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Loeys Dietz Syndrome and pregnancy: A case report with literature review and a proposed focused management protocol
International Journal of Cardiology 214 (2016) 491–492
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Correspondence
Loeys Dietz Syndrome and pregnancy: A case report with literature review and a proposed focused management protocol Matthew Cauldwell a,⁎, Roshni R Patel a, Anselm Uebing b, Michael A. Gatzoulis b, Lorna Swan b a b
Department of Obstetrics, Chelsea and Westminster Hospital, 369 Fulham Road, London, United Kingdom Adult Congenital Heart Disease Centre, Royal Brompton Hospital, Sydney Street, London, United Kingdom
a r t i c l e
i n f o
Article history: Received 7 January 2016 Received in revised form 31 March 2016 Accepted 3 April 2016 Available online 7 April 2016 Keywords: Loeys Dietz Syndrome Pregnancy and management
Case: a 35 year old nulliparous female was referred to the cardiac obstetric service at 9 weeks gestation. She had a family history of Loeys Dietz Syndrome (LDS); both father and her uncle were known carriers (alive in their sixties); and two distant relatives had aortic dissections in their fifties, one of which was fatal. The patient had a dilated aortic root on echo (37 mm) and minor dysmorphic features. A pelvic ultrasound confirmed a dichorionic diamniotic twin pregnancy of 9 weeks gestation. Genetic testing confirmed she had inherited her familial TGFBR2 mutation (specific mutationTGFBR2 c.1489N T p.(Arg497Ter)). A baseline MRI scan at 11 weeks showed a dilated root of 43 mm, dilatation of the descending aorta and tortuous iliac vessels. The patient underwent extensive counselling with the cardiologist, geneticist and the obstetrician. She elected to proceed with the pregnancy. A foetal ultrasound at 16 weeks' gestation demonstrated twin 2 to have severe growth restriction (b 5th centile) and a large cleft palate (suggestive of LDS). Given these findings and the additional risks of a twin pregnancy the patient opted for selective termination. Thereafter, she had serial imaging of her aorta as well and foetal imaging cardiac MRI showed no progression in aortic dilatation. Following multi-disciplinary discussion at 30 weeks gestation, an elective caesarean section under general anaesthesia was planned at 34 weeks' gestation to prevent aortic dissection to avoid labour and co-ordinate care from cardiologists, cardiac anaesthetists and vascular surgeons. A live female infant was delivered in good condition requiring admission to the neonatal unit for 6 days and was discharged on day 7. Genotyping of the infant has been deferred at present. The patient remained an inpatient for 7 days, had re-
⁎ Corresponding author. E-mail address: [email protected] (M. Cauldwell).
http://dx.doi.org/10.1016/j.ijcard.2016.04.025 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
peat imaging prior to discharge and had an uncomplicated recovery in this time. Elective aortic root replacement is planned. LDS is an autosomal dominant condition, which is characterised by thoracic aortic aneurysms, cleft palate, hypertelorism and arterial tortuosity. It was first identified in a group of patients with ‘Marfan-like’ features who also displayed thoracic aortic aneurysms [1]. The mutation was identified in genes encoding transforming growth factor beta receptor 1 or 2 (TFGBR1 and TGFBR2) and the term LDS was coined [2–3]. Mutations in SMAD3 are also sometimes included in this group. To date there are a handful of case series and reports of LDS and pregnancy [4–7]. However guidance on the management of pregnancy is lacking and therefore can only be extrapolated from information pertaining to other aortopathies [8–9]. In females of childbearing age where a diagnosis of LDS has been established it is paramount that a referral is made to a tertiary centre as to provide comprehensive advice on risks associated with pregnancy. It remains challenging to quantify the risk of dissection as aortic diameters are not highly predictive [8]. In the largest case series to date of 31 women with LDS with 93 livebirths there was only one fatal aortic dissection occurring in the postpartum period [5]. However in their original publication Loeys et al. described a more unfavourable prognosis with 4 aortic dissections and 2 uterine ruptures in a series of 21 pregnancies [3].Women with LDS wishing to become pregnant who have an aortic root measuring 40 mm or greater would be seriously considered