Arch Gynecol Obstet (2014) 289:1145–1150 DOI 10.1007/s00404-013-3118-z
CASE REPORT
Complete hydatidiform mole and a coexistent fetus following ovulation induction in a patient with Sheehan’s syndrome: a first case report and review of literature Xuekun Huang • Jingyao Liang • Yonghan Huang Juanhua Huang
•
Received: 15 July 2013 / Accepted: 26 November 2013 / Published online: 8 December 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract Pregnancy in Sheehan’s syndrome (SS) is extremely rare. We present the first reported case of twin pregnancy with complete hydatiform mole (CHM) and a coexistent fetus (CHCF) in a patient with SS. A 29-yearold Chinese patient with SS became pregnant following one cycle of ovulation induction with human menopausal gonadotropin after secondary infertility. A normal live fetus and a low echogenic mass suspected hydatidiform mole (HM) were detected by ultrasound examinations at gestational week 8. The couple highly desired to continue the pregnancy because it is very hard to get pregnant for the patients with SS. However, the pregnancy was terminated for the size of the HM component increased rapidly at gestational week 15. Histological examinations confirmed CHCF. Genetic studies showed that the CHM genome was derived from paternal diploidy, and the normal fetus was from biparental genomes. Furthermore, a literature review on these topics is included. This case highlighted that even in a patient with SS, twin pregnancy with CHCF can still occur after ovulation induction. Keywords Sheehan’s syndrome Hydatiform mole Fetus Ovulation induction Twin pregnancy
X. Huang and J. Liang contributed equally to this work. X. Huang (&) Y. Huang J. Huang Reproductive Medicine Center, Department of Obstetrics and Gynaecology, The First People’s Hospital of Foshan, Foshan 528000, Guangdong, People’s Republic of China e-mail: [email protected] J. Liang Department of Neurology, Chinese PLA General Hospital, Beijing 100853, People’s Republic of China
Introduction Sheehan’s syndrome (SS) is characterized by hypopituitarism during or several years after delivery, caused by severe pregnancy-related hemorrhage and hypovolemia leading to ischemic pituitary necrosis. The prevalence of SS is estimated to be about 100–200 in 1,000,000 women [1]. A retrospective analysis carried out in Iceland reported the prevalence of 5.1 per 100,000 women in 2009 [2]. The clinical manifestation may present with lactation failure, breast atrophy, amenorrhea, sterility, loss of pubic and/or axillary hair, skin depigmentation, hypothyroidism and hypoadrenalism. Depending on the extent of pituitary destruction, varying the degrees of hypopituitarism, ranging from only selective pituitary deficiencies to panhypopituitarism, and relevant clinical manifestations are observed in patients. It is very rare for a patient with SS to get pregnant spontaneously, although it is possible in patients with partial hypopituitarism with preserved secretion of gonadotropins, and in those with selective impairment of gonadotropin secretion or panhypopituitarism by ovulation induction with exogenous gonadotropins. To date, only about 36 patients with SS have been reported to successfully become pregnant in the English language literature. Nineteen of them published before 1980 were reviewed by Grimes and Brooks [3], thirteen between 1980 and 2000 by Kriplani et al. [4] and four after 2000 by us (Table 1). Likewise, hydatiform mole (HM) and coexistent fetus (es) are rarely seen during clinical practice, with an estimated incidence of 1 in 22,000–100,000 pregnancies [5]. HM is mainly subdivided into complete hydatidiform mole (CHM) and a coexistent fetus (CHCF) and partial hydatidiform mole (PHM) and a coexistent fetus based on gross morphological, histological and cytogenetic criteria. CHM
123
1146
Arch Gynecol Obstet (2014) 289:1145–1150
Table 1 Successful pregnancy in patients with SS published after 2000 and our patient Case
Author (References)
Age (years) and parity of onset SS
Duration of SS before pregnancy (years)
Pituitary insufficient (deficient hormones)
Hormone therapy (daily dose)
Ovulation induction
Outcome
1
Algun [13]
33, P1
5
Partial (GH, TSH, PRL, LH)
Prednisolone (7.5 mg) L-thyroxin (100 mg)
None
Successful delivery (one baby)
2
See [14]
33, P2
2.5
Partial (GH, TSH, PRL)
Prednisolone (7.5 mg) L-thyroxine (100 lg) GH (0.15 mg)
None
Successful delivery (one baby)
3
Hao [15]
41, P3
2
Partial
Hydrocortisone Levothyroxine sodium
None
Successful delivery
4
Jain [16]
20, P1
3.5
Partial (PRL)
Ethinyl estradiol (4 mg) Medroxy progesterone acetate (5 mg) estrogen Progesterone
Gn
Successful delivery (37 weeks, one baby)
5
Huang (our case)
27, P1
2
Total
Prednisolone (7.5 mg) Levothyroxine sodium (100 mg) Climen (1 mg)
Gn
Abortion (15 weeks, twin pregnancy with CHM and a fetus)
pregnancy is more common than PHM, which is probably because PHM mostly coexisting with abnormal triploid fetus tends to miscarriage in the first trimester, while CHM and coexistent normal karyotype fetus dose allow for expectant management [6, 7]. The widespread application of assisted conception has been considered as one of possible risk factors for the increasing rates of HM. Here, we presented a sterile patient with SS, and twin pregnancy with CHCF following ovulation induction. To our best knowledge, this is first reported CHCF in a patient with SS.
