the commonest type of conjoined twins, representing 40% of cases and cardiovascular involvement is common. In 90% they share a pericardium but major structural cardiac anomalies are present in at least 75% of cases [13]. Structural heart disease is frequently present in other forms of fusion and the degree of cardiac involvement may be the determining factor for whether postnatal separation is possible. Laterality defects are a feature in both thoracopagus and parapagus (joined side-by-side) twins usually occurring in the twin on the right side [14]; conjoined twins are more often female by a factor of 3:1 [13].
1.1. Aetiology of primary structural cardiac anomalies The aetiology of primary structural congenital heart disease in MC twins is poorly understood. One hypothesis to explain the increased incidence of structural anomalies in MZ twins includes a relationship between the twinning process and a susceptibility to another insult such that cardiac development in at least one twin is affected [3]. Another suggestion is that there is an unequal division of the embryonic cell mass allowing for unequal potential for development [2]. Identical genes in an apparently identical environment might be expected to produce identical phenotypes but this is not always the case, whether the heart is normal or abnormal but there is a paucity of studies exploring this important observation. Even in the context of an abnormal karyotype the phenotypes can differ as in Hillebrand's description of a pair of MC twins with 22q11deletion, both with classic phenotypes but with discordant cardiac lesions [15]. In another case report [16] one twin had hypoplastic left heart syndrome, while the other had only a bicuspid aortic valve, thus clinically different phenotypic manifestations of a left heart problem arose from a presumed similar genotype. It is
2. Acquired cardiac anomalies Acquired cardiac lesions are the consequence of haemodynamic abnormalities which can occur as a result of TTTS. The greatest risk from TTTS is for premature delivery but a significant proportion of the morbity and mortality of this disease arises from its cardiovascular effects which particularly affect the recipient twin. The majority of twins affected by TTTS are MC/DA although, more rarely, MC/MA pregnancies twins can be affected and its severity can be assessed according to recognised staging criteria [19] (Table 1). The diagnosis is suspected in the presence of unequal liquor pockets, the recipient twin having polyhydramnios while the donor has oligohydramnios; in addition there may be growth discordancy with intrauterine growth retardation, sometimes severe, in the donor twin (Fig. 3). Cardiac lesions acquired during pregnancy predominantly affect the right side of the heart of the recipient twin and include cardiomyopathy, ventricular hypertrophy, atrioventricular valvar regurgitation and right ventricular outflow tract obstruction (RVOTO). In addition, in response to the increasing oxygen requirements of the hypertrophied myocardium, changes take place in the coronary arteries to favour supply to the right ventricle whose workload increases disproportionately. It is a matter of conjecture as to the long
Table 1 Staging of twin-to-twin transfusion syndrome (Quintero et al. [19].) Stage 1 Stage 2 Stage 3
Stage 4 Stage 5
Donor bladder still visible, fetal dopplers normal (DV, umbilical artery and vein) Donor bladder not visible, fetal dopplers normal Donor bladder not visible, critically abnormal fetal dopplers (AEDF in donor cord +/− AEDF in DV in recipient) Presence of hydrops Intrauterine death of 1 or both twins
DV: ductus venosus; AEDF: absent end diastolic flow.
176
Figure 3 Discordant growth in a monochorionic twin pregnancy with twin-to-twin transfusion syndrome.
term effects of this fetal coronary pathology in an apparent normal survivor of TTTS. Cardiac lesions affecting the recipient in this way are additional to primary structural lesions and may be temporary and reversible or progressive, both during the pregnancy and after birth. In contrast to these developments in the recipient twin, acquired cardiac pathology of the donor is usually minimal [20]. Twin reversed arterial perfusion (TRAP) sequence occurs in approximately 1:35,000 pregnancies, (1% of MC twins) and represents the most extreme form of TTTS. In this situation the structurally normal pump (donor) twin perfuses an acardiac recipient through superficial arterial anastomses but inadequately such that somatic development is compromised and abnormal in the acardiac twin. The increased demands on the pump twin can lead to cardiac failure and hydrops, the time of onset being largely dependent on the size of the parasitic twin [21].
2.1. Aetiology of acquired cardiac anomalies The aetiology of acquired cardiac lesions is complex but perhaps more logical than that of the structural lesions now that the disease process involved in TTTS is better understood. Transamnionic connections are always present in monochorionic placentae but TTTS only develops in a proportion of these pregnancies. These placental anastomoses can be of 3 types1. deep arterio-venous anastomoses (A-V) 2. superficial arterio-arterial anastomoses (A-A) 3. superficial veno-venous anastomoses (V-V) The deep anastomoses allow for unidirectional flow from one twin (the donor) to the other (the recipient) and the superficial anastomoses are considered to be protective allowing for flow back to the initiating side. All MC twins have deep A-V anastomoses and in TTTS the compensatory A-A/V-V anastomoses are insufficient. The presence of superficial anastomoses not only reduces the likelihood of TTTS developing but also improves the outcome if it does develop.
