Turner's syndrome and pregnancies after oocyte donation

Tuija Foudila, Viveca Söderström-Anttila and Outi Hovatta1

Infertility Clinic, The Family Federation of Finland, Kalevankatu 16, FIN-00100 Helsinki Finland


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A total of 20 clinical pregnancies was achieved among 18 women with Turner's syndrome who were treated in an oocyte donation programme. The oocytes were donated by voluntary unpaid donors. A mean of 1.8 embryos per transfer was given to each recipient by way of 28 fresh and 25 frozen embryo transfers. With fresh and frozen embryos, 13 and seven pregnancies respectively were achieved. The clinical pregnancy rate per fresh embryo transfer was 46%, and the implantation rate 30%, being similar to the corresponding rates among our oocyte recipients with primary ovarian failure in general. The corresponding rates with frozen embryos were 28 and 19%. Of these pregnancies, 40% ended in miscarriage. This high rate may be explained by uterine factors. Six women were hypertensive during pregnancy, a rate comparable with that in other oocyte donation pregnancies. All these women delivered by Caesarean section. Pregnancy and implantation rates after oocyte donation were high in women with Turner's syndrome, but the risk of cardiovascular and other complications is high. Careful assessment before and during follow-up of pregnancy are important. Transfer of only one embryo at a time to avoid the additional complications caused by twin pregnancy is recommended.

Key words: endometrium/miscarriage/oocyte donation/pregnancy/Turner's syndrome


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In Turner's syndrome, 95–98% of women are infertile (Weiss, 1971Go; Lippe, 1991Go). This is due to accelerated loss of oocytes from the ovaries after the 18th week of fetal life or over the first few postnatal months or years (Singh and Carr, 1966Go; Weiss, 1971Go). About 5–10% of the girls still have follicles at the time of puberty, and they undergo pubertal development and have menstrual periods (Lindsten, 1963Go; Lippe, 1991Go). Spontaneous pregnancies have been reported, especially in women with Turner's mosaicism (Singh et al., 1980Go; Kohler et al., 1985Go; Meyer et al., 1989Go; Swapp et al., 1989Go; Verschraegen-Spae et al., 1992Go; Tarani et al., 1998Go), but also in women with non-mosaic Turner's syndrome (Philip and Sele, 1976Go; Nielsen et al., 1979Go; Wray et al., 1981Go; Baudier et al., 1985Go; Varela et al., 1991Go; Magee et al., 1998Go). Occasional pregnancies have been reported in women using hormonal replacement therapy because of primary amenorrhoea (Blumenthal and Allanson, 1997Go).

Oocyte donation is now an option in the treatment of childlessness in Turner's syndrome. Subjects with Turner's syndrome have been included in oocyte donation programmes since the early days of this treatment (Abdalla et al., 1990Go; Sauer and Paulson, 1990Go; Press et al., 1995Go; Khastgir et al., 1997Go). Pregnancy rates of Turner's syndrome subjects have been similar to those among other women in oocyte donation programmes (Press et al., 1995Go; Khastgir et al., 1997Go) or lower (Yaron et al., 1996Go), but relatively small numbers of these cases have been described. Impaired receptivity of endometrium in these patients has been suspected (Rogers et al., 1992Go; Yaron et al., 1996Go).

We have treated 18 women with Turner's syndrome in our oocyte donation programme, and report here the pregnancy results.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Eighteen subjects with Turner's syndrome were treated in the oocyte donation programme of the Family Federation of Finland from 1991 to February 1998. Before treatment, careful clinical assessment was also carried out by a specialist in internal medicine, whenever indicated, to minimize the risk of cardiovascular and other undesirable events during pregnancy.

One of the subjects had had coarctation of the aorta, which had been operated upon in childhood. She also had epilepsy, which was well controlled with sodium valproate medication. One had had aplasia of the vagina, which had been treated operatively. Thyroid antibodies had been detected in two women. Two had unexplained hepatopathies with slightly to moderately elevated enzyme concentrations. Two had hypertension, which was treated by metoprolol tartrate medication in one case, and followed-up in the other. No women were excluded from the programme because of illnesses.

One subject had had spontaneous menarche with one spontaneous period. Her karyotype was 46X, i(Xq).

The oocytes were obtained from healthy voluntary donors, recruited through the media. They were younger than 35 years of age, and they did not receive any financial reward. For ovarian stimulation, they were down-regulated using a long-acting gonadotrophin-releasing hormone (GnRH) agonist, goserelin (Zoladex; Zeneca Pharma, Helsinki, Finland), giving a single injection (3.6 mg) at the mid-luteal phase of the previous cycle. Human menopausal gonadotrophin (Pergonal; Serono, Aubonne, Switzerland) or follicle stimulating hormone (Fertinorm-HP; Serono) was used for stimulation. Human chorionic gonadotrophin (HCG) (Profasi; Serono), 5000 IU, was given when the largest one to three follicles were at least 18 mm in diameter. Transvaginal ultrasound-guided follicle aspiration was carried out 34–36 h later.

