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Cardiovascular risks of pregnancy in women with Turner syndrome
LETTER TO THE EDITOR Cardiovascular risks of pregnancy in women with Turner syndrome Letter to the Editor: The recent paper from Boissonnas et al. (1) reporting the tragic death from aortic dissection and rupture of a women with Turner syndrome in the third trimester of an oocyte donation pregnancy raises important issues concerning the current guidelines for attempting pregnancy in women with this disorder (2). The current American Society for Reproductive Medicine (ASRM) guidelines require preliminary cardiovascular screening using echocardiography to identify women with known risk factors for aortic complications such as abnormal aortic valve, aortic dilation (diameter >4 cm), or coarctation. However, recent studies show that routine transthoracic echocardiography fails to reveal significant pathology in many women with Turner syndrome (3, 4) and that 4 cm may signify aortic dilation in small women (5). Cardiac magnetic resonance imaging (MRI) rarely fails to visualize the aortic valve and is clearly superior to echocardiography in detecting abnormalities of the aorta, which is clearly visualized in both ascending and descending aspects. For this reason, the 2006 meeting of the Turner Syndrome Consensus Conference recommended that all women with Turner syndrome contemplating pregnancy should undergo a cardiac MRI, preferably at a tertiary care center with expertise in cardiac imaging (6). In the reported case, the woman had a cardiac echo done in her community that reported no abnormalities, while the study done in the referral center at 16 weeks of gestation showed a bicuspid aortic valve and dilation of the ascending aorta. We have shown that standard benchmarks for ascending aortic dilation are not relevant to small-statured women with Turner syndrome (5). Aortic diameter is proportional to body size, thus size-based nomograms are used to diagnose aortic dilation in children, but this is not routine for adults. We measured ascending aortic diameters at the level of the pulmonary artery origin using MRI in a large group of women with Turner syndrome and age-matched female controls and normalized for body size differences by dividing the diameters by the body surface area (aortic size index [ASI]). The 50th percentile for control ASI was 1.7, and the 95th percentile was 2 cm/m2. About one-quarter of the Turner group (40 of 166) exceeded the 95th percentile, and most of these women had aortic diameters in the ‘‘normal range,’’ that is, less than 3.5 cm (5). We do not have the prospective aortic diameter for the patient in the case report by Boissonnas et al. (1), but it was probably in that range since her screening echo was deemed unremarkable. However, at 16 weeks of gestation, her aortic diameter was 39 mm; normalized to her body surface, her ASI was 2.84 cm/m2, which represents extreme dilation (5). Five 0015-0282/09/$36.00
patients from our group with ASI >2 have either dissected or undergone surgical repair of the dilated aorta during 4 years of follow-up, and hence we regard this measure (ASI >2 cm/m2) as a significant indicator of risk for aortic complications and a contraindication for attempting pregnancy or any activity that would unduly stress the aorta. The arbitrary diameter of 4 cm cited by the current ASRM recommendation was actually established for (tall) adults with Marfan syndrome and is too high for women with Turner syndrome. We report a case of a 30-year-old woman with 45,X Turner syndrome who became pregnant by oocyte donation before the publication of the 2005 ASRM guidelines. In the third month of a singleton pregnancy she was examined by a cardiologist who found a bicuspid aortic valve with mild to moderate stenosis but a ‘‘normal’’ ascending aortic diameter (3.57 cm). If this had been normalized to her body surface area, the ASI would have been 2.63 cm/m2. She was warned of the risks of dissection and informed about possible symptoms and scheduled for monthly follow-up with repeat echocardiography. She was stable with a low normal blood pressure until the beginning of the third trimester when her ascending aortic diameter was found to have increased by more than 10% to 3.97 cm. This is in contrast to the normal pregnancy increase in ascending aortic diameter of 0.5%–1% beginning usually at the end of the second trimester and peaking at delivery (7). Beta-blocker therapy was initiated, and weekly echocardiography thereafter showed stable aortic diameters; her blood pressure remained very low, and she could not continue beta-blocker treatment. An elective C-section at 37 weeks yielded a normal baby without complications. Unfortunately 3 years afterward she experienced acute aortic dissection and died at the age of 33. A prior survey of pregnancy in women with Turner syndrome estimated a 2% maternal mortality rate (8), a rate that is 100-fold greater than the death rate in the general population for all causes during pregnancy. There is reason to believe that it may even be higher. Furthermore, those women with Turner syndrome who do not have a catastrophic event during pregnancy may not have gone safely through pregnancy. As in the case reported here, women with Turner syndrome who have underlying cardiovascular abnormality such as abnormal aortic valve structure and/or ascending aortic dilation may experience excessive aortic dilation during pregnancy that increases their risk for complications and premature mortality years later. In light of these observations, we suggest that the ASRM practice guidelines for assisted reproductive technology (ART) in women with Turner syndrome be revised as follows:
Fertility and Sterility Vol. 91, No. 5, May 2009 Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.