N. Manning Approximately 85% of the superficial anastomoses can be identified transabdominally with colour Doppler during the 2nd trimester of pregnancy. In pregnancies with TTTS the circulatory sequelae in the recipient twin include increased blood volume, atrial distension and the release of atrial natriuretic peptide (ANP) resulting in polyuria and polyhydramnios. A consequence of hypervolaemia and cardiac overload is biventricular, but predominantly right ventricular hypertrophy and dilatation and impaired cardiac function. Atrioventricular valve regurgitation, particularly on the right side of the heart can lead to hydrops and, in some recipients, is associated with progressive RVOTO. Placental vascular resistance increases in the donor who is hypovolaemic with oligohydramnios and usually growth retarded but does not develop the acquired structural cardiac anomalies as seen in the recipient [5,20]. There is evidence that the cardiac dysfunction which may develop early in the recipient twin is the result of pressure rather than volume load [22]. Diastolic functional impairment occurs before systolic dysfunction and, by prolonging relaxation time, is more important than systolic dysfunction in compromising fetal circulation and producing hydrops [20]. Fetal hypertension, thickened vascular media and secondary altered humoral circulating factors including elevated levels of endothelin in the recipient twin all contribute to increasing afterload which causes systolic dysfunction [22]. Myocyte proliferation, stimulated by the increasing workload, causes cardiac hypertrophy which in turn can contribute to the progressive RVOTO seen in some recipient twins [23,24]. This obstruction may be at valvar or subvalvar level or in combination and may progress postnatally. Blood flow is known to play a crucial role in the development and growth of cardiac chambers and arteries; it is suggested that as a result of the altered haemodynamics in the recipient twin including severe tricuspid regurgitation and ventricular hypertrophy, flow through the right ventricular outflow tract is reduced. This in turn can lead to obstruction of the right ventricular outflow tract even to the extent of functional pulmonary atresia. As a consequence of hypovolaemia in the donor twin, the renin–angiotensin system (RAS) is activated with up-regulation in the donor and down-regulation in the recipient [2,25]. Arterial compliance is reduced in the donor with possible long term effects including hypertension and renal damage. It is suggested that these changes in the RAS system may be crucial in the pathogenesis of TTTS by aggravating the oligohydramnios, increasing arterial resistance, contributing to placental dysfunction and thus to intrauterine growth restriction. The cardiovascular complications are usually more severe with advancing stages of TTTS. Attempts at treatment of this potentially lethal condition remain controversial; for milder forms of TTTS this may involve serial amnioreductions but more severe cases are offered laser ablation to the deep anastomoses on the assumption that division of the communicating vessels will halt the disease. Cardiovascular complications in the recipient twin are not halted by amnioreductions and in fact may progress [20]; in contrast, following laser therapy for severe TTTS cardiovascular complications may regress to the point of normalisation in
The influence of twinning on cardiac development Table 2
Twins and the relative risk of cardiac anomalies DC/DA MC/ (all DZ + DA 1/3 MZ)
Risk of primary − structural CHD Risk of acquired − cardiac disease Risk of iatrogenic CHD −
+
MC/ Conjoined MA ++
+++
++ +/− − (if TTTS) − + −
(See text for further details).
the majority of fetuses, although neonatal assessment is still recommended as progression postnatally has been described in the pre-ablation era [26,27].
Figure 4
177 Altered humoral influences in TTTS can result in impaired diastolic function in the recipient but increased systolic performance in the donor twin; neonatal assessment is appropriate for both twins [26,27]. There is the potential for progression of RVOTO in the recipient twin and hypertension may be a feature for both but particularly in the donor [25]. 2.1.1. Implications for adult health Changes occurring in the cardiovascular system of both twins may serve as an example for fetal origins of adult disease; potential mechanisms causing heart disease include the alteration of the hormonal environment with altered blood pressure, changes in blood flow and vessel distensibility as well as abnormal differentiation of myocardial cells and changes in coronary artery growth, especially in the recipient twin [23].
Algorithm for the management of cardiac issues in monochorionic twin pregnancies.
178
3. ‘Iatrogenic’ cardiac complications in twins The use of non steroidal anti-inflammatory drugs (NSAIDs) in pregnancy is controversial but may have a role in the management of monoamniotic twins. For these twins there is a high rate of fetal loss, in some series as high as 50–70% of fetuses. Although preterm delivery and fetal abnormality account for some of this figure, the risk is mainly due to the consequences of cord entanglement which begins during the first trimester in the absence of a dividing membrane. The rationale for NSAID use is to reduce liquor volume thereby reducing fetal movement and the opportunity for further cord entanglement. However NSAIDs have the potential to cause constriction or even closure of the arterial duct in utero with serious cardiovascular consequences including severe tricuspid regurgitation, right ventricular failure, hydrops and perhaps neonatal pulmonary hypertension. One study suggests that in the context of TTTS the donor twin is more susceptible to in utero ductal closure when exposed to NSAIDs, perhaps due to relative hypoxia [28]. There may also be longer term issues relating to their use with evidence to suggest that fetuses exposed to NSAIDs prenatally may be more likely to develop symptomatic patent ductus arteriosus if born prematurely and less likely to respond to medical treatment for this condition (Table 2).
4. Conclusions The incidence of monochorionic twins is increasing, partly due to the increasing number of pregnancies conceived by assisted reproduction programmes which can double the incidence of MZ twinning [29]. Monochorionic twins are associated with an increased risk of adverse outcome compared to DC twins. In addition to the risks of TTTS itself, MC twins have a significantly increased risk of cardiac anomalies, whether primary structural lesions or acquired as a result of complications during the pregnancy. This justifies offering a detailed cardiac assessment for all MC twins, initially to establish normal anatomy and then to check for any evolving lesions or cardiac dysfunction in pregnancies complicated by TTTS. Postnatally cardiac development can be influenced by early events occurring in utero, in particular with TTTS and these may need to be followed up through childhood. There are few survivors of severe TTTS studied in their late teens so far but potential long term consequences of the fetal pathophysiological changes occurring in TTTS suggest that they may be at risk of hypertension and premature coronary artery disease; translating this observation into practical clinical advice is currently not possible.
