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 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 MRI rarely fails to visualize the aortic valve and is clearly superior to echocardiography in detecting abnormalities of the aorta, which is clearly visualized both in ascending and descending aspects. For this reason the 2006 meeting of Turner syndrome consensus conference recommended that all women with Turner syndrome contemplating pregnancy needed to 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 not routinely 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 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”, i.e., 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 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 prior to 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 BSA, 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 2nd 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 three 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 gotten safely through pregnancy. As in the case reported here, women with Turner syndrome that 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 ART in women with Turner syndrome be revised as follows:
• 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 prior to 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, MD
National Institutes of Health
Eunice Kennedy Shriver National Institute of Child Health and Human Development
Turner Syndrome Society Medical Advisory Board
Douglas Rosing, MD
National Institutes of Health
National Heart, Lung and Blood Institute
Richard Reindollar, MD
Dartmouth-Hitchcock Medical Center
1. Boissonnas CC, Davy C, Bornes M, Arnaout L, Meune C, Tsatsatris V, Mignon A, Jouannet P: Careful cardiovascular screening and follow-up of women with Turner syndrome before and during pregnancy is necessary to prevent maternal mortality. Fertility and Sterility In Press, Corrected Proof.
2. The Practice Committee of the American Society for Reproductive M: Increased maternal cardiovascular mortality associated with pregnancy in women with Turner syndrome. Fertility and Sterility 2005, 83:1074-75.
3. Ho VB, Bakalov VK, Cooley M, Van PL, Hood MN, Burklow TR, Bondy CA: 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, Bondy CA: Aortic Valve Disease in Turner Syndrome. Journal of the American College of Cardiology 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 G: 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. Obstetrics and gynecology 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. Fertility and Sterility 2003, 80:498-501.
Published online in Fertility and Sterility doi: 10.1016/j.fertnstert.2009.01.061
To the Editor:
The report by Boissonnas et al (1) describing the tragic loss due to a ruptured aortic dissection of a young woman with Turner Syndrome (TS) shortly after giving birth sharpens the focus on important issues surrounding artificial reproductive technology (ART) in Turner women.
The authors are correct that their decision to proceed with ART was fully consistent with the 2005 guideline of the ASRM practice committee (2) (published again in the November supplement of the Journal). Furthermore, they should be commended for emphasizing the inadequacy of that guideline in allowing those with an aortic root dilated up to 4 cm to proceed with pregnancy. Indeed, a 4 cm aorta is dangerously dilated relative to the short stature of most TS women.
Matura et al (3) (mentioned in the discussion) provide a useful aortic root diameter (2.5 cm/m2) where aortic dissection is likely to occur. Hopefully any TS women would be counseled to not proceed with ART well before the aorta attains a 4 cm diameter or 2.5 cm/m2. To be safe, a Z-score >2 should be the size where aortic root dilation is first diagnosed. Unfortunately Boissonnas et al. do not go nearly far enough in pointing out the other shortcomings of the ASRM practice committee report. The report states that any “significant” cardiac abnormality should be considered an absolute contraindication to pregnancy, yet provides no clarity regarding what abnormality might be significant. The non-obstructed bicuspid aortic valve (often thought of as a minor finding) is undoubtedly a significant cardiac malformation in the setting of TS. Furthermore, in our recent review (4) of the case literature approximately 10% of the aortic dissections occurring among all TS women had neither congenital heart disease nor systemic hypertension. In fact, one individual in that group without other risk factors was pregnant at the time of her catastrophic aortic dissection.
On the other hand, the risk of aortic dissection during pregnancy in the general population is vanishingly small. (5) Thus, there probably is an aortopathy in TS that leads to aortic root enlargement independently of other known risk factors. (6) It must be concluded that every TS women who is contemplating ART, regardless of whether she has other risk factors or not, has a significantly increased susceptibility to aortic dissection compared to non-TS pregnant women.
Michael Silberbach, MD
Medical Advisory Board, Turner Syndrome Society of the United States
Doernbecher Children’s Hospital
1. Boissonnas CC, Davy C, Bornes M, Arnaout L, Meune C, Tsatsatris V, Mignon A, Jouannet P. Careful cardiovascular screening and follow-up of women with Turner syndrome before and during pregnancy is necessary to prevent maternal mortality. Articles in press, Nov. 4, Fertil Steril. 2008.
2. Reindollar RH. Increased maternal cardiovascular mortality associated with pregnancy in women with Turner syndrome. The Practice Committee of the American Society for Reproductive Medicine. Fertility and Sterility. April 2005;83(4):1074.
3. Matura LA, Ho VB, Rosing DR, Bondy CA. Aortic dilatation and dissection in Turner syndrome. Circulation. Oct 9 2007;116(15):1663-70.