for surgery prior to pregnancy. Aortic growth has not been longitudinally assessed in women with LDS during pregnancy. The American College of Cardiology guidance suggests monthly or bimonthly assessment of known thoracic aortic aneurysm in pregnancy [10]. Nevertheless, the mortality if dissection does occur in pregnancy remains high at approximately 80% [11]. Assessment and follow-up during pregnancy remains critical. Close blood pressure monitoring is essential and use of β-blockers may be considered. In some studies of Marfan's patients β blockers have been shown to limit aortic dilatation, but these findings are not universal [12,13]. Angiotensin receptor blockers are contraindicated in pregnancy. If beta-blockers are prescribed foetal growth needs to be monitored closely (risk of growth restriction). Prenatal diagnosis should be discussed with the parents because albeit invasive testing carries a risk of miscarriage of about 1%. IVF with pre-implantation genetic diagnosis (PGD) is an alternative that should be discussed pre-conception. Decisions regarding delivery need to involve the high risk pregnancy and heart disease multidisciplinary team. There are no studies that compare vaginal delivery with caesarean section. Vaginal delivery may be
492
Correspondence
Table 1 Proposed focused guidance for managing pregnancy in known LDS.
Pre-pregnancy
Pregnancy
Delivery
Postpartum
Cardiology
Obstetric
Comprehensive imaging including cerebral circulation Assessment of need for aortic surgery prior to pregnancy Discussion regarding medication Patient education re symptoms of dissection/emergency care plan Managed in tertiary expert joint cardiac high risk obstetric service. Meticulous BP control Echo and/or MRI monthly
Preconception folic acid General lifestyle modifications Referral to IVF unit if wishes to consider PGD Discussion regarding prenatal diagnosis Chorionic villous sampling if requested Detailed foetal anomaly imaging Regular foetal surveillance with growth scans (especially if on beta-blockers). Obstetric anaesthetic review with comprehensive delivery planning
Co-ordinated planned delivery at gestation guided by clinical scenario Consider risk of uterine rupture or other vascular complications. Delivery either by planned C/S or induction of labour with regional pain relief (if possible) Onsite vascular and cardiothoracic surgical backup Meticulous BP control Avoid ergometrine and boluses of oxytocin or equivalent. Prolonged post-delivery inpatient stay (7–14 days) due to heightened risk of dissection Update post-delivery imaging including MRA or CT angiogram prior to discharge. Consider re-introduction of ARBS (limited data regarding breastfeeding). Initiate/advise long acting contraception.
associated with less blood loss; however the mode of delivery will often be dictated by gestation and other logistics. In several of the inherited aortopathies, uterine rupture can occur and if this is the case labour should probably be avoided. At the time of delivery and in the immediate postpartum period there should be vascular and cardiothoracic support to cover for arterial complications. There is also a risk of intracerebral complications. Following delivery there should be extended inpatient monitoring as this is a period of heightened risk, as up to 20% of dissections occur in the postpartum period in those with underlying aortopathy [14]. Post-delivery imaging is paramount and prior to discharge. If appropriate, elective surgery should be scheduled. In summary cases of LDS remain relatively uncommon. Management should be undertaken in a tertiary setting with expertise in aortopathy and pregnancy. All patients with a family history of autosomal dominant aortopathy should be offered preconception counselling. We submit focused guidance for managing pregnancies in LDS (Table 1). Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] C. Boileau, G. Jondeau, M.C. Babron, M. Coulon, J.A. Alexandre, L. Sakai, et al., Autosomal dominant Marfan-like connective-tissue disorder with aortic dilation and skeletal anomalies not linked to the fibrillin genes, Am J Hum Genet 53 (1) (Jul 1993) 46–54. [2] B.L. Loeys, J. Chen, E.R. Neptune, D.P. Judge, M. Podowski, T. Holm, et al., A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2, Nat Genet 37 (3) (Mar 2005) 275–281. [3] B.L. Loeys, U. Schwarze, T. Holm, B.L. Callewaert, G.H. Thomas, H. Pannu, et al., Aneurysm syndromes caused by mutations in the TGF-beta receptor, N Engl J Med 355 (8) (Aug 24 2006) 788–798.