5. Key guidelines Fig. 4 - U/S for early prenatal assessment of chorionicity and amnionicity in all twin pregnancies to determine appropriate level of surveillance - assessment of nuchal translucency at 12 weeks
N. Manning - check maternal cervical length at 18 and 23 weeks (defines risk of prematurity) for conjoined twins - detailed cardiac assessment and referral to Specialist Unit for all monochorionic twins - look for superficial placental anastomoses from 16– 18 weeks - fetal echocardiography to assess cardiac anatomy (16– 20 weeks) - if superficial placental anastomoses are present — 2–3 weekly assessments for evidence of TTTS developing - if no anastomoses, more frequent assessments (1× weekly) - in presence of TTTS, assessment of cardiac function in the recipient twin +/− evolving structural cardiac anomaly - treatment of TTTS if appropriate - continued cardiac monitoring following treatment - deliver at 37 weeks if uncomplicated, not later than 33 weeks if TTTS - neonatal cardiac assessment of recipient (in particular for function + RVOTO + blood pressure) - blood pressure measurement and renal function evaluation in donor - follow up through infancy if any abnormality detected in utero or newborn period - implications for follow up through later childhood/adult life unknown
6. Research directions - causes of monozygotic twinning, factors reducing the risk - connection of twinning process with primary structural cardiac anomalies - timing of the definition of laterality and its relationship with heterotaxy in monoamniotic and conjoined twins - factors involved in the initiation of TTTS and its severity - genetic factors influencing different phenotypes for both identical karyotypes and environment (in absence of TTTS) - role of humeral responses to TTTS and their long term consequences through childhood and beyond
Acknowledgement I am grateful to Dr Nick Archer for his advice with the manuscript.
References [1] Manning N, Archer N. A study to determine the incidence of structural congenital heart disease in monochorionic twins. Prenat Diagn 2006;26(11):1062–4. [2] 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 casecontrol study of 136 monochorionic twin pregnancies. Heart 2002;88:271–7. [3] Burn J, Corney G. Congenital heart defects and twinning. Acta Genet Med Gemellol 1984;33:61–9. [4] Pajkrt E, Jauniaux E. First-trimester diagnosis of conjoined twins. Prenat Diagn 2005;25:820–6.
The influence of twinning on cardiac development [5] Galea P, Jain V, Fisk NM. Insights into the pathophysiology of twin–twin transfusion syndrome. Prenat Diagn 2005;25: 777–85. [6] Jamar M, Lemarchal C, Lemair V, Koulischer L, Bours V. A low rate of trisomy 21 in twin-pregnancies: a cytogenetics retrospective study of 278 cases. Genet Couns 2003;14(4):395–400. [7] Koivurova S, Hartikainen AL, Gissler M, Hemminki E, Sovio U, Jarvelin M-R. Neonatal outcome and congenital malformations in children born after in-vitro fertilization. Hum Reprod 2002;17(5): 1391–8. [8] Hoffman JIE. Incidence of congenital heart disease:1. Postnatal incidence. Pediatr Cardiol 1995;16:103–13. [9] Digilio MC, Marino B, Giannico S, Giannotti A, Dallapiccola B. Atrioventricular canal defect and hypoplastic left heart syndrome as discordant congenital heart defects in twins. Teratology 1999;60:206–8. [10] Penman Splitt M, Burn J, Goodship J. Defects in the determination of left–right asymmetry. J Med Genet 1996;33:498–503. [11] Kuehl KS, Loffredo C. Risk factors for heart disease associated with abnormal sidedness. Teratology 2002;66:242–8. [12] Vogel M, Archer N, Manning N. Heterotaxy in monoamniotic twins. Poster presentation at 4th annual symposium on advances in perinatal cardiology, St Petersburg, Florida; 2006. [13] Andrews RE, McMahon CJ, Yates RWM, Cullen S, de Laval MR, Kiely EM, et al. Echocardiographic assessment of conjoined twins. Heart 2006;92:382–7. [14] Levin M, Roberts DJ, Holmes LB, Tabin C. Laterality defects in conjoined twins. Nature 1996;384:321. [15] Hillebrand G, Siebert R, Simeoni E, Santer R. DiGeorge syndrome with discordant phenotype in monozygotic twins. J Med Genet 2000;37(9):E23. [16] Mu TS, McAdams RM, Bush DM. A case of hypoplastic left heart syndrome and bicuspid aortic valve in monochorionic twins. Pediatr Cardiol 2005;26:884–5. [17] Gringras P, Chen W. Mechanisms for differences in monozygous twins. Early Hum Dev 2001;64:105–17. [18] Sommer IEC, Ramsey NF, Mandl CW, Kahn RS. Language lateralization in monozygotic twin pairs concordant and discordant for handedness. Brain 2002;125:2710–8.