The collected oocytes were pre-incubated in 5% CO2 in air at 37°C for 2–4 h before insemination with spermatozoa (100–450x103) from the recipient's partner. Percoll density gradient centrifugation was used for preparation of semen.

The women with Turner's syndrome usually continued their pre-existing hormonal replacement therapy (HRT) until they were known to be due to receive donated oocytes within a few months. The replacement therapy was then changed to oral oestradiol valerate (Progynova; Schering, Turku, Finland) and micronized vaginally administered progesterone (Lugesteron; Leiras, Turku, Finland), 600 mg, daily. Oestradiol was used as a fixed dose, 4 mg at first, but it was increased to 6 or 8 mg if the endometrium was thinner than 6–7 mm in an ultrasound scan carried out during a test cycle before the first treatment cycle. The echo pattern of the endometrium was also recorded. The actual embryo transfer cycles were also monitored by an ultrasound scan before transfer.

The HRT was timed so that the subjects started receiving oestradiol 4–5 days before the donor's ovarian stimulation commenced. Progesterone was started 1 day before or on the day of the donor's oocyte retrieval. One or two embryos were usually transferred to the recipient's uterine cavity on the second day after oocyte retrieval. Excess embryos were frozen using propanediol as a cryoprotectant. Frozen embryos were similarly transferred during later HRT cycles.

The serum HCG concentration was measured 14–17 days after embryo transfer. If it reflected a positive result, similar HRT was continued for up to 12 weeks. The pregnancies were carefully followed-up in collaboration with the antenatal units of the obstetric hospitals concerned.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Hormone replacement therapy
An oestradiol dose of 4 mg was used in 20 fresh embryo transfer cycles resulting in nine pregnancies (45%), 6 mg in six fresh embryo transfer cycles, which resulted in three pregnancies, and 8 mg in two such cycles, one of which resulted in a pregnancy leading to full term birth. In 18 frozen embryo transfer cycles, 4 mg of oestradiol was used, and five pregnancies were obtained, 6 mg was used in six cycles resulting in two pregnancies, and 8 mg in one cycle which resulted in normal pregnancy. In nine cycles, the endometrium was thinner or equal to 6.5 mm at the time of embryo transfer, but no transfers were cancelled at this stage. These nine cycles resulted in three pregnancies (pregnancy rate 33%, implantation rate 20%), which continued to full term. In the six other patients, who had received an increased dose of oestradiol, the endometrium was thicker.

Treatment with fresh embryos
Thirteen clinical and one biochemical pregnancies were achieved among 17 recipients in 28 transfers of a mean of 1.8 fresh embryos (Table IGo). The clinical pregnancy rate per embryo transfer was 46%, and the implantation rate 30%. There was one twin pregnancy which ended in intrauterine death of one twin and termination of the pregnancy because the second twin had encephalocele. Six other pregnancies ended in spontaneous abortion, the miscarriage rate being 54%.


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Table I. Treatments with fresh embryos
 
Treatment with frozen embryos
Twelve women had received frozen embryos (Table IIGo); a mean of 1.8 embryos per transfer. Twenty-five embryo transfers resulted in seven clinical pregnancies and one biochemical pregnancy (clinical pregnancy rate per transfer 28%). One pregnancy ended in miscarriage (14%), and one was a twin pregnancy. The implantation rate was 19%.


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Table II. Treatment with frozen embryos
 
Pregnancies and deliveries
Six women had hypertension during pregnancy. In two cases, it was a pre-existing condition, two had mild transient hypertension, and two were pre-eclamptic. Two women had mild cholestasis of pregnancy.

Twelve healthy infants were born in 11 deliveries. One pregnancy is still ongoing.

All 11 deliveries were by Caesarean section. The indications were small pelvis and lack of spontaneous contractions, partial placenta praevia in one, and intrauterine growth retardation of the fetus of one pre-eclamptic mother.

The mean (range) birth weight of the singletons was 2852 (1500–3370) g. One infant was small for gestational age: 1500 g at 36 weeks. The mother had pre-eclampsia. The mean gestational age was 38 (range 36–39) weeks. The birth weights of the twins were 2130 and 2810 g. They were born at 36 weeks of gestation, and the mother had severe bleeding (5000 ml) as a result of placenta accreta during delivery. Supravaginal amputation of the uterus was needed to stop the bleeding. She has recovered well.

There was a total of eight miscarriages (40% of all clinical pregnancies).


