Turner syndrome and spontaneous pregnancy

Universidade Federal do Triângulo Mineiro, Minas Gerais, Brazil

DOI:10.5935/1676-2444.20180065

Corresponding author

Alessandra Bernadete Trovó de Marqui
Instituto de Ciências Biológicas e Naturais; Departamento de Patologia, Genética e Evolução; Campus I
Praça Manoel Terra, 3330
CEP: 38015-050; Uberaba-MG, Brasil
Phone: +55 (34) 3700-6434
Fax: +55 (34) 3700-6466
e-mail: alessandratrovo@hotmail.com and alessandra.marqui@uftm.edu.br

INTRODUCTION

Turner syndrome (TS) is characterized by the partial or total absence of an X chromosome and affects approximately one for every 2,500 female births. Cardinal features include short stature, gonadal dysgenesis, and infertility⁽¹⁾.

The diagnosis of this genetic condition is performed by karyotype tests study, and about 40%-60% of patients with TS exhibit monosomy for the X-chromosome (45,X), followed by mosaicism of a 45,X cell line with, at least , another cell line; the others have structural abnormalities of the X-chromosome^(2-5). The presence of the Y-chromosome is associated with a high risk of developing gonadoblastoma, and molecular analysis to detect Y-chromosome sequences is indicated regardless of the karyotype of the TS patient⁽⁶⁾.

A previous study showed impaired fertility in TS⁽⁴⁾. In this regard, for most patients, infertility is unavoidable. In order to achieve maternity, such patients may resort to adoption or assisted reproduction techniques (ART), such as heterologous in vitro fertilization (IVF) (oocyte donation), the most common option, or homologous/autologous (use of the TS patient’s own gametes)^{(7, 8)}. A study with 276 adult patients with TS showed that 87.7% of them had no children and 12.3% had children. From this latter value, 9.1% chose adoption; 1.4% achieved spontaneous pregnancy; 1.4% has chosen ART and 0.4% referred spontaneous pregnancy and ART⁽⁹⁾.

Based on these data, a minority of TS patients can conceive spontaneously, without the need to use the aforementioned options. In the literature, there is only one review study, published in 2015, on spontaneous pregnancy in TS⁽¹⁰⁾. In Brazil, there is still no statistical data on the prevalence of pregnancy in TS patients⁽¹¹⁾. Therefore, the purpose of this study is to increase knowledge about this topic, which is incipient, thus calling for further research.

OBJECTIVE

The objective of this study is to describe patients with TS who had spontaneous pregnancy and, when possible, to present the frequency of this outcome in this genetic condition.

MATERIAL AND METHODS

This is a literature review performed in the MedLine/PubMed database (http://www.ncbi.nlm.nih.gov/pubmed/) in August 2018, using the descriptors “Turner syndrome and spontaneous pregnancy”. The following filters were activated: articles with publication date in the last 10 years that present the descriptors in the title/abstract.

Twenty-nine articles were identified in the electronic search. The inclusion criteria were: research articles, original or case reports; published in English or Portuguese; available free of charge in full version and closely related to the research topic. After the application of these criteria, 22 articles were excluded for the following reasons: revision (n = 8), revision and French language (n = 3), not related to the subject in question (n = 10) and no availability of the full version for free (n = 1). This selection was based on the reading of the title and/or abstract. Thus, after applying the inclusion and exclusion criteria, the number of articles selected were seven. However, a further two articles^{(11, 12)} were included after consulting the reference lists of these seven studies, totaling nine scientific articles.

RESULTS

Table 1 presents the characterization of the nine studies included in this literature review regarding the type of study and number of patients with TS investigated, objective, TS patients and spontaneous pregnancy and frequency. TS information regarding the karyotype of patients and age at diagnosis, as well as pregnancy (age, number and outcome) are presented in Table 2.

DISCUSSION

The present study aims to describe TS patients who had spontaneous pregnancies and, when possible, to determine their frequency. There is only one review on this topic in the literature, conducted in 2015, which presented results of studies published in the period from 1960 to 2014⁽¹⁰⁾. Only three studies^{(4, 13, 14)} are common between both reviews. One of the studies included in this literature review also carried out a review of the literature⁽¹⁵⁾.

It presented results from four extensive studies on spontaneous pregnancies in TS^{(5, 9, 16, 17)}. These studies analyzed 1,648 women with TS, 86 reached spontaneous conception (5.2%), 128 babies were born and most patients (76.7%) presented karyotype 45,X/46,XX. In the present literature review, which included three extensive studies^{(5, 9, 16)}, the overall frequency of spontaneous pregnancy was 4.5%.