179 [19] Quintero RA, Morales WJ, Allen MH, Bornick PW, Johnson PK, Kruger M. Staging of twin–twin transfusion syndrome. J Perinatol 1999;19(8Pt 1):550–5. [20] Barrea C, Alkazaleh F, Ryan G, McCrindle BW, Roberts A, Bigras J-L, et al. Prenatal cardiovascular manifestations in the twinto-twin transfusion syndrome recipients and the impact of therapeutic amnioreduction. Am J Obstet Gynecol 2005;192: 892–902. [21] Wong AE, Sepulveda W. Acardiac anomaly: current issues in prenatal assessment and treatment. Prenat Diagn 2005;25(9): 796–806. [22] Raboisson MJ, Fouron JC, Lamoureux J, Leduc L, Grignon A, Proulx F, et al. Early intertwin differences in myocardial performance during the twin-to-twin transfusion syndrome. Circulation 2004;110:3043–8. [23] Chescheir NC. Twin-to-twin transfusion syndrome: a model for the fetal origins of adult health. Paediatr Perinat Epidemiol 2005;19(suppl1):32–6. [24] Lougheed J, Sinclair BG, Fung Kee Fung K, Bigras J-L, ryan G, Smallhorn JF, et al. Acquired right ventricular outflow tract obstruction in the recipient twin in twin–twin transfusion syndrome. J Am Coll Cardiol 2001;38:1533–8. [25] Mahieu-Caputo D, Muller F, Joly D, Gubler M-C, Lebidois J, Fermont L, et al. Pathogenesis of twin-to-twin transfusion syndrome: the rennin–angiotensin system hypothesis. Fetal Diagn Ther 2001;16:241–4. [26] Herberg U, Gross W, Bartmann P, Banek CS, Hecher K, Breuer J. Long term follow up of severe twin to twin transfusion syndrome after laser coagulation. Heart 2006;92:95–100. [27] Fesslova V, Villa L, Nava S, Mosca F, Nicolini U. Fetal and neonatal echocardiographic findings in twin–twin transfusion syndrome. Am J Obstet Gynecol 1998;179(4):1056–62. [28] Shehata BM, Bare JB, Denton TD, Habib MN, Black JO. Premature closure of the ductus arteriosus: variable response among monozygotic twins after in utero exposure to indomethacin. Fetal Pediatr Pathol 2006;25:151–7. [29] Hankins GVD, Saade GR. Factors influencing twins and zygosity. Paediatr Perinat Epidemiol 2005;19(Suppl 1):8–9.
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / e a r l h u m d e v
BEST PRACTICE GUIDELINE ARTICLE
The influence of twinning on cardiac development Nicky Manning ⁎ Department of Paediatric Cardiology (Fetal Cardiology), Oxford Children's Hospital, The John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
KEYWORDS Twins; Congenital heart disease; Monozygotic; Monochorionic; Dichorionic; Twin-to-twin transfusion syndrome
Abstract The risk for a cardiac anomaly in a twin pregnancy is increased, particularly in monochorionic twins. This is relevant in terms of fetal diagnosis as well as for the management of the pregnancy; there are also implications for the neonatal period and possibly beyond. The risk for a cardiac abnormality depends on the type of monochorionic twin as determined by the timing of embryonic division. Prenatal identification of twin type and the relative risks for a cardiac anomaly are discussed along with theories for the aetiology of the different cardiac lesions. © 2008 Elsevier Ireland Ltd. All rights reserved.
Contents 1.
Primary structural cardiac anomalies . . . . . . . . . . 1.1. Aetiology of primary structural cardiac anomalies 2. Acquired cardiac anomalies . . . . . . . . . . . . . . . . 2.1. Aetiology of acquired cardiac anomalies . . . . 2.1.1. Implications for adult health . . . . . . 3. ‘Iatrogenic’ cardiac complications in twins . . . . . . . 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . 5. Key guidelines . . . . . . . . . . . . . . . . . . . . . . . 6. Research directions . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The risk of complications and adverse outcome is greater in twin pregnancies compared to singletons, mainly due to the increased risk of prematurity. However a significant contribu⁎ Tel.: +44 01865 231313; fax: +44 01865 234211. E-mail address: [email protected].
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
175 175 175 176 177 178 178 178 178 178 178
tion to this higher morbidity and mortality is made by the cardiac complications of being a twin. This includes an increased risk of structural congenital heart disease (CHD) [1] and also of acquired cardiac complications associated with the twinning process. The incidence of heart disease is higher in monochorionic twins [2] and a proportion of these anomalies
0378-3782/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2008.01.009
174
N. Manning
are acquired as a result of altered haemodynamics, particularly in the recipient twin affected by twin-to-twin transfusion syndrome (TTTS). This review will focus on abnormalities of cardiac development associated with twinning. Twins account for around 2% of all pregnancies; approximately two thirds of these are dizygotic (DZ), resulting from fertilisation of two oocytes and are as genetically different as singleton siblings (non identical). The remaining third are monozygotic (MZ) following the division of a single embryonic cell mass after fertilisation and are identical. Monozygotic twins are at an increased risk of CHD [3] and this risk varies according to the type of MZ twin, as determined by the timing of division of the single fertilised embryo (Fig. 1). Chorionicity refers to the type of placentation and it is chorionicity rather than zygosity that determines the risk to the pregnancy and so defines the appropriate level of surveillance. Zygosity cannot be diagnosed by ultrasound other than by the observation of different sexes in some sets of dizygotic twins. However chorionicity can be established prenatally by ultrasound, most accurately during the 1st trimester, by the demonstration of a ‘lambda sign’ — a structure consisting of 2 layers of chorion within 2 layers of amnion (Fig. 2). In approximately one third of MZ twins the lambda sign is present and the twins are dichorionic (and thus also diamniotic). In the remaining two thirds the lambda sign is absent and the twins are therefore monochorionic. For monochorionic twins it is then possible to define amniocity; the presence of a thin dividing membrane (2 layers of amnion without a chorion) indicates that the twins are monochorionic and diamniotic (MC/DA). Absence of a dividing membrane and the presence of umbilical cord entanglement confirm that the twins are monochorionic and monoamniotic (MC/MA). The later the division of the cell mass, the higher the risk for the pregnancy for all complications including cardiac anomalies. In the case of conjoined twins, division is incomplete. This rare condition can be diagnosed by ultrasound, increasingly during the first trimester [4]. Monochorionic twins are at an increased risk for complications during pregnancy, in particular for developing twinto-twin transfusion syndrome (TTTS); approximately 15% of MC twin pregnancies develop TTTS [5]. Assessment of nuchal translucency can be particularly helpful in twin pregnancies. Although the incidence of
Figure 1
Figure 2 Ultrasound image demonstrating the lambda sign seen with dichorionic twins.