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Women with known congenital cardiovascular disease (e.g., bicuspid aortic valve or aortic coarctation) or hypertension should not undertake pregnancy. Women with ‘‘no known’’ defects still need a full cardiovascular evaluation including cardiac MRI at a center with expertise in cardiovascular imaging before attempting pregnancy, with particular attention to the aortic valve and aortic diameters. Women with an aortic size index greater than 2 cm/m2 should not attempt pregnancy. Finally, while the above parameters are believed to identify women at special risk for cardiovascular complications of pregnancy, Turner women without these features may have a latent vasculopathy that could be exacerbated by pregnancy. Therefore serious attention must be given to advising prospective ART patients about these concerns.
Carolyn Bondy, M.D. National Institute of Child Health and Human Development National Institutes of Health Turner Syndrome Society Medical Advisory Board Bethesda, MD Douglas Rosing, M.D. National Heart, Lung, and Blood Institute National Institutes of Health Bethesda, MD
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Letters to the Editor
Richard Reindollar, M.D. Dartmouth-Hitchcock Medical Center Obstetrics and Gynecology Lebanon, NH December 16, 2008 REFERENCES 1. Boissonnas CC, Davy C, Bornes M, Arnaout L, Meune C, Tsatsatris V, et al. Careful cardiovascular screening and follow-up of women with Turner syndrome before and during pregnancy is necessary to prevent maternal mortality. Fertil Steril. 2. The Practice Committee of the American Society for Reproductive Medicine. Increased maternal cardiovascular mortality associated with pregnancy in women with Turner syndrome. Fertil Steril 2005;83:1074–5. 3. Ho VB, Bakalov VK, Cooley M, Van PL, Hood MN, Burklow TR, et al. Major vascular anomalies in Turner syndrome: prevalence and magnetic resonance angiographic features. Circulation 2004;110:1694–700. 4. Sachdev V, Matura LA, Sidenko S, Ho VB, Arai AE, Rosing DR, et al. Aortic valve disease in Turner syndrome. J Am Coll Cardiol 2008;51:1904–9. 5. Matura LA, Ho VB, Rosing DR, Bondy CA. Aortic dilatation and dissection in Turner syndrome. Circulation 2007;116:1663–70. 6. Bondy CA, for The Turner Syndrome Consensus Study Group. Care of girls and women with Turner syndrome: a guideline of the Turner syndrome study group. J Clin Endocrinol Metab 2007;92:10–25. 7. Easterling TR, Benedetti TJ, Schmucker BC, Carlson K, Millard SP. Maternal hemodynamics and aortic diameter in normal and hypertensive pregnancies. Obstet Gynecol 1991;78:1073–7. 8. Karnis MF, Zimon AE, Lalwani SI, Timmreck LS, Klipstein S, Reindollar RH. Risk of death in pregnancy achieved through oocyte donation in patients with Turner syndrome: a national survey. Fertil Steril 2003;80:498–501.
