Pregnancy after aortic root replacement in Loeys–Dietz syndrome: High risk of aortic dissection
Abstract
Loeys–Dietz syndrome due to mutations in TGFBR1 and 2 is associated with early and aggressive aortic aneurysm and branch vessel disease. There are reports of uncomplicated pregnancy in this condition, but there is an increased risk of aortic dissection and uterine rupture. Women with underlying aortic root aneurysm are cautioned about the risk of pregnancy-related aortic dissection. Prophylactic aortic root replacement is recommended in women with aortopathy and aortic root dilatation to lessen the risk of pregnancy. There is limited information in the literature about the outcomes of pregnancy after root replacement in Loeys–Dietz syndrome. We present a case series of three women with Loeys–Dietz syndrome who underwent elective aortic root replacement for aneurysm disease and subsequently became pregnant and underwent Cesarean section delivery. Each of these women were treated with beta blockers throughout pregnancy. Surveillance echocardiograms and noncontrast MRA studies during pregnancy remained stable demonstrating no evidence for aortic enlargement. Despite the normal aortic imaging and careful observation, two of the three women suffered acute aortic dissection in the postpartum period. These cases highlight the high risk of pregnancy following aortic root replacement in Loeys–Dietz syndrome. Women with this disorder are recommended to be counseled accordingly. © 2016 Wiley Periodicals, Inc.
INTRODUCTION
Loeys–Dietz syndrome (LDS), due to mutations in TGFBR1 and TGFBR2, is an autosomal dominant disorder with craniofacial and skeletal features, aortic and branch vessel aneurysms, and arterial tortuosity [Loeys et al., 2006]. While early and more aggressive vascular disease may differentiate this condition from Marfan syndrome, many with LDS have predominant aortic root aneurysm which has been successfully treated with aortic root replacement surgery [Loeys et al., 2006].
Women with aortopathy are at risk for aortic dissection related to pregnancy [Braverman, 2010]. Aortic root replacement surgery has been recommended before pregnancy for aneurysm disease in women at risk [Regitz-Zagrosek et al., 2011]. However, prophylactic root replacement does not guarantee the absence of risk, as the distal aorta remains susceptible to acute aortic dissection [McDermott et al., 2007]. Case series of pregnancy outcomes in LDS also include the risk of acute aortic dissection [Loeys et al., 2006; Attias et al., 2009; Tran-Fadulu et al., 2009]. There is very limited information about the outcomes of pregnancy in women with LDS who have undergone prior aortic root replacement. Herein, we report the case histories of three women with Loeys–Dietz syndrome (due to mutations in TGFBR1 and TGFBR2) and prior valve-sparing aortic root replacement for aneurysm who had subsequent pregnancy and delivery. Two of three women suffered acute aortic dissection in the early post-partum period. This highlights the high risk of aortic dissection related to pregnancy after root replacement in women with LDS.
METHODS
The clinical histories of the 35 adults with LDS due to mutations in TGFBR1 and TGFBR2 treated at Washington University School of Medicine were reviewed. Thirteen women had 31 uncomplicated pregnancies and deliveries. There were six elective Caesarean sections and seven vaginal deliveries. In these women, there were no uterine, aortic, or vascular complications. Eleven of 13 women having 29 pregnancies did not know they had LDS during pregnancy, while two women were aware of the diagnosis of LDS before pregnancy. None of these women had prior aortic surgery before pregnancy.
Three women with LDS each had a prior elective aortic valve-sparing root replacement for aneurysm disease and then a subsequent pregnancy and delivery. The clinical features, pregnancy management, and outcomes for these three cases are presented herein.
Case 1
The patient is a 43-year-old woman, who at age 38 years old became pregnant for the first time in 2010. Earlier in life, she was diagnosed as having “Marfan syndrome.” At age 25, she underwent valve-sparing root replacement for an aortic root aneurysm (at the sinuses of Valsalva) measuring 48 mm. Yearly echocardiograms and biannual chest MRA studies were unremarkable from 1997 to 2010. The patient had elongated fingers, mild pectus excavatum, positive wrist sign, mildly bluish sclera, soft, and translucent skin with easily visible veins on her arms, chest, and legs. She did not have ectopia lentis or scoliosis. Her father had a fatal aortic dissection at age 42; a paternal cousin (male) had an aortic dissection at age 31 and another paternal cousin (male) died of aortic rupture at age 32. In 2010, due to her clinical features of LDS, mutation analysis was performed, demonstrating a pathogenic mutation in exon 5 of TGFBR1: c.848A>C (His283Pro).