aneuploidy is lower in MC twins [6], discordant nuchal measurements suggest that the risk for developing TTTS in that pregnancy is increased as well as the risk for a structural cardiac anomaly in that fetus. A dichorionic diamniotic twin (DC/DA), whether DZ or MZ, is not considered to be at an increased risk of structural congenital heart disease (CHD) except perhaps when conceived by in vitro fertilisation [7]. A dichorionic diamniotic twin pregnancy with no other risk factors for CHD will still have twice the risk of at least one of the fetuses having CHD compared to a singleton pregnancy. For the purposes of this review abnormal cardiac development in twin pregnancies will be divided into: A) ‘primary’ structural cardiac lesions B) ‘acquired’ cardiac lesions: functional heart disease acquired as a result of TTTS C) ‘iatrogenic’ cardiac disease: influence of non steroidal anti-inflammatory drugs (NSAIDs) Aetiologies, both speculative and evidence based, will be discussed.
Timing of embryonic division and subsequent type of monozygotic twin pregnancy.
The influence of twinning on cardiac development
175
1. Primary structural cardiac anomalies
proposed that the differences could be at molecular level [17] or be due to the occurrence of a de novo mutation in one twin [2]. Disturbance of laterality in MZ twins has been better explored. Heterotaxy results from failure to establish left– right asymmetry during embryological development and one theory suggests that if MC/MA twinning occurs around the time that the left–right axis is defined, this process could be impaired in one twin. The relatively late division of the embryonic mass in both MA and conjoined twins may thus explain the higher incidence of laterality defects in this context. The left side of the body is thought to determine laterality and it is proposed that late division could cause the right half to become separated from its point of reference thus interfering with the heart looping sequence [3]. The fact that it is usually the right twin in a conjoined pair with heterotaxy supports this theory. It has been suggested that abnormalities of laterality in singleton pregnancies may result from the loss of an undiagnosed MZ twin very early in pregnancy [18].
The population risk for structural congenital heart disease is 8:1000 live births [8] and various factors are known to increase this risk, including the presence of MC twins. 1. monochorionic diamniotic twins The risk for at least 1 of a MC/DA twin pair having some form of CHD is approximately 7% and if one twin is affected, the risk to the other twin is increased up to 25% [1]. Although the lesion most frequently seen is a VSD, all types of CHD are represented in this group; when present in both fetuses concordancy for the lesion has been variably reported between 25% and 46% [9]. 2. monochorionic monoamniotic twins For MC/MA twins the risk is higher than for MC/DA twins [1] for all types of cardiac anomaly but with a significant increase in disturbance of laterality; heterotaxy is an unusual diagnosis (1:24,000 births [10]) but was reported to be increased (with an odds ratio of 4.8 for an affected twin compared to a singleton) in a series of MZ twins in which amnionicity was not defined [11]. In a small series of MC/MA twins, heterotaxy was present in at least one twin in 3/10 sets [12]. 3. conjoined twins Twins joined at thoracic level (thoracopagus) are the commonest type of conjoined twins, representing 40% of cases and cardiovascular involvement is common. In 90% they share a pericardium but major structural cardiac anomalies are present in at least 75% of cases [13]. Structural heart disease is frequently present in other forms of fusion and the degree of cardiac involvement may be the determining factor for whether postnatal separation is possible. Laterality defects are a feature in both thoracopagus and parapagus (joined side-by-side) twins usually occurring in the twin on the right side [14]; conjoined twins are more often female by a factor of 3:1 [13].
1.1. Aetiology of primary structural cardiac anomalies The aetiology of primary structural congenital heart disease in MC twins is poorly understood. One hypothesis to explain the increased incidence of structural anomalies in MZ twins includes a relationship between the twinning process and a susceptibility to another insult such that cardiac development in at least one twin is affected [3]. Another suggestion is that there is an unequal division of the embryonic cell mass allowing for unequal potential for development [2]. Identical genes in an apparently identical environment might be expected to produce identical phenotypes but this is not always the case, whether the heart is normal or abnormal but there is a paucity of studies exploring this important observation. Even in the context of an abnormal karyotype the phenotypes can differ as in Hillebrand's description of a pair of MC twins with 22q11deletion, both with classic phenotypes but with discordant cardiac lesions [15]. In another case report [16] one twin had hypoplastic left heart syndrome, while the other had only a bicuspid aortic valve, thus clinically different phenotypic manifestations of a left heart problem arose from a presumed similar genotype. It is
2. Acquired cardiac anomalies Acquired cardiac lesions are the consequence of haemodynamic abnormalities which can occur as a result of TTTS. The greatest risk from TTTS is for premature delivery but a significant proportion of the morbity and mortality of this disease arises from its cardiovascular effects which particularly affect the recipient twin. The majority of twins affected by TTTS are MC/DA although, more rarely, MC/MA pregnancies twins can be affected and its severity can be assessed according to recognised staging criteria [19] (Table 1). The diagnosis is suspected in the presence of unequal liquor pockets, the recipient twin having polyhydramnios while the donor has oligohydramnios; in addition there may be growth discordancy with intrauterine growth retardation, sometimes severe, in the donor twin (Fig. 3). Cardiac lesions acquired during pregnancy predominantly affect the right side of the heart of the recipient twin and include cardiomyopathy, ventricular hypertrophy, atrioventricular valvar regurgitation and right ventricular outflow tract obstruction (RVOTO). In addition, in response to the increasing oxygen requirements of the hypertrophied myocardium, changes take place in the coronary arteries to favour supply to the right ventricle whose workload increases disproportionately. It is a matter of conjecture as to the long
Table 1 Staging of twin-to-twin transfusion syndrome (Quintero et al. [19].) Stage 1 Stage 2 Stage 3
Stage 4 Stage 5
Donor bladder still visible, fetal dopplers normal (DV, umbilical artery and vein) Donor bladder not visible, fetal dopplers normal Donor bladder not visible, critically abnormal fetal dopplers (AEDF in donor cord +/− AEDF in DV in recipient) Presence of hydrops Intrauterine death of 1 or both twins
DV: ductus venosus; AEDF: absent end diastolic flow.