doi:10.1016/j.fertnstert.2009.01.061
Vol. 91, No. 5, May 2009
patients from our group with ASI >2 have either dissected or undergone surgical repair of the dilated aorta during 4 years of follow-up, and hence we regard this measure (ASI >2 cm/m2) as a significant indicator of risk for aortic complications and a contraindication for attempting pregnancy or any activity that would unduly stress the aorta. The arbitrary diameter of 4 cm cited by the current ASRM recommendation was actually established for (tall) adults with Marfan syndrome and is too high for women with Turner syndrome. We report a case of a 30-year-old woman with 45,X Turner syndrome who became pregnant by oocyte donation before the publication of the 2005 ASRM guidelines. In the third month of a singleton pregnancy she was examined by a cardiologist who found a bicuspid aortic valve with mild to moderate stenosis but a ‘‘normal’’ ascending aortic diameter (3.57 cm). If this had been normalized to her body surface area, the ASI would have been 2.63 cm/m2. She was warned of the risks of dissection and informed about possible symptoms and scheduled for monthly follow-up with repeat echocardiography. She was stable with a low normal blood pressure until the beginning of the third trimester when her ascending aortic diameter was found to have increased by more than 10% to 3.97 cm. This is in contrast to the normal pregnancy increase in ascending aortic diameter of 0.5%–1% beginning usually at the end of the second trimester and peaking at delivery (7). Beta-blocker therapy was initiated, and weekly echocardiography thereafter showed stable aortic diameters; her blood pressure remained very low, and she could not continue beta-blocker treatment. An elective C-section at 37 weeks yielded a normal baby without complications. Unfortunately 3 years afterward she experienced acute aortic dissection and died at the age of 33. A prior survey of pregnancy in women with Turner syndrome estimated a 2% maternal mortality rate (8), a rate that is 100-fold greater than the death rate in the general population for all causes during pregnancy. There is reason to believe that it may even be higher. Furthermore, those women with Turner syndrome who do not have a catastrophic event during pregnancy may not have gone safely through pregnancy. As in the case reported here, women with Turner syndrome who have underlying cardiovascular abnormality such as abnormal aortic valve structure and/or ascending aortic dilation may experience excessive aortic dilation during pregnancy that increases their risk for complications and premature mortality years later. In light of these observations, we suggest that the ASRM practice guidelines for assisted reproductive technology (ART) in women with Turner syndrome be revised as follows:
Fertility and Sterility Vol. 91, No. 5, May 2009 Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.
e31
Women with known congenital cardiovascular disease (e.g., bicuspid aortic valve or aortic coarctation) or hypertension should not undertake pregnancy. Women with ‘‘no known’’ defects still need a full cardiovascular evaluation including cardiac MRI at a center with expertise in cardiovascular imaging before attempting pregnancy, with particular attention to the aortic valve and aortic diameters. Women with an aortic size index greater than 2 cm/m2 should not attempt pregnancy. Finally, while the above parameters are believed to identify women at special risk for cardiovascular complications of pregnancy, Turner women without these features may have a latent vasculopathy that could be exacerbated by pregnancy. Therefore serious attention must be given to advising prospective ART patients about these concerns.
Carolyn Bondy, M.D. National Institute of Child Health and Human Development National Institutes of Health Turner Syndrome Society Medical Advisory Board Bethesda, MD Douglas Rosing, M.D. National Heart, Lung, and Blood Institute National Institutes of Health Bethesda, MD
e32
Letters to the Editor
Richard Reindollar, M.D. Dartmouth-Hitchcock Medical Center Obstetrics and Gynecology Lebanon, NH December 16, 2008 REFERENCES 1. Boissonnas CC, Davy C, Bornes M, Arnaout L, Meune C, Tsatsatris V, et al. Careful cardiovascular screening and follow-up of women with Turner syndrome before and during pregnancy is necessary to prevent maternal mortality. Fertil Steril. 2. The Practice Committee of the American Society for Reproductive Medicine. Increased maternal cardiovascular mortality associated with pregnancy in women with Turner syndrome. Fertil Steril 2005;83:1074–5. 3. Ho VB, Bakalov VK, Cooley M, Van PL, Hood MN, Burklow TR, et al. Major vascular anomalies in Turner syndrome: prevalence and magnetic resonance angiographic features. Circulation 2004;110:1694–700. 4. Sachdev V, Matura LA, Sidenko S, Ho VB, Arai AE, Rosing DR, et al. Aortic valve disease in Turner syndrome. J Am Coll Cardiol 2008;51:1904–9. 5. Matura LA, Ho VB, Rosing DR, Bondy CA. Aortic dilatation and dissection in Turner syndrome. Circulation 2007;116:1663–70. 6. Bondy CA, for The Turner Syndrome Consensus Study Group. Care of girls and women with Turner syndrome: a guideline of the Turner syndrome study group. J Clin Endocrinol Metab 2007;92:10–25. 7. Easterling TR, Benedetti TJ, Schmucker BC, Carlson K, Millard SP. Maternal hemodynamics and aortic diameter in normal and hypertensive pregnancies. Obstet Gynecol 1991;78:1073–7. 8. Karnis MF, Zimon AE, Lalwani SI, Timmreck LS, Klipstein S, Reindollar RH. Risk of death in pregnancy achieved through oocyte donation in patients with Turner syndrome: a national survey. Fertil Steril 2003;80:498–501.
doi:10.1016/j.fertnstert.2009.01.061
Vol. 91, No. 5, May 2009