The frequency of spontaneous pregnancy ranged from 1.26% to 5.6% (Table 1). Pregnancy occurred in 57 (12%) of the 482 Swedish patients with TS, and spontaneous pregnancy occurred in 23 of the 57 women with TS (40%), especially those with mosaic karyotype (45,X/46,XX)⁽¹⁶⁾. The frequency of spontaneous pregnancy in TS may be undervalued, since many women with this chromosomal anomaly and with preserved fertility may not have been diagnosed⁽⁴⁾. In addition, we must consider that phenotypic variability in TS is large, from patients with exuberant body dysmorphic disorder to those almost indistinguishable from the general population^{(18, 19)}. Therefore, those with no evident dysmorphisms are difficult to diagnose and many of them may have spontaneous pregnancies, and the cytogenetic diagnosis may be not performed or possibly delayed or randomly. The studies included in this review described a total of 62 TS patients with spontaneous pregnancy, with a total of 153 pregnancies (Tables 1 and 2).

In the present review, four studies described patients with pure karyotype (45,X) who conceived spontaneously^{(4, 5, 9, 13)}. Our data disagree with those previously published that reported that there was no report of a woman with TS karyotype 45,X and spontaneous pregnancy⁽¹⁷⁾. A case report described a patient 45,X with three pregnancies, her first daughter exhibiting normal karyotype; her second pregnancy ended in spontaneous abortion and the third pregnancy resulted in the birth of a girl with karyotype 45,X⁽²⁰⁾.

Seven studies described spontaneous pregnancy in mosaic karyotype^{(5, 9, 11, 12, 14-16)}. According to the literature, spontaneous pregnancy is usually more frequent in patients with mosaic TS^{(17, 21)}.

Three studies reported TS patients with karyotype 45,X/47,XXX^{(9, 14, 15)} with a predominance of healthy children. One of these patients underwent amniocentesis at 16 weeks of gestation, which revealed a fetus with 46,XX karyotype. This procedure was adopted due to the greater risk of aneuploidy among the descendants of TS women⁽¹⁵⁾. Two other successful pregnancies also occurred in a 33-year-old female with mosaic TS (45,X/47,XXX) who conceived spontaneously and exhibited short stature as the sole manifestation of the syndrome⁽²²⁾. On the other hand, a previous study described a 26-year-old TS patient with this same karyotype and five miscarriages. The patient exhibited type 1 Diabetes mellitus, endometrial cancer and, in her family history, her mother presented recurrent loss of pregnancy. Their first, third, fourth, fifth and sixth pregnancies resulted in miscarriages in the first trimester. Her second pregnancy resulted in the birth of a healthy daughter with a karyotype 46,XX⁽²³⁾. Another recent case report described a 10-year-old girl with TS with mosaic karyotype (45,X/47,XXX) who exhibited mild phenotype of short stature and spontaneous puberty⁽²⁴⁾. In this case, patient follow-up is recommended to verify the occurrence of pregnancy. Karyotype 45,X/47,XXX is rare, and only 1.5% of TS patients exhibit this chromosomal constitution⁽²⁴⁾.

In the present study, there was a predominance of karyotype 45,X/46,XX (42 patients) among the 62 who had spontaneous pregnancy (Table 2). From the 22 mosaic TS patients investigated, 17 of them were 45,X/46,XX, and 16 from the 22 conceived, of which, 11 spontaneously and five by IVF⁽²¹⁾. The karyotype 45,X/46,XX was also the most prevalent, since it was found in 25 from the 31 TS patients who presented spontaneous pregnancy⁽¹⁷⁾.

Regarding the age of TS diagnosis, only one occurred at birth and eight patients were diagnosed between the ages of 18 months and 16 years. According to the literature, from the 138 TS cases aged from 0 to 18 years, 14 (10.1%) were diagnosed between 0 and 1 years; 67 (48.6%) between 1 and 12 years (mostly between 7 and 12 years); and 57 (41.3%) between the ages of 12 and 18 years⁽¹⁸⁾.

An interesting finding was the TS diagnosis in adulthood, in three studies^{(4, 12, 14)}. Interestingly, two patients had the TS diagnosis after pregnancy^{(4, 14)}. A study with 178 patients with TS showed that 76.4% of the girls were diagnosed in childhood/adolescence due to their short stature, and only 12.4% in adult life⁽³⁾. This study also showed that the mean age at diagnosis was 12.6 years, which is lower in those with karyotype 45,X⁽³⁾. The patient with TS and triple mosaicism (45,X/47,XX,+21/46,XX) was only submitted to karyotyping after their second pregnancy. Her first child died at birth, and after cytogenetic analysis, it was established that she had Down syndrome. In the second pregnancy, the patient was submitted to amniocentesis and the result also showed that the child had Down syndrome⁽¹²⁾. These ascertain that the TS diagnosis in this patient was at random. Due to her history, the patient decided to undergo preimplantation genetic diagnosis in the future⁽¹²⁾.