[4] D. Attias, C. Stheneur, C. Roy, G. Collod-Béroud, D. Detaint, L. Faivre, et al., Comparison of clinical presentations and outcomes between patients with TGFBR2 and FBN1 mutations in Marfan syndrome and related disorders, Circulation 120 (25) (Dec 22 2009) 2541–2549. [5] V. Tran-Fadulu, H. Pannu, D.H. Kim, G.W. Vick 3rd, C.M. Lonsford, A.L. Lafont, et al., Analysis of multigenerational families with thoracic aortic aneurysms and dissections due to TGFBR1 or TGFBR2 mutations, J Med Genet 46 (9) (Sep 2009) 607–613. [6] D. Fujita, N. Takeda, H. Morita, M. Kato, H. Nishimura, R. Inuzuka, et al., A novel mutation of TGFBR2 causing Loeys–Dietz syndrome complicated with pregnancyrelated fatal cervical arterial dissections, Int J Cardiol 201 (Dec 15 2015) 288–290. [7] J. Cronin, H. Bazick Cuschieri, X. Dong, G. Oswald, M. Russo, H. Dietz, et al., Anesthesia considerations for cesarean delivery in a patient with Loeys–Dietz syndrome, A A Case Rep 4 (4) (Feb 15 2015) 47–48. [8] G. MacCarrick, J.H. Black 3rd, S. Bowdin, I. El-Hamamsy, P.A. Frischmeyer-Guerrerio, A.L. Guerrerio, et al., Loeys–Dietz syndrome: a primer for diagnosis and management, Genet Med 16 (8) (Aug 2014) 576–587. [9] V. Regitz-Zagrosek, C. Blomstrom Lundqvist, C. Borghi, R. Cifkova, R. Ferreira, J.M. Foidart, et al., ESC guidelines on the management of cardiovascular diseases during pregnancy: the Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC), Eur Heart J 32 (24) (Dec 2011) 3147–3197; F. Immer, Ann Thorac Surg (2003). [10] L.F. Hiratzka, G.L. Bakris, J.A. Beckman, R.M. Bersin, V.F. Carr, D.E. Casey Jr., et al., Guidelines for the diagnosis and management of patients with thoracic aortic disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine, Circulation 121 (13) (Apr 6 2010) e266–e369. [11] C.M. Huisman, J.J. Zwart, J.W. Roos-Hesselink, J.J. Duvekot, J. van Roosmalen, Incidence and predictors of maternal cardiovascular mortality and severe morbidity in the Netherlands: a prospective cohort study, PLoS One 8 (2013), e56494. [12] D.R. Gersony, M.A. McClaughlin, Z. Jin, W.M. Gersony, The effect of beta-blocker therapy on clinical outcome in patients with Marfan's syndrome: a meta-analysis, Int J Cardiol 114 (3) (2007 Jan 18) 303–308. [13] L. Gao, Q. Mao, D. Wen, L. Zhang, X. Zhou, R. Hui, The effect of beta-blocker therapy on progressive aortic dilatation in children and adolescents with Marfan's syndrome: a meta-analysis, Acta Paediatr 100 (9) (2011 Sep) e101–e105. [14] J. Lind, The Marfan and Ehlers–Danlos Syndromes and Pregnancy. 2000 (Erasmus MC: University Medical Center Rotterdam/Dissertation. Available at: http://hdl.handle.net/1765/21113. Last accessed 23rd March 2015).