Case A 29-year-old patient, gravida 2, para 0, presented to our outpatient clinic in January 2012. Her chief complaint was amenorrhea over 2 years and sought medical advice for conception. She had a history of a pregnancy 2 years earlier, and the local hospital reported that she underwent a cesarean section at term for placental abruption causing severe hemorrhage and fetal death. After the operation, she failed to lactate and menstruate, and gradually had breast atrophy, loss of pubic and axillary hair, a decrease in libido and easy fatigability. The low levels of related hormones (Table 2) and failure in response to stimulation tests (thyrotrophin-releasing hormone (TRH), luteinizing hormonereleasing hormone (LHRH) and insulin tolerance test) were suggestive of panhypopituitarism. The magnetic resonance imaging (MRI) of pituitary revealed completely empty sella (Fig. 1). According to a history of secondary amenorrhoea following postpartum hemorrhage, and hormonal analysis and MRI results, a diagnosis of SS was
123
Table 2 Hormonal values of the patient Hormone
Units
Patient values
Normal values
FT3
pmol/L
3.37
FT4
pmol/L
3.84
11.4–23.2
TSH
mIU/L
0.207
0.35–5.5
PRL
ng/mL
1.08
2.8–14.6*
ACTH
pg/mL
2.14
0–46
3.54–6.47
GH
ng/mL
\0.05
0.1–10
Cortisol
lg/dL
\1
3.9–22
FSH
IU/L
1.99
4–9.3*
LH
IU/L
0.46
1.4–13.3*
E2
ng/L
5.69
35.8–157*
FT3 free triiodothyronine, FT4 free thyroxine, TSH Thyroid stimulating hormone, PRL prolactin, ACTH adrenocorticotropic hormone, GH growth hormone, FSH follicle-stimulating hormone, LH luteinising hormone, E2 estradiol * Follicular phase
made by local hospital. She received replacement therapy with prednisolone (7.5 mg/day) and levothyroxine sodium (100 mg/day). Some of her symptoms were improved about 3 months after treatment, but menstruation still did not occurred. Two years later, she visited our outpatient clinic for assisted conception. Her husband’s semen analysis was normal. A hysterosalpingogram showed that the left fallopian tube was normal, but the right fallopian tube was not patent. After the sixth cycle of hormone replacement treatment with Climen (estradiol valerate and cyproterone, 1 mg/day), follicular growth was stimulated using 150 IU of human menopausal gonadotropin (hMG) for 1 week, but ultrasonogram revealed there was no follicular
Arch Gynecol Obstet (2014) 289:1145–1150
1147
Fig. 1 The sagittal (a) and coronary (b) magnetic resonance imaging (MRI) of the brain showing a diminutive pituitary (short arrow) and an empty sella turcica (long arrow)
Fig. 2 Ultrasound picture of CHCF and a normal placenta at gestational week 12
development in bilateral ovaries. hMG was increased dose up to 225 IU for 1 week, and ultrasonogram showed two ovarian follicles (2.2 9 1.5 and 1.6 9 1.2 cm) in the left ovary and three ovarian follicles (2.3 9 1.8, 1.7 9 1.7 and 1.5 9 1.5 cm) in the right ovary, and thickness of endometrium was 0.8 cm. Ovulation was induced with 8,000 IU of human chorionic gonadotropin (hCG) intramuscular injection, followed by copulation. Ultrasonogram on the 3rd day of hCG injection revealed ovulation. Serum b-hCG level on the 11th day of ovulation was 29.0 IU/L. Progesterone (40 mg/day) and hCG (2,000 IU/day) were given to prevent miscarriage until gestational week 15. Two gestational sacs (GS) with fetal cardiac activity and an additional low echogenic mass suspected of having HM were detected on ultrasound examination at gestational week 8. The couple highly desired to continue the
pregnancy because it is very hard to get pregnant for the patients with SS and required to closely monitor the development of the mass. At gestational week 12, the appearance of low echogenic mass became multicystic (68 9 58 9 78 mm) and was suggestive of HM (Fig. 2). She had intermittently slight vaginal bleeding, but she did not have development of hypertension, generalized edema, hyperemesis, cough and dyspnea from gestational week 8–15. Successive ultrasound examination demonstrated that the mass increased rapidly in size (106 9 46 9 130 mm, at gestational week 15). Intra-amniotic administration of rivanol and repeat curettage were performed to terminate the pregnancy after counseling with the couple. Histopathologic examination showed edematous villi with frequent cistern formation and hyperplastic trophoblast (Fig. 3). Genetic studies were carried out to clarify origin
