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Increased maternal cardiovascular mortality associated with pregnancy in women with Turner syndrome (2012)


REVIEW METHODS

To evaluate the impact of Turner syndrome on pregnancy outcomes after oocyte donation, a search of Medline from 1950 to January 2011 was performed. We used combinations of medical subject headings ‘‘Turner syndrome,’’ ‘‘oocyte donation,’’ ‘‘pregnancy,’’ ‘‘complications,’’ ‘‘cardiovascular,’’ and ‘‘screening.’’ The reference lists of relevant articles were reviewed for further reports. Only English-language articles were selected, and the search was restricted to published articles. Review articles were included. The relevance of included articles was assessed by one committee member, with subsequent consultation by the committee as a whole. Because the majority of the studies were case series and reviews, methods of aggregation and analysis were limited to tabulation and summarization. The document was revised by the Practice Committee on several occasions.


DISCUSSION

Turner syndrome results fromthe partial or complete loss of an X chromosome, with or without cell-line mosaicism, and is defined phenotypically as patients with short stature, primary amenorrhea, and other characteristics of variable penetrance, including cardiac, skeletal, and renal malformations. The prevalence is 1 in 2,000 live-born girls (1), with 5%–50% exhibiting cardiovascular malformations and 1 in 40 dying of aortic dissection by the age of 85 years (2–4).

Oocyte donation offers women with Turner syndrome the opportunity to achieve pregnancy. However, the increased cardiovascular demands of pregnancy may pose unique and serious risks for these women (5–7). Whereas the risk of maternal death in the general population is approximately 1/10,000, the risk of death during the perinatal period from aortic dissection or rupture in women with Turner syndrome is approximately 2% (8–10). When evaluating pregnancy outcomes in patients with Turner syndrome, distinction is not made between a ‘‘pure’’ 45,X karyotype and a mosaic pattern, and therefore all Turner syndrome patients should be considered to be at risk (9, 11, 12).

We do not have sufficient information to determine whether people with gonadal digenesis without Turner phenotype are at increased risk. Women with Turner syndrome at greatest risk of aortic dissection and rupture include those exhibiting baseline or progressive aortic root dilation, bicuspid aortic valve, coarctation of the aorta with or without prior surgical repair, and hypertension (6, 7). However, aortic dissection may also occur in the absence of known risk factors and at an aortic diameter of <4 cm (13). Prompt recognition of dissection may provide the opportunity for successful surgical intervention in some, though not all, women. Some institutions use transesophogeal echocardiography instead of magnetic resonance imaging (MRI).

Women with Turner syndrome expressing interest in oocyte donation should be carefully evaluated with both echocardiography and MRI, preferably by a cardiologist with expertise in adult congenital heart disease. Aortic diameter may not be an appropriate predictor of risk in women with Turner syndrome, because of their small stature and body surface area. Therefore aortic size measured by MRI should be adjusted for body surface area and reported as the aortic size index (ASI). An ASI >2.0 cm/m2 identifies those patients at a particularly increased risk for dissection (13). In a group of 166 women with Turner syndrome with a mean age of 36 years and followed for a mean of 3 years, 33% of the women with ASI >2.5 cm/m2 experienced aortic dissection (13). Any risk factor or significant abnormality found on imaging is best regarded as a contraindication to pregnancy. Even those having a normal evaluation should be thoroughly counseled regarding the risk of cardiac complications and death during pregnancy, because aortic dissection may still occur. Indeed, approximately one-half of aortic dissections occur in the third trimester or postpartum (8). Patients should be counseled that pregnancy carries not only a risk of maternal death, but also a potentially increased risk of premature death in the months and years after delivery because of pregnancy-related aortic dilation or not yet identified changes of the vessel wall (14, 15). All patients should be offered surrogacy and adoption as alternatives for having a family.

Those with normal evaluations who choose to proceed with donor oocyte require careful observation and frequent reevaluation during pregnancy (9, 16, 17). Specific recommendations for surveillance in women with Turner syndrome during pregnancy include: 1) treatment of hypertension; 2) periodic echocardiography or MRI and consultation with a cardiologist; 3) women in stable condition having an ascending ASI <2 cm/m2 may attempt vaginal delivery under epidural anesthesia; and 4) women exhibiting baseline or progressive aortic root dilation should have an elective cesarean delivery under epidural anesthesia before the onset of labor. In those patients who choose to proceed with ART, elective single-embryo transfer should be preferred, because multiple gestation increases the risks of perinatal complications (9). In addition, the obstetrician should be aware that complications such as preeclampsia and gestational diabetes also occur with increased frequency in pregnant patients with Turner syndrome.

For Turner syndrome patients who achieved pregnancy with donor oocytes, one study found reported that approximately 40% had no complications, 40% had pregnancyassociated hypertension, and the remainder had a range of significant morbidities including aortic rupture, gestational diabetes mellitus, eclampsia, and acute liver failure (9). It is worth noting that in this study only 37.6% of the patients were prescreened with echocardiography or thoracic MRI. Four-fifths of these women had a cesarean section, and one in twelve had postpartum hemorrhage. Approximately 40% of the infants were born prematurely and had a mean birth weight of 2,599 g (9).


SUMMARY

The risk of death during pregnancy from aortic dissection and rupture may be 2% or higher for women with Turner syndrome. In addition, pregnancy-related changes to the aorta may increase the risk of aortic dissection, aortic rupture, and premature death in subsequent years.


