Fertility in Turner Syndrome

Risks of the Mother

Pregnant women with TS require tertiary medical and obstetric care due to increased risk of pregnancy-related complications. These include thyroid dysfunction, obesity, diabetes, hypertension and preeclampsia, which occur in approximately 40% of patients with TS compared with 6–12% of the general population.^[2,29–31] Severe complications such as deterioration of congenital heart disease, heart failure, aortic dissection and sudden death are well described.^[32–34] Importantly, women with TS are at increased risk of development of aortic cystic medial necrosis independent of congenital heart disease; 10% of patients with aortic dilatation, dissection or rupture have no prior cardiac risk factors.^[35,36] Women with TS are at significant risk for aortopathy and also for short stature – it is thus important to assess aortic size corrected for body surface area (aortic size index), although dissection can still occur at smaller aortic sizes in the absence of valve and arch abnormalities.^[36,37]

In an unbiased study of 115 women from a national TS cytogenetic registry in Sweden, the risk of aortic dissection was found to be 1%, and in a review of 101 TS pregnancies from oocyte donation programs in the United States, the risk of maternal death due to aortic dissection was estimated to be at least 2%.^[4,38] The risk of aortic dissection is associated with factors such as congenital cardiovascular malformation (particularly bicuspid aortic valve, coarctation of the aorta and aortic root dilatation), history of foetal lymphoedema, hypertension, obesity and multiple pregnancy.^[39,40] Multiple embryo transfer is strongly contraindicated in women with TS.^[30,41] A review of pregnancies in 93 women demonstrated inadequacies of care, with only 37·6% prescreened with echocardiography or MRI: 37·8% experienced hypertensive illness and two died from aortic rupture.^[2] Prematurity occurred in 38·3%, more commonly in those who were hypertensive; inta-uterine growth restriction occurred in 27·5%, and there was one foetal demise associated with preeclampsia. Only 40% had an entirely normal pregnancy.

Women with known cardiovascular malformations should therefore consider avoiding pregnancy entirely; cardiac exclusion criteria for pregnancy have been suggested by consensus in French and US groups^[1,32,40,42] (Table 2). Termination of pregnancies due to factors associated with maternal TS risk has been reported.^[17]

Involvement of a cardiologist for prepregnancy risk assessment and frequent review during pregnancy is recognized as essential. Initial evaluation should include echocardiogram and MRI of cardiac anatomy and aortic dimensions, although it is unclear whether this screening will eliminate any risk. Some TS women who had aortic dissection showed a preceding increase in ascending aortic diameter and had a high aortic size index (normalized diameter to surface area).^[36] However, the presence of normal aortic dimensions does not exclude the risk of sudden aortic dissection.^[37]

While vaginal delivery may be possible, elective or emergency caesarean section may be required to minimize cardiac risk, to manage foeto-pelvic disproportion due to maternal short stature and narrow pelvis, or to expedite delivery in management of preeclampsia.^[7,30]

Table 1. Parenting options for women with Turner syndrome
Adoption	Parenting of a child who cannot be cared for by their biological parents.
Surrogacy	Planned pregnancy which is carried by another female on behalf of the woman with TS. Gametes used can be donated or the patient's own.
Heterologous IVF	Use of donated gametes to create an embryo for implantation in a pregnancy carried by the woman with TS.
Homologous IVF	Use of the patient's own gametes to create an embryo for implantation in a pregnancy carried by the woman with TS.

Table 2. Recommended contraindications to pregnancy in women with Turner syndrome
History of aortic surgery or aortic dissection
Coarctation of the aorta
Aortic size index >2·5 cm/m² or maximal aortic diameter 3·5 cm
Uncontrolled hypertension despite treatment
Portal hypertension with oesophageal varicose veins
Other major cardiac anomaly