The patient had been treated with atenolol and losartan. Upon becoming pregnant, losartan was discontinued. An echocardiogram demonstrated normal appearance of the aortic root replacement. A noncontrast MRA demonstrated mild carotid, vertebral, and basilar artery tortuosity; mild prominence of the coronary buttons; a maximal ascending aortic diameter of 34 mm, and a main pulmonary artery diameter of 36 mm. The descending aorta was normal. The aortic dimensions remained stable as evidenced by every 8 week echocardiogram and once per trimester MRA. An elective C-section was performed at 35 weeks gestation. The procedure was uncomplicated and the patient breastfed her newborn child.
Two days postpartum, the patient complained of acute pain in the neck, head, and back. A CT scan demonstrated an acute aortic dissection in the distal aortic arch, extending into the left carotid artery, terminating at the level of the renal arteries. The following day, she complained of recurrent back pain. CT scan demonstrated impending rupture and open aortic surgery was performed with an interposition Dacron graft placement in the distal arch and proximal descending aorta. Four days later, the patient developed an acute left hemothorax and cardiovascular collapse requiring cardiopulmonary resuscitation. Angiography demonstrated dehiscence of the proximal graft anastomosis treated with endovascular repair using a Zenith® TX2® TAA Endovascular Graft (Cook Medical, Inc, Bloomington, IN). Later that evening a CT scan demonstrated a leaking pseudoaneurysm of the distal graft suture line with a contained rupture. Endovascular repair was performed, placing two 28 × 140 mm Zenith® TX2® TAA Endovascular Grafts (Cook Medical, Inc, Bloomington, IN) into the Dacron graft. Her course was complicated by ischemic optic neuropathy from the hypotension.
Three weeks later, a CT scan demonstrated an asymptomatic retrograde aortic dissection extending from the distal aortic arch to the ascending aorta terminating at the site of the prior aortic root graft. Over the next 8 weeks, the patient had gradual improvement in functional capacity. The ascending aorta at the site of dissection continued to enlarge reaching 5.8 cm in diameter. Three months after the initial postpartum aortic dissection, she underwent open aortic surgery with replacement of ascending aorta, arch, and proximal descending aorta. She has remained stable over the past 5 years.
Case 2
The patient is a 37-year-old woman who was evaluated in our center following a postpartum acute aortic dissection. At age 14, the patient was diagnosed with “Marfan syndrome.” At age 17, she underwent aortic valve-sparing root replacement for a 5 cm aortic aneurysm. At age 33, she became pregnant. At 12 weeks gestation, mutation analysis was performed, but there were no mutations present in FBN1. Further testing demonstrated a heterozygous mutation in exon 7 of TGFBR2: c1589-1590 delCA; p.Thr530serfsX10, reported as pathogenic, leading to the diagnosis of LDS.
The patient was treated with metoprolol throughout pregnancy. One month before delivery, a noncontrast MRA of the chest to pelvis revealed normal aortic dimensions with the ascending aorta measuring 3.1 cm and a normal descending aorta. Two weeks before delivery an echocardiogram reported normal appearance of the valve-sparing root replacement. She delivered by Cesarean section at 34 weeks gestation and breastfed her newborn child. Before discharge, she developed neck pain and difficulty swallowing. One day after discharge, the patient developed severe back pain and neck pain. A CT scan demonstrated an acute ascending aortic dissection distal to the root graft involving the great vessels and extending to the iliac arteries. She was treated medically. Six weeks postpartum, she was referred to Washington University Medical Center for further evaluation.