123
1148
Arch Gynecol Obstet (2014) 289:1145–1150
Fig. 3 Histopathology of CHM (original magnification 340). a, b showing edematous villi with frequent cistern formation (short arrow) and hyperplastic trophoblast (long arrow)
of the fetus, and of the normal and HM villi of the placenta. Genomic DNA extracted from the fetus, molar tissue and parental peripheral blood leukocytes was amplified using polymerase chain reaction (PCR) with fluorescently labeled polymorphic markers from different chromosomes as previously described [8]. Analysis of the PCR products using ABI Prism GeneScan software (Applied Biosystems Ltd, UK) revealed the normal diploid fetus (46, XY) with biparental genome and HM (46, XX) with paternal diploidy. These results confirmed the clinical impression of CHCF. Her serum b-hCG level declined progressively and returned to normal at 6 weeks until today.
Discussion Sheehan’s syndrome, hypopituitarism following postpartum pituitary necrosis, may involve a deficiency of one, several or all the pituitary trophic hormones, and spontaneous amelioration may occur [9]. Prolactin (PRL) and growth hormone (GH) are often two of the hormones lost earliest in SS because PRL and GH cells are located in the lower lateral region of the pituitary gland, where they are most susceptible to be damaged by ischemic necrosis [10, 11]. PRL and GH are deficient in 90–100 % of patients, and cortisol secretion, gonadotropin and thyroid stimulating hormone (TSH) are decreased in 50–100 % of patients [12]. The hypofunction of gonad and the effect of sex hormone axis are common in SS, which may result in cessation or disorder of menses. So it is hard for the patients with SS to get pregnant. Only 36 patients (not including our 1) with SS have been reported to have pregnancy up to now [3, 4, 13–16], some of which depended on the preservation of partial gonadotrophic function after the pituitary apoplexy event [15, 17]. In the present case, SS was diagnosed based on a history of postpartum hemorrhage and failure of lactation and characteristic clinical presentation comprising of secondary amenorrhea, breast atrophy, loss of pubic and axillary hair, a decrease in libido and easy fatigability. MRI revealed
123
loss of pituitary gland mass, and low levels of pituitary hormones [PRL, GH, cortisol, adrenocorticotropic hormone (ACTH), TSH, follicle-stimulating hormone (FSH) and luteinising hormone (LH)] as well as a decrease in response to stimulation tests demonstrated panhypopituitarism. Twin pregnancy occurred following ovulation induction with gonadotropins (hMG/hCG) in this case. Since it first was reported a successful attempt to induce ovulation and subsequent pregnancy using anterior pituitary extract in 1939 [18], only ten patients with SS have been reported to have conceived following gonadotropin treatment. Four of them were reviewed by Grimes and Brooks [3], and five of them reviewed by Kriplani et al. [4] and the other one reported by Jain [16]. Furthermore, we found that, so far, only three patients with panhypopituitarism (not including our 1) have a successful pregnancy following induction of ovulation with hMG/hCG [18–20]; two of them have twin pregnancy, and all of them have a successful outcome of pregnancy. Unfortunately, twin pregnancy with HM and coexistent fetus following induction of ovulation with hMG/hCG in our patient with panhypopituitarism had to be terminated by abortion because HM increased rapidly in size. The pathogenesis and the natural history of SS have not been exactly clarified, although enlargement of pituitary gland, small sella size, disseminated intravascular coagulation and autoimmunity have been suggested to play a role in SS [21]. The general principle of treatment