The minimum age in spontaneous pregnancy of TS patients was 21 years and the maximum was 32 years. A relatively recent study evaluated the reproductive and obstetric outcomes of natural conception and IVF in 22 mosaic TS patients and showed that the median age at the first spontaneous pregnancy was 23 years and at diagnosis, 34.5⁽²¹⁾.

Our results also showed that repeated pregnancy was common in most studies^{(5, 9, 12-14, 16)}. Considering that spontaneous pregnancy in TS is a rare condition, repeated pregnancy should be even more uncommon⁽¹⁴⁾.

In the gestational outcome, an expressive number of children born and abortions were observed, the latter with values of 54.9%⁽¹⁶⁾ and 34.6%⁽⁵⁾. A previous review of the literature showed that from the 160 pregnancies that occurred in 74 women with TS, 29% ended in spontaneous abortion, 7% led to the stillbirth outcome, 20% gave birth to malformed babies (TS, Down syndrome, etc.) and only in 38% of the cases healthy children were born⁽²⁵⁾. Another study reported a total of 52 pregnancies, of which 17 (32.7%) resulted in liveborn and 35 (67.3%), in abortion⁽²¹⁾. According to Bernard et al. (2016)⁽⁵⁾, from the 30 children born, the karyotyping test was performed only in 11 of the 17 girls, two of whom were diagnosed with TS [(45,X/46,X,r(X) and 47,X,der(X) t(X;Y)x2/46,X,der(X)t(X;Y)]. One of the studies mentioned as a limitation the non-accomplishment of the karyotyping tests in the descendants of TS women⁽¹⁶⁾. Problems arising from birth occurred in five of the 68 children (37 of them conceived by spontaneous pregnancy), that is, 7%. It is worth mentioning that 80% of them (4/5) were born from spontaneous pregnancies⁽¹⁶⁾. There was a report of the birth of a child with cerebral palsy, but there were no children with chromosomal alterations⁽⁹⁾.

An even higher frequency of spontaneous pregnancy (7.6% – 31/410) was described by Birkebaek et al. (2002)⁽¹⁷⁾ and two women became pregnant after IVF. In this study, there was a predominance of mosaic karyotype (n = 27) among the 33 pregnant women with TS and the birth of 64 children (32 girls and 32 boys) in 61 pregnancies⁽¹⁷⁾. Karyotyping test was performed in 25 of the 64 children and six of them exhibited chromosomal alterations⁽¹⁷⁾.

There are few studies published in the literature on spontaneous pregnancy in TS^{(5, 9, 16)}, which evidences the need for further research in this area, in order to clarify the actual frequency of spontaneous conception in this genetic condition.

It is recommended that during the pregnancy of a TS patient, a multidisciplinary team composed of specialists in the field of maternal-fetal medicine, cardiology and endocrinology should closely monitor these pregnant women due to risks, such as worsening of cardiovascular diseases during pregnancy and specific complications. The team should provide those patients who wish to keep going to the end of pregnancy to perform a thorough risk assessment and genetic counseling prior to conception, in addition to rigorous neonatal follow-up⁽¹¹⁾.

CONCLUSION

The present study described patients with TS and spontaneous pregnancy with pure and mosaic (more frequent) karyotype. The frequency ranged from 1.26% to 5.6%. It is believed that this value may be underestimated, since few studies have primarily investigated spontaneous pregnancy in this genetic condition and many TS patients may not have been diagnosed because of the wide phenotypic variation associated with this chromosomal abnormality.

FINANCING

This study received no funding.

DECLARATION OF CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

REFERENCES

1. Paolucci DG, Bamba V. Turner syndrome: care of the patient: birth to late adolescence. Pediatr Endocrinol Rev. 2017; 14 (Suppl 2): 454-61.

2. de Araújo C, Galera BB, Galera MF, de Medeiros SF. [Clinical and cytogenetic aspects of the Turner syndrome in the Brazilian Western region]. Rev Bras Ginecol Obstet. 2010; 32(8): 381-5.

3. Jung MP, Amaral JL, Fontes RG, Costa AT, Wuillaume SM, Cardoso MHCA. Diagnóstico da síndrome de Turner: a experiência do Instituto Estadual de Diabetes e Endocrinologia – Rio de Janeiro, de 1970 a 2008. Rev Bras Saúde Matern Infant. 2010; 10(1): 117-24.

4. Alves M, Bastos M, Almeida Santos T, Carrilho F. [Gonadal function in Turner syndrome]. Acta Med Port. 2013; 26(6): 655-63.