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Correspondence
Loeys Dietz Syndrome and pregnancy: A case report with literature review and a proposed focused management protocol Matthew Cauldwell a,⁎, Roshni R Patel a, Anselm Uebing b, Michael A. Gatzoulis b, Lorna Swan b a b
Department of Obstetrics, Chelsea and Westminster Hospital, 369 Fulham Road, London, United Kingdom Adult Congenital Heart Disease Centre, Royal Brompton Hospital, Sydney Street, London, United Kingdom
a r t i c l e
i n f o
Article history: Received 7 January 2016 Received in revised form 31 March 2016 Accepted 3 April 2016 Available online 7 April 2016 Keywords: Loeys Dietz Syndrome Pregnancy and management
Case: a 35 year old nulliparous female was referred to the cardiac obstetric service at 9 weeks gestation. She had a family history of Loeys Dietz Syndrome (LDS); both father and her uncle were known carriers (alive in their sixties); and two distant relatives had aortic dissections in their fifties, one of which was fatal. The patient had a dilated aortic root on echo (37 mm) and minor dysmorphic features. A pelvic ultrasound confirmed a dichorionic diamniotic twin pregnancy of 9 weeks gestation. Genetic testing confirmed she had inherited her familial TGFBR2 mutation (specific mutationTGFBR2 c.1489N T p.(Arg497Ter)). A baseline MRI scan at 11 weeks showed a dilated root of 43 mm, dilatation of the descending aorta and tortuous iliac vessels. The patient underwent extensive counselling with the cardiologist, geneticist and the obstetrician. She elected to proceed with the pregnancy. A foetal ultrasound at 16 weeks' gestation demonstrated twin 2 to have severe growth restriction (b 5th centile) and a large cleft palate (suggestive of LDS). Given these findings and the additional risks of a twin pregnancy the patient opted for selective termination. Thereafter, she had serial imaging of her aorta as well and foetal imaging cardiac MRI showed no progression in aortic dilatation. Following multi-disciplinary discussion at 30 weeks gestation, an elective caesarean section under general anaesthesia was planned at 34 weeks' gestation to prevent aortic dissection to avoid labour and co-ordinate care from cardiologists, cardiac anaesthetists and vascular surgeons. A live female infant was delivered in good condition requiring admission to the neonatal unit for 6 days and was discharged on day 7. Genotyping of the infant has been deferred at present. The patient remained an inpatient for 7 days, had re-
⁎ Corresponding author. E-mail address: [email protected] (M. Cauldwell).
http://dx.doi.org/10.1016/j.ijcard.2016.04.025 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
peat imaging prior to discharge and had an uncomplicated recovery in this time. Elective aortic root replacement is planned. LDS is an autosomal dominant condition, which is characterised by thoracic aortic aneurysms, cleft palate, hypertelorism and arterial tortuosity. It was first identified in a group of patients with ‘Marfan-like’ features who also displayed thoracic aortic aneurysms [1]. The mutation was identified in genes encoding transforming growth factor beta receptor 1 or 2 (TFGBR1 and TGFBR2) and the term LDS was coined [2–3]. Mutations in SMAD3 are also sometimes included in this group. To date there are a handful of case series and reports of LDS and pregnancy [4–7]. However guidance on the management of pregnancy is lacking and therefore can only be extrapolated from information pertaining to other aortopathies [8–9]. In females of childbearing age where a diagnosis of LDS has been established it is paramount that a referral is made to a tertiary centre as to provide comprehensive advice on risks associated with pregnancy. It remains challenging to quantify the risk of dissection as aortic diameters are not highly predictive [8]. In the largest case series to date of 31 women with LDS with 93 livebirths there was only one fatal aortic dissection occurring in the postpartum period [5]. However in their original publication Loeys et al. described a more unfavourable prognosis with 4 aortic dissections and 2 uterine ruptures in a series of 21 pregnancies [3].Women with LDS wishing to become pregnant who have an aortic root measuring 40 mm or greater would be seriously considered for surgery prior to pregnancy. Aortic growth has not been longitudinally assessed in women with LDS during