This study reviews pregnancy in a cohort of 276 TS women participating in a natural history study defined by stringent karyotype analyses and comprehensive clinical evaluation. This analysis provides essential information on characteristics of women that experience spontaneous pregnancies, and compares feto-maternal outcomes in spontaneous and ART-related pregnancies. The data presented here contribute to a more complete knowledge base that will enhance the ability of care providers to counsel women with TS and help these women make more informed decisions concerning pregnancy.
The frequency of spontaneous pregnancy among women with ‘pure, 45,X’ TS is not established. There are several case reports of pregnancies among Turner women with 45,X in the peripheral blood karyotype (9
), some of which report additional X or Y chromosome material detected in blood or other tissues using variable methods with unreported standardized procedures and quality controls. We report spontaneous menarche, pubertal development, and pregnancy in 5/276 women (1.8%) with short stature and other clinical features of TS in which the diagnosis of TS was established by missing all or major parts of one sex chromosome in greater than 70% of their 50-cell PBL karyotype. Interestingly, the proportion of pure, or nearly pure, 45,X individuals was greater in the spontaneous pregnancy group; three of the five fertile women had 100% 45,X cells, one had 98% 45,X cells with 2% 46,XX, and one had 90% 45,X cells with 10% 46,XdelXp.
These women had a total of 7 spontaneous pregnancies, three of which were unexpected and unintentional. Two of these unintended pregnancies were in a participant who had her second unintended pregnancy while taking oral contraceptives for birth control. This woman was diagnosed at birth because of lymphedema, her karyotype was 45,X on 200 leukocyte preparations, and she has extreme short stature, cardiac and renal anomalies, and hearing loss. We cite her case to make two important points. The first is that spontaneous (and unintended) pregnancy is quite possible even in women with apparently pure 45,X and classic TS. These spontaneous pregnancies were associated with spontaneous menarche and pubertal development in our cohort. As such, appropriate education and pregnancy prevention measures must be part of care for girls with TS that demonstrate spontaneous puberty. In particular, given reports of acute, catastrophic events associated with TS pregnancies, counseling for older girls and young women with TS should include potential for spontaneous pregnancy, use of effective contraceptive methods to avoid unwanted pregnancy, education regarding the risk for life-threatening cardiovascular pregnancy complications, and information on parenting alternatives such as adoption or surrogacy. The second important issue relates to the genetic predisposition to infertility in TS. Examples of spontaneous fertility in 45,X individuals demonstrate the likelihood that there are many genetic loci contributing to oocyte generation and survival, and thus affecting overall fertility. Fertile women with 45,X TS likely have autosomal alleles that enhance fertility by compensating for haplo-insufficiency for unknown X-linked genes involved in ovarian function.
Some early reports suggest an excess of miscarriage, fetal malformations, and chromosomal defects such as trisomy 21 in spontaneous Turner pregnancies (10
). However, the apparent excess risk for trisomy 21 may be more closely associated with advanced maternal age than X-chromosome deficiency in Turner syndrome according to case reports (13
). The seven spontaneous pregnancies reported here produced live born, normal appearing infants without chromosomal anomalies. A fertile, 45,X woman may produce oocytes containing either a normal, single X or no sex chromosome, resulting in zygotes that are either eukaryotic or 45,X. In the latter case, the gestation is unlikely to survive (40
), but in the rare cases of survival, the resulting zygote would have TS (26
). On the other hand, if pregnancy occurs in a woman with a structurally abnormal X chromosome, there is a distinct possibility of passing the abnormal chromosome to offspring, which could then have phenotype similar to the mother. Thus, the specific maternal karyotype should be considered when counseling TS women regarding reproduction and potential risks for offspring.
Our series is notable for a high rate of Cesarean delivery. In fact, Cesarean section was performed in 10 of 13 deliveries, including all 6/6 deliveries in the ART pregnancy group. The major reason cited for Cesarean section in our study group was feto-pelvic disproportion, which is expected given the small stature and narrow pelvis in most women with TS (2
). Considering that many women with TS have a predisposition to aortopathy that may be augmented during pregnancy or labor, the use of Cesarean section for delivery is reasonable.
An increased rate of pregnancy induced hypertensive (PIH) disorders has been reported in gestations following oocyte donation in general, and may be even greater among women with TS (15
). There were no cases of PIH in the 7 spontaneous pregnancies reported here. Among the 6 oocyte donation pregnancies, there was one case of pre-eclampsia in a twin gestation. The risk for this complication in TS is highly related to multiple gestations, as noted more than one decade ago by Hovatta et al
Severe cardiovascular outcomes should also be considered in addition to obstetric complications of note in this population. Although there were no aortic dissections or deaths in the subjects presented here, there is an approximately 2% risk of pregnancy-associated death and aortic dissection in TS women in ART pregnancies (17
). It is plausible that pregnancy associated hemodynamic and hormonal factors may promote deterioration in the compromised cardiovascular system of women with TS. It remains unknown, however, if apparently healthy Turner women with normal cardiovascular anatomy and function determined by adequate screening— including cardiac magnetic resonance (42
)— are at increased risk, as all the well-documented catastrophic complications have occurred in women with underlying aortic pathology (43
Three of the nine women with pregnancies in this series had bicuspid aortic valves (BAV). Two of those women had spontaneous pregnancies and retained normal valve function and normal (BSA-indexed) aortic diameters years later. The third woman with BAV had a twin ART pregnancy that was complicated by pre-eclampsia, and she has a markedly dilated aorta. Although we do not have pre-pregnancy aortic measurements, we view this as a likely complication of her pregnancy. We evaluated the effects of pregnancy on aortic diameter, but our sample size was underpowered to detect significant differences in aortic size. Larger sample sizes are essential to accommodate investigations of the effects of age, type of pregnancy, and aortic valve structure on the aortas of TS women during and after pregnancy. Another important issue that requires further investigation concerns the potential extra risk of oocyte donation versus spontaneous pregnancy. The 2% risk of aortic dissection is obtained from oocyte donation pregnancies (17
), while case reports suggest a lesser risk in spontaneous pregnancies in women with TS (49
). It is unknown whether catastrophic events occur in the 50% of patients with normal cardiovascular systems because existing data do not include adequate evaluation of the maternal cardiovascular system.
Further reporting of large cohorts, including detailed descriptions of maternal age, full karyotype, pre- and post-pregnancy cardiovascular status, method of conception, delivery method, and feto-maternal outcomes is necessary to elucidate the relationship between these factors and outcome in TS pregnancies. Studies including this essential data are necessary for the evaluation of risk associated with pregnancy in TS women via large, prospective registry or balanced meta-analysis. However, until such analysis is possible, the potentially fatal downstream effects of preeclampsia, aortic dissection, and other complications that may be increased in TS pregnancies warrant patient education regarding the potential for spontaneous pregnancy, comprehensive cardiovascular screening prior to conception (42
), single embryo transfer in ART, and caution regarding unintentional pregnancies TS women overall.