176
Figure 3 Discordant growth in a monochorionic twin pregnancy with twin-to-twin transfusion syndrome.
term effects of this fetal coronary pathology in an apparent normal survivor of TTTS. Cardiac lesions affecting the recipient in this way are additional to primary structural lesions and may be temporary and reversible or progressive, both during the pregnancy and after birth. In contrast to these developments in the recipient twin, acquired cardiac pathology of the donor is usually minimal [20]. Twin reversed arterial perfusion (TRAP) sequence occurs in approximately 1:35,000 pregnancies, (1% of MC twins) and represents the most extreme form of TTTS. In this situation the structurally normal pump (donor) twin perfuses an acardiac recipient through superficial arterial anastomses but inadequately such that somatic development is compromised and abnormal in the acardiac twin. The increased demands on the pump twin can lead to cardiac failure and hydrops, the time of onset being largely dependent on the size of the parasitic twin [21].
2.1. Aetiology of acquired cardiac anomalies The aetiology of acquired cardiac lesions is complex but perhaps more logical than that of the structural lesions now that the disease process involved in TTTS is better understood. Transamnionic connections are always present in monochorionic placentae but TTTS only develops in a proportion of these pregnancies. These placental anastomoses can be of 3 types1. deep arterio-venous anastomoses (A-V) 2. superficial arterio-arterial anastomoses (A-A) 3. superficial veno-venous anastomoses (V-V) The deep anastomoses allow for unidirectional flow from one twin (the donor) to the other (the recipient) and the superficial anastomoses are considered to be protective allowing for flow back to the initiating side. All MC twins have deep A-V anastomoses and in TTTS the compensatory A-A/V-V anastomoses are insufficient. The presence of superficial anastomoses not only reduces the likelihood of TTTS developing but also improves the outcome if it does develop.
N. Manning Approximately 85% of the superficial anastomoses can be identified transabdominally with colour Doppler during the 2nd trimester of pregnancy. In pregnancies with TTTS the circulatory sequelae in the recipient twin include increased blood volume, atrial distension and the release of atrial natriuretic peptide (ANP) resulting in polyuria and polyhydramnios. A consequence of hypervolaemia and cardiac overload is biventricular, but predominantly right ventricular hypertrophy and dilatation and impaired cardiac function. Atrioventricular valve regurgitation, particularly on the right side of the heart can lead to hydrops and, in some recipients, is associated with progressive RVOTO. Placental vascular resistance increases in the donor who is hypovolaemic with oligohydramnios and usually growth retarded but does not develop the acquired structural cardiac anomalies as seen in the recipient [5,20]. There is evidence that the cardiac dysfunction which may develop early in the recipient twin is the result of pressure rather than volume load [22]. Diastolic functional impairment occurs before systolic dysfunction and, by prolonging relaxation time, is more important than systolic dysfunction in compromising fetal circulation and producing hydrops [20]. Fetal hypertension, thickened vascular media and secondary altered humoral circulating factors including elevated levels of endothelin in the recipient twin all contribute to increasing afterload which causes systolic dysfunction [22]. Myocyte proliferation, stimulated by the increasing workload, causes cardiac hypertrophy which in turn can contribute to the progressive RVOTO seen in some recipient twins [23,24]. This obstruction may be at valvar or subvalvar level or in combination and may progress postnatally. Blood flow is known to play a crucial role in the development and growth of cardiac chambers and arteries; it is suggested that as a result of the altered haemodynamics in the recipient twin including severe tricuspid regurgitation and ventricular hypertrophy, flow through the right ventricular outflow tract is reduced. This in turn can lead to obstruction of the right ventricular outflow tract even to the extent of functional pulmonary atresia. As a consequence of hypovolaemia in the donor twin, the renin–angiotensin system (RAS) is activated with up-regulation in the donor and down-regulation in the recipient [2,25]. Arterial compliance is reduced in the donor with possible long term effects including hypertension and renal damage. It is suggested that these changes in the RAS system may be crucial in the pathogenesis of TTTS by aggravating the oligohydramnios, increasing arterial resistance, contributing to placental dysfunction and thus to intrauterine growth restriction. The cardiovascular complications are usually more severe with advancing stages of TTTS. Attempts at treatment of this potentially lethal condition remain controversial; for milder forms of TTTS this may involve serial amnioreductions but more severe cases are offered laser ablation to the deep anastomoses on the assumption that division of the communicating vessels will halt the disease. Cardiovascular complications in the recipient twin are not halted by amnioreductions and in fact may progress [20]; in contrast, following laser therapy for severe TTTS cardiovascular complications may regress to the point of normalisation in
The influence of twinning on cardiac development Table 2
Twins and the relative risk of cardiac anomalies DC/DA MC/ (all DZ + DA 1/3 MZ)
Risk of primary − structural CHD Risk of acquired − cardiac disease Risk of iatrogenic CHD −
+
MC/ Conjoined MA ++
+++
++ +/− − (if TTTS) − + −
(See text for further details).