4. Carlson M, Silberbach M. Dissection of the aorta in Turner syndrome: two cases and review of 85 cases in the literature. J Med Genet. Dec 2007;44(12):745-9.
5. Oskoui R, Lindsay J, Jr. Aortic dissection in women < 40 years of age and the unimportance of pregnancy. Am J Cardiol. Apr 15 1994;73(11):821-3.
6. Lopez L, Arheart KL, Colan SD, Stein NS, Lopez-Mitnik G, Lin AE, Reller MD, Ventura R, Silberbach M. Turner Syndrome Is an Independent Risk Factor for Aortic Dilation in the Young. Pediatrics. June 1, 2008 2008;121(6):e1622-7.
Published online in Fertility and Sterility doi: 10.1016/j.fertnstert.2009.01.060
The Authors Respond:
We thank Dr. Silberbach, Dr. Bondy and collaborators for their thoughtful letters and comments. We do agree that ASRM recommendations (1) should be modified for a better control of cardiovascular risk in women with Turner syndrome (TS) attempting pregnancy. Thanks to the study of Matura et al (2), we know that the aortic diameter should be normalized to body surface area, particularly in women with TS because of their small size. We agree that women with TS should be accepted in oocyte donation (OD) program only if their aortic size index (ASI) is <2cm/m2. Moreover, we do agree with Dr. Silberbach that even an isolated bicuspid aortic valve (BAV) is a powerful predictor for aortic complications. An ASI > 2cm/m2, a BAV and other congenital heart disease should be contraindications for OD because of an unacceptable risk of aortic dissection during or after pregnancy. Hypertension, when moderated and controlled, should also be discussed before attempting a pregnancy because of the enhanced risk of toxemia and preeclampsia and their deleterious consequences on the thoracic aorta. Others abnormalities like renal and metabolic defects should also be taken into account for acceptance of pregnancy.
We think that the cardiovascular screening (CVS) of women with TS before OD should be done in a center with good expertise in cardiovascular imaging. Both magnetic resonance imaging (MRI) and transthoracic echocardiography (TTE) have their advantages and limitations in the assessment of thoracic aorta. The diagnosis of a bicuspid valve is easier with TTE than with MRI, especially in bicuspid valves with raphe, which represent 50% of cases (3), but MRI is indicated when echogenicity is not good enough and has the advantage of analyzing the entire aorta. If both techniques can be used for CVS before OD, TTE will be preferred for careful follow-up during pregnancy. Furthermore, we think that the same referent center should do the preconception screening and should ensure the cardiovascular follow-up during pregnancy when possible.
Turner women, without any cardiac abnormalities such as BAV, aortic coarctation, aortic dilation or hypertension, remain at a significantly higher risk of aortic dissection during pregnancy because of their “latent” aortopathy (4). Furthermore, the physiologic increase in aortic diameter during pregnancy can hasten the modifications in the aortic wall and the dilatation of the aorta and lead to premature death in the years following pregnancy. Patients must be informed of this risk.
After the dramatic death we reported, all women with TS requesting OD in our center were carefully screened again. We were surprised to observe the gap between current cardiovascular evaluations made during childhood and/or adulthood and the malformations we discovered, particularly undetected BAV. We also noticed a lack of follow-up after childhood for most patients. There is a real need for a better follow-up of Turner women, particularly at the beginning of adulthood and before any pregnancy attempt, as recently recommended (5).
Céline Chalas Boissonnas, MD
Pierre Jouannet, MD
Biology of Reproduction
Céline Davy, MD
Medicine of Reproduction
Laure Cabanes, MD
1. Increased maternal cardiovascular mortality associated with pregnancy in women with Turner syndrome. The Practice Committee of the American Society for Reproductive Medicine. Fertility and Sterility 2005;83(4):1074.
2. Matura LA, Ho VB, Rosing DR, Bondy CA. Aortic dilatation and dissection in Turner syndrome. Circulation 2007;116:1663-70.
3.Roberts WC: The congenitally aortic bicuspid aortic valve. A study of 85 autopsy cases. Am J Cardiol 1970;26:72-83.
4. Lopez L, Arheart KL, Colan SD, Stein NS, Lopez-Mitnik G, Lin AE, Reller MD, Ventura R, Silberbach M. Turner Syndrome Is an Independent Risk Factor for Aortic Dilation in the Young. Pediatrics 2008;121(6):e1622-7.
5. Bondy CA for The Turner Syndrome Consensus Study G. Care of Girls and Women with Turner Syndrome: A Guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab 2007; 92:10-25.
Published online in Fertility and Sterility doi: 10.1016/j.fertnstert.2009.01.059