5. Bernard V, Donadille B, Zenaty D, et al. Spontaneous fertility and pregnancy outcomes amongst 480 women with Turner syndrome. Hum Reprod. 2016; 31(4): 782-8.

6. de Marqui AB, da Silva-Grecco RL, Balarin MA. [Prevalence of Y-chromosome sequences and gonadoblastoma in Turner syndrome]. Rev Paul Pediatr. 2016; 34(1): 114-21.

7. Hewitt JK, Jayasinghe Y, Amor DJ, et al. Fertility in Turner syndrome. Clin Endocrinol (Oxf). 2013; 79(5): 606-14.

8. Oktay K, Bedoschi G, Berkowitz K, et al. Fertility preservation in women with Turner syndrome: a comprehensive review and practical guidelines. J Pediatr Adolesc Gynecol. 2016; 29(5): 409-16.

9. 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(7): 2251-6.

10. Gorduza V, Petrariu F. Outcome of spontaneous pregnancy in turner syndrome. Acta Endocrinologica. 2015; 11(3): 348-55.

11. Vieira CAFA, Fontenele EGP, Albuquerque AM, Quezado R, Mendes ADN, Magalhães RA. Síndrome de Turner – desfecho de uma gestação espontânea. Rev Med UFC. 2017; 57(2): 69-72.

12. Mačkić-Đurović M, Stomornjak-Vukadin M, Ibrulj S. Turner syndrome: a unique mosaic case with 45,X/47,XX,+21/46,XX cell lines. Iran J Med Sci. 2018; 43(4): 436-9.

13. Mortensen KH, Rohde MD, Uldbjerg N, Gravholt CH. Repeated spontaneous pregnancies in 45,X Turner syndrome. Obstet Gynecol. 2010; 115(2 Pt 2): 446-9.

14. Alves C, Silva SF. Spontaneous procreation in Turner syndrome: report of two pregnancies in the same patient. Syst Biol Reprod Med. 2012; 58(2): 113-5.

15. Mavridi A, Ntali G, Theodora M, Stamatelopoulos K, Michala L. A spontaneous pregnancy in a patient with Turner syndrome with 45,X/47,XXX mosaicism: a case report and review of the literature. J Pediatr Adolesc Gynecol. 2018; 31(6): 651-4.

16. Bryman I, Sylvén L, Berntorp K, et al. Pregnancy rate and outcome in Swedish women with Turner syndrome. Fertil Steril. 2011; 95(8): 2507-10.

17. Birkebaek NH, Crüger D, Hansen J, Nielsen J, Bruun-Petersen G. Fertility and pregnancy outcome in Danish women with Turner syndrome. Clin Genet. 2002; 61(1): 35-9.

18. Carvalho AB, Guerra-Junior G, Baptista MTM, Marques-de-Faria AP, Lemos-Marini SHV, Maciel-Guerra AT. Turner syndrome: a pediatric diagnosis frequently made by non-pediatricians. J Pediatr (Rio J) 2010; 86(2): 121-5.

19. Miguel Neto J, Marini SHVL, Faria APM, Guerra Júnior G, Guerra ATM. Fatores associados a atraso no diagnóstico da síndrome de Turner. Rev Paul Pediatr. 2011; 29(1): 67-72.

20. Cools M, Rooman RP, Wauters J, Jacqemyn Y, Du Caju MV. A nonmosaic 45,X karyotype in a mother with Turner’s syndrome and in her daughter. Fertil Steril. 2004; 82(4): 923-5.

21. Doğer E, Çakıroğlu Y, Ceylan Y, Ulak E, Özdamar Ö, Çalışkan E. Reproductive and obstetric outcomes in mosaic Turner’s syndrome: a cross-sectional study and review of the literature. Reprod Biol Endocrinol. 2015; 13: 59.

22. Bouchlariotou S, Tsikouras P, Dimitraki M, et al. Turner’s syndrome and pregnancy: has the 45,X/47,XXX mosaicism a different prognosis? Own clinical experience and literature review. J Matern Fetal Neonatal Med. 2011; 24(5): 668-72.

23. Sahinturk S, Ozemri Sag S, Ture M, et al. A fertile patient with 45X/47XXX mosaicism. Genet Couns. 2015; 26(1): 29-34.

24. Lim HH, Kil HR, Koo SH. Incidence, puberty, and fertility in 45,X/47,XXX mosaicism: report of a patient and a literature review. Am J Med Genet A. 2017 May 9.

25. Tarani L, Lampariello S, Raguso G, et al. Pregnancy in patients with Turner’s syndrome: six new cases and review of literature. Gynecol Endocrinol. 1998; 12(2): 83-7.