the majority of fetuses, although neonatal assessment is still recommended as progression postnatally has been described in the pre-ablation era [26,27].
Figure 4
177 Altered humoral influences in TTTS can result in impaired diastolic function in the recipient but increased systolic performance in the donor twin; neonatal assessment is appropriate for both twins [26,27]. There is the potential for progression of RVOTO in the recipient twin and hypertension may be a feature for both but particularly in the donor [25]. 2.1.1. Implications for adult health Changes occurring in the cardiovascular system of both twins may serve as an example for fetal origins of adult disease; potential mechanisms causing heart disease include the alteration of the hormonal environment with altered blood pressure, changes in blood flow and vessel distensibility as well as abnormal differentiation of myocardial cells and changes in coronary artery growth, especially in the recipient twin [23].
Algorithm for the management of cardiac issues in monochorionic twin pregnancies.
178
3. ‘Iatrogenic’ cardiac complications in twins The use of non steroidal anti-inflammatory drugs (NSAIDs) in pregnancy is controversial but may have a role in the management of monoamniotic twins. For these twins there is a high rate of fetal loss, in some series as high as 50–70% of fetuses. Although preterm delivery and fetal abnormality account for some of this figure, the risk is mainly due to the consequences of cord entanglement which begins during the first trimester in the absence of a dividing membrane. The rationale for NSAID use is to reduce liquor volume thereby reducing fetal movement and the opportunity for further cord entanglement. However NSAIDs have the potential to cause constriction or even closure of the arterial duct in utero with serious cardiovascular consequences including severe tricuspid regurgitation, right ventricular failure, hydrops and perhaps neonatal pulmonary hypertension. One study suggests that in the context of TTTS the donor twin is more susceptible to in utero ductal closure when exposed to NSAIDs, perhaps due to relative hypoxia [28]. There may also be longer term issues relating to their use with evidence to suggest that fetuses exposed to NSAIDs prenatally may be more likely to develop symptomatic patent ductus arteriosus if born prematurely and less likely to respond to medical treatment for this condition (Table 2).
4. Conclusions The incidence of monochorionic twins is increasing, partly due to the increasing number of pregnancies conceived by assisted reproduction programmes which can double the incidence of MZ twinning [29]. Monochorionic twins are associated with an increased risk of adverse outcome compared to DC twins. In addition to the risks of TTTS itself, MC twins have a significantly increased risk of cardiac anomalies, whether primary structural lesions or acquired as a result of complications during the pregnancy. This justifies offering a detailed cardiac assessment for all MC twins, initially to establish normal anatomy and then to check for any evolving lesions or cardiac dysfunction in pregnancies complicated by TTTS. Postnatally cardiac development can be influenced by early events occurring in utero, in particular with TTTS and these may need to be followed up through childhood. There are few survivors of severe TTTS studied in their late teens so far but potential long term consequences of the fetal pathophysiological changes occurring in TTTS suggest that they may be at risk of hypertension and premature coronary artery disease; translating this observation into practical clinical advice is currently not possible.
5. Key guidelines Fig. 4 - U/S for early prenatal assessment of chorionicity and amnionicity in all twin pregnancies to determine appropriate level of surveillance - assessment of nuchal translucency at 12 weeks
N. Manning - check maternal cervical length at 18 and 23 weeks (defines risk of prematurity) for conjoined twins - detailed cardiac assessment and referral to Specialist Unit for all monochorionic twins - look for superficial placental anastomoses from 16– 18 weeks - fetal echocardiography to assess cardiac anatomy (16– 20 weeks) - if superficial placental anastomoses are present — 2–3 weekly assessments for evidence of TTTS developing - if no anastomoses, more frequent assessments (1× weekly) - in presence of TTTS, assessment of cardiac function in the recipient twin +/− evolving structural cardiac anomaly - treatment of TTTS if appropriate - continued cardiac monitoring following treatment - deliver at 37 weeks if uncomplicated, not later than 33 weeks if TTTS - neonatal cardiac assessment of recipient (in particular for function + RVOTO + blood pressure) - blood pressure measurement and renal function evaluation in donor - follow up through infancy if any abnormality detected in utero or newborn period - implications for follow up through later childhood/adult life unknown
6. Research directions - causes of monozygotic twinning, factors reducing the risk - connection of twinning process with primary structural cardiac anomalies - timing of the definition of laterality and its relationship with heterotaxy in monoamniotic and conjoined twins - factors involved in the initiation of TTTS and its severity - genetic factors influencing different phenotypes for both identical karyotypes and environment (in absence of TTTS) - role of humeral responses to TTTS and their long term consequences through childhood and beyond
Acknowledgement I am grateful to Dr Nick Archer for his advice with the manuscript.