The patient had a family history of aortic disease. Her mother died at age 56 from acute aortic dissection. Her maternal grandmother had been diagnosed with “Marfan syndrome” and had club feet. One maternal cousin had an acute aortic dissection and another underwent aortic root replacement for aneurysm. The patient had campylodactyly with contracture release, club feet with multiple operations, and scoliosis. On physical examination, she was 71 inches tall and weighed 134 pounds. She had blue sclera, hypertelorism, prominent frontal bone, broad uvula with a raphe, abnormal teeth enamel, receding hairline, soft velvety skin, easily visible veins, mild scoliosis, campylodactyly, striae atrophicae, widened scars, and marked pectus excavatum. A CT angiogram demonstrated the prior root replacement and an aortic dissection flap extending from ascending aorta to the iliac arteries. The ascending aorta measured 4 cm and the descending 3.5 cm. Over the next 9 months, serial CT angiograms demonstrated progressive enlargement of the aorta, with the ascending aorta measuring 4.8 cm, and descending aorta measuring 4.3 cm. Eleven months after the acute postpartum aortic dissection, the patient underwent open surgical graft replacement of the ascending aorta, arch, and two thirds of the descending aorta. She has remained stable over the past 36 months.
Case 3
The patient is a 29-year-old woman with Loeys–Dietz syndrome and prior aortic root replacement who had an uncomplicated pregnancy and delivery in 2012 at age 26. She was first evaluated at our institution in 2007. Before then, she was previously labeled as having “Marfan syndrome.” She had no family history of aortic disease. On examination, her height was 68 inches and weight 122 pounds. She had mild hypertelorism; bluish sclera, bifid uvula, elongated fingers, scoliosis requiring Harrington rod placement, pectus excavatum, soft translucent skin with visible veins, and striae atrophicae. An echocardiogram demonstrated a dilated aortic root measuring 4.2 cm at the sinuses of Valsalva, mitral valve prolapse with mild mitral regurgitation, and tricuspid valve prolapse with moderate tricuspid regurgitation. On MR angiography from head to pelvis, the aortic root measured 4.5 cm. There were no other aneurysms and no arterial tortuosity. Lumbosacral dural ectasia was present. Mutation analysis discovered a pathogenic mutation in exon 4 of TGFBR2: c.1240G>C (p.Ala414Pro). In late 2007, the patient underwent elective valve-sparing root replacement and pectus excavatum repair. Approximately 3 years after root replacement, the patient became pregnant. Losartan was discontinued and she continued beta blocker therapy. Serial echocardiograms and noncontrast MRA scans were performed during her pregnancy and the aorta remained stable. There was no aortic enlargement or aneurysm formation. She underwent elective Cesarean section and tubal ligation at 34 weeks, and her course was uncomplicated.
DISCUSSION
It is well established that pregnancy is a risk factor for aortic dissection in women with underlying aortopathy [Braverman, 2010; Hiratzka et al., 2010]. Heightened risk may be related to multiple factors, including hemodynamic forces, hormonal changes, or alterations in signaling pathways related to pregnancy [Smok, 2014]. In Marfan syndrome, increasing aortic root diameter correlates with risk of dissection during pregnancy [Pyeritz, 1981]. It is recommended that aortic root replacement be performed before pregnancy in women with aneurysms to lessen risk of dissection [Regitz-Zagrosek et al., 2011; Smok, 2014]. However, aortic root replacement does not entirely protect a woman from distal aortic dissection related to pregnancy in Marfan syndrome [McDermott et al., 2007]. Loeys–Dietz syndrome has a more aggressive aortic and vascular phenotype than Marfan syndrome [Loeys et al., 2006]. There is emerging information in the literature about risks and outcomes of pregnancy in LDS due to TGFBR1 and TGFBR2 mutations (Table I). The seminal report by Loeys et al. cautioned of the potentially high risk of pregnancy [Loeys et al., 2006]. Of the 12 women who had 21 pregnancies in this report, there were four aortic dissections and two uterine ruptures. The series by Attias et al. reported that 17 women with TGFBR2 mutations had 39 pregnancies and there was one sudden death postpartum [Attias et al., 2009]. The series by Tran-Fadulu et al. reported no complications among the nine women with TGFBR1 mutations who had 30 pregnancies, and one acute aortic dissection among the 22 women with TGFBR2 mutations who had 61 pregnancies [Tran-Fadulu et al., 2009]. In our current series, among the 13 women with LDS and no prior aortic surgery, there were no complications during 31 pregnancies (Table I).