CONCLUSIONS

  • Turner syndrome is a relative contraindication for pregnancy, and patients should be encouraged to consider alternatives, such as gestational surrogacy or adoption.
  • Cardiology and maternal-fetal medicine consultation for evaluation and careful screening are required before considering pregnancy by oocyte donation.
  • Cardiac MRI revealing any significant abnormality and/or ASI >2 cm/m2 represents an absolute contraindication for attempting pregnancy in a woman with Turner syndrome.
  • Women with Turner syndrome having a normal cardiac MRI and evaluation who decide to attempt pregnancy after thorough counseling are still at much higher risk for associated morbidity and mortality and require careful observation and frequent formal reevaluation throughout gestation and postpartum.


Acknowledgments:

This report was developed under the direction of the Practice Committee of the American Society for Reproductive Medicine as a service to its members and other practicing clinicians. Although this document reflects appropriate management of a problem encountered in the practice of reproductive medicine, it is not intended to be the only approved standard of practice or to dictate an exclusive course of treatment. Other plans of management may be appropriate, taking into account the needs of the individual patient, available resources, and institutional or clinical practice limitations. The Practice Committee and the Board of Directors of the American Society for Reproductive Medicine have approved this report.

The following members of the ASRM Practice Committee participated in the development of this document. All committee members disclosed commercial and financial relationships with manufacturers or distributors of goods or services used to treat patients. Members of the committee who were found to have conflicts of interest based on the disclosed relationships did not participate in the discussion or development of this document.

Samantha Pfeifer, M.D.; R. Dale McClure, M.D.; William Catherino, M.D., Ph.D.; Marcelle Cedars, M.D.; John Collins, M.D.; Owen Davis, M.D.; Jeffery Goldberg, M.D.; Michael Thomas, M.D.; Catherine Racowsky, Ph.D.; Eric Widra, M.D.; Mark Licht, M.D.; Clarisa Gracia, M.D.; Robert Rebar, M.D.; Andrew La Barbera, Ph.D.

REFERENCES

  1. Nielsen J, Wohlert M. Sex chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Birth Defects Orig Artic Ser 1990;26:209–23.
  2. Mazzanti L, Cacciari E, Italian Study Group for Turner Syndrome (ISGTS). Congenital heart disease in patients with Turner’s syndrome. J Pediatr 1998;133:688–92.
  3. Gotzsche CO, Krag-Olsen B, Nielsen J, Sorensen KE, Kristensen BO. Prevalence of cardiovascular malformations and association with karyotypes in Turner’s syndrome. Arch Dis Child 1994;71:433–6.
  4. Schoemaker MJ, Swerdlow AJ, Higgins CD, Wright AF, Jacobs PA, United Kingdom Clinical Cytogenetics Group. Mortality in women with Turner syndrome in Great Britain: a national cohort study. J Clin Endocrinol Metab 2008;93:4735–42.
  5. Bondy CA. Aortic dissection in Turner syndrome. Curr Opin Cardiol 2008;23:519–26.
  6. Lin AE, Lippe BM, Deffner ME. Aortic dilation, dissection, and rupture in patients with Turner syndrome. J Pediatr 1986;109:820–6.
  7. Lin AE, Lippe B, Rosenfeld RG. Further delineation of aortic dilation, dissection, and rupture in patients with Turner syndrome. Pediatrics 1998;102:e12.
  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.
  9. Chevalier N, Letur H, Lelannou D, Ohl J, Cornet D, Chalas-Boissonnas C, et al. Materno-fetal cardiovascular complications in Turner syndrome after oocyte donation: insufficient prepregnancy screening and pregnancy follow-up are associated with poor outcome. J Clin Endocrinol Metab 2011;96:e260–7.
  10. Hagman A, K€allen K, Barren€as ML, Landin-Wilhelmsen K, Hanson C, Bryman I, Wennerholm UB. Obstetric outcomes in women with Turner karyotype. J Clin Endocrinol Metab 2011;96:3475–82.
  11. Hadnott TN, Gould HN, Gharib AM, Bondy CA. Outcomes of spontaneous and assisted pregnancies in Turner syndrome: the U.S. National Institutes of Health experience. Fertil Steril 2011;95:2251–6.
  12. Bryman I, Sylven L, Berntorp K, Innala E, Bergstrom I, Hanson C, et al. Pregnancy rate and outcome in Swedish women with Turner syndrome. Fertil Steril 2011;95:2507–10.
  13. Matura L, Ho V, Rosing D, Bondy C. Aortic Dilatation and dissection in Turner syndrome. Circulation 2007;116:1663–70.
  14. Gravholt CH, Landin-Wilhelmsen K, Stochholm K, Hjerrild BD, Ledet T, Djurhuus CB, et al. Clinical and epidemiological description of aortic dissection in Turner’s syndrome. Cardiol Young 2006;16:430–6.
  15. Bondy C, Rosing D, Reindollar R. Cardiovascular risks of pregnancy in women with Turner syndrome. Fertil Steril 2009;91:e31–2.
  16. Cabanes L, Chalas C, Christin-Maitre S, Donadille B, Felten ML, Gaxotte V, et al. Turner syndrome and pregnancy: clinical practice. Recommendations for the management of patients with Turner syndrome before and during pregnancy. Eur J Obstet Gynecol Reprod Biol 2010;152:18–24.
  17. 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 2009;91:929.e5–7.

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