pregnancy. The American College of Cardiology guidance suggests monthly or bimonthly assessment of known thoracic aortic aneurysm in pregnancy [10]. Nevertheless, the mortality if dissection does occur in pregnancy remains high at approximately 80% [11]. Assessment and follow-up during pregnancy remains critical. Close blood pressure monitoring is essential and use of β-blockers may be considered. In some studies of Marfan's patients β blockers have been shown to limit aortic dilatation, but these findings are not universal [12,13]. Angiotensin receptor blockers are contraindicated in pregnancy. If beta-blockers are prescribed foetal growth needs to be monitored closely (risk of growth restriction). Prenatal diagnosis should be discussed with the parents because albeit invasive testing carries a risk of miscarriage of about 1%. IVF with pre-implantation genetic diagnosis (PGD) is an alternative that should be discussed pre-conception. Decisions regarding delivery need to involve the high risk pregnancy and heart disease multidisciplinary team. There are no studies that compare vaginal delivery with caesarean section. Vaginal delivery may be
492
Correspondence
Table 1 Proposed focused guidance for managing pregnancy in known LDS.
Pre-pregnancy
Pregnancy
Delivery
Postpartum
Cardiology
Obstetric
Comprehensive imaging including cerebral circulation Assessment of need for aortic surgery prior to pregnancy Discussion regarding medication Patient education re symptoms of dissection/emergency care plan Managed in tertiary expert joint cardiac high risk obstetric service. Meticulous BP control Echo and/or MRI monthly
Preconception folic acid General lifestyle modifications Referral to IVF unit if wishes to consider PGD Discussion regarding prenatal diagnosis Chorionic villous sampling if requested Detailed foetal anomaly imaging Regular foetal surveillance with growth scans (especially if on beta-blockers). Obstetric anaesthetic review with comprehensive delivery planning
Co-ordinated planned delivery at gestation guided by clinical scenario Consider risk of uterine rupture or other vascular complications. Delivery either by planned C/S or induction of labour with regional pain relief (if possible) Onsite vascular and cardiothoracic surgical backup Meticulous BP control Avoid ergometrine and boluses of oxytocin or equivalent. Prolonged post-delivery inpatient stay (7–14 days) due to heightened risk of dissection Update post-delivery imaging including MRA or CT angiogram prior to discharge. Consider re-introduction of ARBS (limited data regarding breastfeeding). Initiate/advise long acting contraception.
associated with less blood loss; however the mode of delivery will often be dictated by gestation and other logistics. In several of the inherited aortopathies, uterine rupture can occur and if this is the case labour should probably be avoided. At the time of delivery and in the immediate postpartum period there should be vascular and cardiothoracic support to cover for arterial complications. There is also a risk of intracerebral complications. Following delivery there should be extended inpatient monitoring as this is a period of heightened risk, as up to 20% of dissections occur in the postpartum period in those with underlying aortopathy [14]. Post-delivery imaging is paramount and prior to discharge. If appropriate, elective surgery should be scheduled. In summary cases of LDS remain relatively uncommon. Management should be undertaken in a tertiary setting with expertise in aortopathy and pregnancy. All patients with a family history of autosomal dominant aortopathy should be offered preconception counselling. We submit focused guidance for managing pregnancies in LDS (Table 1). Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] C. Boileau, G. Jondeau, M.C. Babron, M. Coulon, J.A. Alexandre, L. Sakai, et al., Autosomal dominant Marfan-like connective-tissue disorder with aortic dilation and skeletal anomalies not linked to the fibrillin genes, Am J Hum Genet 53 (1) (Jul 1993) 46–54. [2] B.L. Loeys, J. Chen, E.R. Neptune, D.P. Judge, M. Podowski, T. Holm, et al., A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2, Nat Genet 37 (3) (Mar 2005) 275–281. [3] B.L. Loeys, U. Schwarze, T. Holm, B.L. Callewaert, G.H. Thomas, H. Pannu, et al., Aneurysm syndromes caused by mutations in the TGF-beta receptor, N Engl J Med 355 (8) (Aug 24 2006) 788–798.