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The high pregnancy rate (46% per fresh and 28% per frozen embryo transfer, 1.8 embryos/embryo transfer) in our survey shows that women with Turner's syndrome are among the best subjects to benefit from oocyte donation. The implantation rates, 30% with fresh and 19% with frozen embryos, were also high and indicate that the endometrium can be well prepared using continuous oral oestradiol, 4–8 mg, combined with 600 mg trans-vaginal micronized progesterone starting 2 or 3 days before embryo transfer. These rates among recipients with Turner's syndrome were similar to those achieved among all our oocyte recipients who had primary ovarian failure (pregnancy rate per embryo transfer 42%, implantation rate 28%; Söderström-Anttila, 1998aGo). This is in contrast to the results of Rogers et al. (1992) and Yaron et al. (1996), who reported low pregnancy and implantation rates in Turner's syndrome. They suggested an inherent endometrial abnormality in Turner's syndrome. The higher pregnancy and implantation rates in our study may be explained by different HRT. Our subjects received higher doses of progesterone by the vaginal route versus an intramuscular one.

The pregnancy and implantation rates in our survey were also higher than those in Turner's syndrome subjects treated by Khastgir et al. (1997). In that survey, the HRT was different. Oestradiol was given stepwise in many patients, and the dose of progesterone was only half of that used in our survey. In oocyte donation programmes, in which occasional Turner's syndrome subjects have been treated, the dosage of oestradiol has been stepwise (Davies et al., 1990Go; Sauer et al., 1991Go; Pados et al., 1992Go), and completetely different progesterone preparations have been used. Also IVF patients as donors (Davies et al., 1990Go; Pados et al., 1992Go; Michalas et al., 1996Go) may have contributed to the lower pregnancy and implantation rates.

Pregnancies among Turner's syndrome women are not without risk. Cardiovascular abnormalities are common in women with Turner's syndrome (Lippe, 1991Go). Coarctation of the aorta is seen in about 10%, and a bicuspid aortic valve is found in about one-third of the women without coarctation (Lippe, 1991Go). Arterial hypertension is frequently seen. Aortic dissection is potentially the most serious complication among subjects with Turner's syndrome. Two fatal cases of aortic dissection have been reported in Turner's syndrome patients during pregnancies which resulted from oocyte donation (Nagel and Tesch, 1997Go). This underlines the importance of careful assessment of these women before treatment, as suggested also by Birdsall and Kennedy (1996). Cardiological investigation with ultrasonography scan or magnetic resonance imaging is necessary before treatment and during the first trimester of pregnancy.

Among our subjects, two had pre-existing hypertension, two had transient hypertension during pregnancy, and two others developed pre-eclampsia. One of them had a growth retarded infant, who was otherwise healthy. The incidence of hypertension among these women was similar to that which we have observed in our oocyte recipients in general (Söderström-Anttila et al., 1998). In Turner's syndrome, there is also a high risk of disturbance of carbohydrate metabolism (Lippe, 1991Go; Holl et al., 1994Go), but there was no case of impaired glucose tolerance among our subjects.

One severe bleeding complication occurred after twin delivery in one of our subjects. We are now transferring only one embryo at a time to women with Turner's syndrome. We can at least avoid the additional risks resulting from twin pregnancy. Because the implantation rate is high in these women, transfer of one embryo is acceptable, and can be highly recommended.

Because of their short stature, all women with Turner's syndrome have a small pelvis, which predisposes them to fetopelvic disproportion. This was the main reason why all our subjects delivered by Caesarean section. In some more favourable cases spontaneous labour and delivery may be possible.

Spontaneous pregnancies among women with Turner's syndrome are associated with a high risk of miscarriage and an increased risk of trisomy 21 in the offspring (King et al., 1978Go; Nielsen et al., 1979Go; Swapp et al., 1989Go). Turner's syndrome can be transmitted from mothers to daughters (Varela et al., 1991Go; Verschragen-Spae et al., 1992; Blumenthal and Allanson, 1997Go; Tarani et al., 1998Go). Although the main causes of miscarriage in Turner's syndrome have been thought to be of genetic origin, there may also be other causes. The miscarriage rate among our subjects was 40%. Three of six pregnancies of Turner's syndrome subjects ended in abortion in a survey reported by Press et al. (1995), and two of five in a study reported by Yaron et al. (1996). In the survey reported by Khastgir et al. (1997), the miscarriage rate was as high as 50%. Low blood flow in a hypoplastic uterus might be one explanation.

The mechanism behind early oocyte loss in Turner's syndrome (Singh and Carr, 1966Go; Weiss, 1971Go) is not known. It would be interesting to know if there is a factor in the second X chromosome which prevents follicular atresia. Because some girls with Turner's syndrome still have follicles in their ovaries during postnatal life, one treatment option in the future might be cryopreservation of ovarian tissue at a young age (Hovatta et al., 1996Go; Newton et al., 1996Go), and later replantation or maturation of ovarian follicles in vitro.


    Notes
 
1 To whom correspondence should be addressed at: Karolinska Institute, Department of Obstetrics and Gynaecology, Huddinge University Hospital, SE 171 86 Huddinge, Sweden Back


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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
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Submitted on June 22, 1998; accepted on October 28, 1998.