Table 3. Assisted reproduction techniques for women with Turner syndrome
Technique	Method	Advantages	Disadvantages	Success rate
Heterologous IVF
Ovum donation and IVF-embryo transfer	Receipt of oocytes from a healthy donor, followed by IVF and fresh or frozen-thawed embryo transfer.	Rate of pregnancy loss and karyotypic abnormalities in offspring reduced. No need for invasive procedures in the child.	The TS mother is not the biological mother.	Established in adult women with TS. Pregnancy rate 17–40% per embryo transfer.
Oocyte donation and cryopreservation	If ovum donation from a relative is performed for a child, the oocytes are cryopreserved until the appropriate time for IVF and embryo transfer.	As above. Maintenance of familial genetic lineage.	Donor must have good ovarian function. Parentage confusion in resultant offspring. Risk of donor coercion.	Mother to daughter oocyte donation and preservation is being performed; however, there are no reported pregnancies in TS.
Homologous IVF
IVF and embryo transfer	Ovarian stimulation, collection of oocytes, then IVF and embryo transfer (fresh or frozen-thawed embryos).		Requires maturation of ovarian follicles. Requires sperm from partner or donor. Not appropriate in children.	An established IVF procedure for the general adult population. Most healthy embryos survive the process. A small number of pregnancies have been reported in women with TS.
Oocyte cryopreservation	Ovarian stimulation, collection of mature oocytes transvaginally and vitrification or slow freezing of oocytes.	Does not require sperm. Does not require surgery.	Requires maturation of ovarian follicles. Requires some physical and psychological maturity. May require a general anaesthetic for oocyte retrieval in adolescents. Not appropriate in prepubertal children.	Over 1000 births have been reported in the general adult population. Case reports exist of oocyte collection in young adolescents and women with TS, no pregnancies reported.
Ovarian tissue cryopreservation	Laparoscopic collection of ovarian tissue containing immature ovarian follicles, which is then cryopreserved. Some reports of in vitro maturation of follicles prior to vitrification.	Ovarian stimulation is not required preoperatively. No lower age limit.	Requires surgery. High rates of loss of oocytes in vitrification and thawing. In vitro maturation of follicles difficult.	More than thirty reported births in adult women. Experimental, but established precedent in children undergoing cancer treatment. No pregnancies in TS.

Table 3. Assisted reproduction techniques for women with Turner syndrome

Technique

Method

Advantages

Disadvantages

Success rate

Heterologous IVF

Ovum donation and IVF-embryo transfer

Receipt of oocytes from a healthy donor, followed by IVF and fresh or frozen-thawed embryo transfer.

Rate of pregnancy loss and karyotypic abnormalities in offspring reduced.
No need for invasive procedures in the child.

The TS mother is not the biological mother.

Established in adult women with TS. Pregnancy rate 17–40% per embryo transfer.

Oocyte donation and cryopreservation

If ovum donation from a relative is performed for a child, the oocytes are cryopreserved until the appropriate time for IVF and embryo transfer.

As above.
Maintenance of familial genetic lineage.

Donor must have good ovarian function.
Parentage confusion in resultant offspring.
Risk of donor coercion.

Mother to daughter oocyte donation and preservation is being performed; however, there are no reported pregnancies in TS.

Homologous IVF

IVF and embryo transfer

Ovarian stimulation, collection of oocytes, then IVF and embryo transfer (fresh or frozen-thawed embryos).

Requires maturation of ovarian follicles.
Requires sperm from partner or donor.
Not appropriate in children.

An established IVF procedure for the general adult population.
Most healthy embryos survive the process.
A small number of pregnancies have been reported in women with TS.

Oocyte cryopreservation

Ovarian stimulation, collection of mature oocytes transvaginally and vitrification or slow freezing of oocytes.

Does not require sperm.
Does not require surgery.

Requires maturation of ovarian follicles.
Requires some physical and psychological maturity.
May require a general anaesthetic for oocyte retrieval in adolescents.
Not appropriate in prepubertal children.

Over 1000 births have been reported in the general adult population.
Case reports exist of oocyte collection in young adolescents and women with TS, no pregnancies reported.

Ovarian tissue cryopreservation

Laparoscopic collection of ovarian tissue containing immature ovarian follicles, which is then cryopreserved.
Some reports of in vitro maturation of follicles prior to vitrification.

Ovarian stimulation is not required preoperatively.
No lower age limit.

Requires surgery.
High rates of loss of oocytes in vitrification and thawing.
In vitro maturation of follicles difficult.

More than thirty reported births in adult women.
Experimental, but established precedent in children undergoing cancer treatment.
No pregnancies in TS.

Table 4. Recommended criteria for consideration of ovarian cryopreservation in children and adolescents with Turner syndrome
Age 14 years and above
Spontaneous pubertal commencement
FSH <40 IU/l
AMH measurable
Normal cardiac status
Informed consent obtained from child and family: including counselling regarding mortality risk, foetal risk and absence of current success using this technology
Institutional clinical or research ethics approval, including criteria for follow-up

Fertility in Turner Syndrome

Risks of the Mother

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References

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