[4] D. Attias, C. Stheneur, C. Roy, G. Collod-Béroud, D. Detaint, L. Faivre, et al., Comparison of clinical presentations and outcomes between patients with TGFBR2 and FBN1 mutations in Marfan syndrome and related disorders, Circulation 120 (25) (Dec 22 2009) 2541–2549. [5] V. Tran-Fadulu, H. Pannu, D.H. Kim, G.W. Vick 3rd, C.M. Lonsford, A.L. Lafont, et al., Analysis of multigenerational families with thoracic aortic aneurysms and dissections due to TGFBR1 or TGFBR2 mutations, J Med Genet 46 (9) (Sep 2009) 607–613. [6] D. Fujita, N. Takeda, H. Morita, M. Kato, H. Nishimura, R. Inuzuka, et al., A novel mutation of TGFBR2 causing Loeys–Dietz syndrome complicated with pregnancyrelated fatal cervical arterial dissections, Int J Cardiol 201 (Dec 15 2015) 288–290. [7] J. Cronin, H. Bazick Cuschieri, X. Dong, G. Oswald, M. Russo, H. Dietz, et al., Anesthesia considerations for cesarean delivery in a patient with Loeys–Dietz syndrome, A A Case Rep 4 (4) (Feb 15 2015) 47–48. [8] G. MacCarrick, J.H. Black 3rd, S. Bowdin, I. El-Hamamsy, P.A. Frischmeyer-Guerrerio, A.L. Guerrerio, et al., Loeys–Dietz syndrome: a primer for diagnosis and management, Genet Med 16 (8) (Aug 2014) 576–587. [9] V. Regitz-Zagrosek, C. Blomstrom Lundqvist, C. Borghi, R. Cifkova, R. Ferreira, J.M. Foidart, et al., ESC guidelines on the management of cardiovascular diseases during pregnancy: the Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC), Eur Heart J 32 (24) (Dec 2011) 3147–3197; F. Immer, Ann Thorac Surg (2003). [10] L.F. Hiratzka, G.L. Bakris, J.A. Beckman, R.M. Bersin, V.F. Carr, D.E. Casey Jr., et al., Guidelines for the diagnosis and management of patients with thoracic aortic disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine, Circulation 121 (13) (Apr 6 2010) e266–e369. [11] C.M. Huisman, J.J. Zwart, J.W. Roos-Hesselink, J.J. Duvekot, J. van Roosmalen, Incidence and predictors of maternal cardiovascular mortality and severe morbidity in the Netherlands: a prospective cohort study, PLoS One 8 (2013), e56494. [12] D.R. Gersony, M.A. McClaughlin, Z. Jin, W.M. Gersony, The effect of beta-blocker therapy on clinical outcome in patients with Marfan's syndrome: a meta-analysis, Int J Cardiol 114 (3) (2007 Jan 18) 303–308. [13] L. Gao, Q. Mao, D. Wen, L. Zhang, X. Zhou, R. Hui, The effect of beta-blocker therapy on progressive aortic dilatation in children and adolescents with Marfan's syndrome: a meta-analysis, Acta Paediatr 100 (9) (2011 Sep) e101–e105. [14] J. Lind, The Marfan and Ehlers–Danlos Syndromes and Pregnancy. 2000 (Erasmus MC: University Medical Center Rotterdam/Dissertation. Available at: http://hdl.handle.net/1765/21113. Last accessed 23rd March 2015).