| Series | Women | Pregnancies | Mutation | Outcomes |
|---|---|---|---|---|
| Loeys et al. [2006] | 12 | 21 | TGFBR1 and TGFBR2 | 4 aortic dissections, 2 uterine ruptures |
| Attias et al. [2009] | 17 | 39 | TGFBR2 | 1 sudden death postpartum |
| Tran-Fadulu et al. [2009] | 9 | 30 | TGFBR1 | 0 complications |
| 22 | 61 | TGFBR2 | 1 aortic dissection | |
| Braverman et al. [2016] | 16 | 34 | TGFBR1 and TGFBR2 | 2 aortic dissections (both after aortic root replacement) 0 uterine ruptures |
On literature review, we found a single case report of pregnancy after aortic root replacement in LDS. Fujita et al. reported the case of a woman previously diagnosed with “Marfan syndrome,” whose first pregnancy was complicated by a postpartum type A aortic dissection and was treated by a valve-sparing root replacement [Fujita et al., 2015]. The patient became pregnant 6 years later and underwent elective Cesarean section at 37 weeks. Echocardiogram and MRI reported no aneurysms during pregnancy. She suffered acute aortic arch dissection on postpartum day 5, which was complicated by carotid and vertebral artery dissections, subarachnoid hemorrhage, and death. Postmortem, she was diagnosed with LDS when a pathogenic mutation was found in exon 5 of TGFBR2: c.1270 T>C; p.Y424H [Fujita et al., 2015].
Two of the three women in our series of LDS who underwent prophylactic aortic root replacement suffered acute aortic dissection related to pregnancy. These aortic dissections occurred in the absence of any aneurysmal enlargement of the aorta. All three women underwent screening and surveillance of the aorta and branches during pregnancy, and all were treated with beta blocker therapy. The case of Fujita detailed above also had no evidence for aortic dilatation during pregnancy. Combining our three cases with the case report of Fujita, we compile four women with LDS who had pregnancy after root replacement and in three (75%) of the women, pregnancy was complicated by postpartum aortic dissection.
The distal aorta is at risk for complications in Marfan syndrome and LDS [Loeys et al., 2006; den Hartog et al., 2015]. Prior root replacement has been associated with abnormal aortic elasticity and accelerated aortic growth distally in Marfan syndrome [Nollen et al., 2003; Groenink et al., 2013; den Hartog et al., 2015]. Among a large cohort of Marfan patients, acute type B (descending aortic) dissection was reported in 9% during a 6-year follow-up [den Hartog et al., 2015]. Most of these patients did not have significantly dilated descending aortas at the time of dissection. Prior root replacement is a risk factor for late type B dissection [den Hartog et al., 2015]. It is theorized that abnormal aortic elastic properties related to the vascular prosthesis may result in higher pulsatile forces on the native aortic arch and proximal descending aorta which can affect distal aortic events [Nollen et al., 2003; Groenink et al., 2013; den Hartog et al., 2015].
It is probable that prior aortic root aneurysm disease and the requirement for graft replacement is a marker for increased aortic risk distally in aneurysm diseases such as Loeys–Dietz syndrome. Women with LDS and prior aortic root replacement are at high risk of pregnancy-related acute aortic dissection and early mortality. Based on our experience, women with LDS and prior root replacement must be appropriately cautioned of the very high risk of pregnancy and until further evidence is accumulated, pregnancy should be avoided in this situation. For women with LDS and prior aortic root replacement who decide to proceed with pregnancy, multidisciplinary management including consultation with medical genetics, high-risk obstetrics, cardiology, anesthesiology, and cardiac surgery is recommended. A transthoracic echocardiogram every 8 weeks and a noncontrast MRA each trimester are recommended. Beta blocker therapy is recommended. Close attention to symptoms which could suggest an acute aortic dissection is imperative and in-hospital observation for 1 week postpartum is proposed. Postpartum aortic imaging with an echocardiogram and MRA in the first week postpartum is recommended to evaluate for any acute changes in the aorta or aortic valve.