References [1] Manning N, Archer N. A study to determine the incidence of structural congenital heart disease in monochorionic twins. Prenat Diagn 2006;26(11):1062–4. [2] 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 casecontrol study of 136 monochorionic twin pregnancies. Heart 2002;88:271–7. [3] Burn J, Corney G. Congenital heart defects and twinning. Acta Genet Med Gemellol 1984;33:61–9. [4] Pajkrt E, Jauniaux E. First-trimester diagnosis of conjoined twins. Prenat Diagn 2005;25:820–6.
The influence of twinning on cardiac development [5] Galea P, Jain V, Fisk NM. Insights into the pathophysiology of twin–twin transfusion syndrome. Prenat Diagn 2005;25: 777–85. [6] Jamar M, Lemarchal C, Lemair V, Koulischer L, Bours V. A low rate of trisomy 21 in twin-pregnancies: a cytogenetics retrospective study of 278 cases. Genet Couns 2003;14(4):395–400. [7] Koivurova S, Hartikainen AL, Gissler M, Hemminki E, Sovio U, Jarvelin M-R. Neonatal outcome and congenital malformations in children born after in-vitro fertilization. Hum Reprod 2002;17(5): 1391–8. [8] Hoffman JIE. Incidence of congenital heart disease:1. Postnatal incidence. Pediatr Cardiol 1995;16:103–13. [9] Digilio MC, Marino B, Giannico S, Giannotti A, Dallapiccola B. Atrioventricular canal defect and hypoplastic left heart syndrome as discordant congenital heart defects in twins. Teratology 1999;60:206–8. [10] Penman Splitt M, Burn J, Goodship J. Defects in the determination of left–right asymmetry. J Med Genet 1996;33:498–503. [11] Kuehl KS, Loffredo C. Risk factors for heart disease associated with abnormal sidedness. Teratology 2002;66:242–8. [12] Vogel M, Archer N, Manning N. Heterotaxy in monoamniotic twins. Poster presentation at 4th annual symposium on advances in perinatal cardiology, St Petersburg, Florida; 2006. [13] Andrews RE, McMahon CJ, Yates RWM, Cullen S, de Laval MR, Kiely EM, et al. Echocardiographic assessment of conjoined twins. Heart 2006;92:382–7. [14] Levin M, Roberts DJ, Holmes LB, Tabin C. Laterality defects in conjoined twins. Nature 1996;384:321. [15] Hillebrand G, Siebert R, Simeoni E, Santer R. DiGeorge syndrome with discordant phenotype in monozygotic twins. J Med Genet 2000;37(9):E23. [16] Mu TS, McAdams RM, Bush DM. A case of hypoplastic left heart syndrome and bicuspid aortic valve in monochorionic twins. Pediatr Cardiol 2005;26:884–5. [17] Gringras P, Chen W. Mechanisms for differences in monozygous twins. Early Hum Dev 2001;64:105–17. [18] Sommer IEC, Ramsey NF, Mandl CW, Kahn RS. Language lateralization in monozygotic twin pairs concordant and discordant for handedness. Brain 2002;125:2710–8.
179 [19] Quintero RA, Morales WJ, Allen MH, Bornick PW, Johnson PK, Kruger M. Staging of twin–twin transfusion syndrome. J Perinatol 1999;19(8Pt 1):550–5. [20] Barrea C, Alkazaleh F, Ryan G, McCrindle BW, Roberts A, Bigras J-L, et al. Prenatal cardiovascular manifestations in the twinto-twin transfusion syndrome recipients and the impact of therapeutic amnioreduction. Am J Obstet Gynecol 2005;192: 892–902. [21] Wong AE, Sepulveda W. Acardiac anomaly: current issues in prenatal assessment and treatment. Prenat Diagn 2005;25(9): 796–806. [22] Raboisson MJ, Fouron JC, Lamoureux J, Leduc L, Grignon A, Proulx F, et al. Early intertwin differences in myocardial performance during the twin-to-twin transfusion syndrome. Circulation 2004;110:3043–8. [23] Chescheir NC. Twin-to-twin transfusion syndrome: a model for the fetal origins of adult health. Paediatr Perinat Epidemiol 2005;19(suppl1):32–6. [24] Lougheed J, Sinclair BG, Fung Kee Fung K, Bigras J-L, ryan G, Smallhorn JF, et al. Acquired right ventricular outflow tract obstruction in the recipient twin in twin–twin transfusion syndrome. J Am Coll Cardiol 2001;38:1533–8. [25] Mahieu-Caputo D, Muller F, Joly D, Gubler M-C, Lebidois J, Fermont L, et al. Pathogenesis of twin-to-twin transfusion syndrome: the rennin–angiotensin system hypothesis. Fetal Diagn Ther 2001;16:241–4. [26] Herberg U, Gross W, Bartmann P, Banek CS, Hecher K, Breuer J. Long term follow up of severe twin to twin transfusion syndrome after laser coagulation. Heart 2006;92:95–100. [27] Fesslova V, Villa L, Nava S, Mosca F, Nicolini U. Fetal and neonatal echocardiographic findings in twin–twin transfusion syndrome. Am J Obstet Gynecol 1998;179(4):1056–62. [28] Shehata BM, Bare JB, Denton TD, Habib MN, Black JO. Premature closure of the ductus arteriosus: variable response among monozygotic twins after in utero exposure to indomethacin. Fetal Pediatr Pathol 2006;25:151–7. [29] Hankins GVD, Saade GR. Factors influencing twins and zygosity. Paediatr Perinat Epidemiol 2005;19(Suppl 1):8–9.