of SS is to replace deficient hormones, which is important not only to correct endocrine abnormalities, but also to reduce mortality caused by hypopituitarism [1]. It has been reported that inadequate hormone replacement treatment in pregnant women with SS has resulted in high fetal and maternal morbidity and mortality [3]. Better ovulation rates in patients with hypopituitarism were obtained when pretreated estrogen and progesterone before hMG induction [22]. Our patient was given pretreatment with Climen (estradiol valerate and cyproterone) for six cycles to improve the uterine size. Exactly dosage of hMG/hCG administered in the first course of therapy was followed by
Arch Gynecol Obstet (2014) 289:1145–1150
ovulation and conception. This is very similar to the case reported previously [18]. Previous publications have reported that pregnancy might improve hypopituitarism due to the hypophysiotropic hormones secreted by the hypothalamus or the pituitary remnants to undergo hyperplasia stimulated by placenta in SS [23, 24]. In contrast, one recent publication reported that pregnancy might aggravate symptoms of SS by stimulating autoimmunity system or due to the long course of disease and the old age (55 years old) [15]. These different findings suggested that pregnancy may affect SS, as we all know that SS affects pregnancy. In a patient with SS, to our best knowledge, this is the first paper to report CHCF, although many series and several case reports have been published regarding HM and coexistent fetus (es). CHM are usually diploid androgenic conceptus, occurring by an ‘empty’ egg (loss of the maternal nuclear genome) with fertilization either by a single haploid sperm cell that duplicates to result in a 46, XX (monospermic) or by two sperms producing a 46, XX or 46, XY (dispermic) [25]. There are excessive trophoblastic growth and no fetal structure due to lack of genes transcribed from maternally derived genes. Most PHM are triploidy diandric conceptus (70 % 69, XXY; 27 % 69, XXX; 3 % 69, XYY), resulting from fertilization of a normal egg by two copies of the paternal genome (either a duplicated spermatozoon or two spermatozoa) [26]. There are fetal tissue, cord and normal villus structures of the placenta. Unlike PHM which is commonly associated with multiple fetal anomalies and is managed by immediate termination of pregnancy, CHM is associated with normal fetal survival and can be considered to continue pregnancy as long as serious maternal complications do not develop. In a large case series comprising 77 twin pregnancies with CHM, about 40 % of 53 continuing pregnancies were reported resulting in livebirths, but nearly 60 % had spontaneous abortion or were terminated because of severe preeclampsia [27]. The majority of series of twin pregnancies with CHM have reported a very high frequency (41–71 %) of pregnancy termination due to severe maternal and fetal complications such as persistent vaginal bleeding, spontaneous abortion, preterm delivery, thromboembolic disease, severe preeclampsia, persistent gestational trophoblastic neoplasia and intrauterine fetal death [27–29]. The management of CHCF is an enormous dilemma between termination of the pregnancy and expectant conservation, especially for the patients of highly desired pregnancy. Some authors support the option of conservative management under strict clinical observation and follow-up after providing the patients a detailed explanation about the potential risks and poor outcomes. In a recent case report, a rescue cerclage for cervical indications was considered a benefit of good outcome in the
1149
patient with CHCF [30], suggesting some potential interventions may improve outcome of some patients with CHCF. The association between HM and assisted conception has not been confirmed, because the number of reported cases is limited. However, it has been suggested that the incidence of HM in the future may increase with the wide use of ovulation-inducing agents [31]. Recent literature in 2009 reviewed 29 studies that reported 159 cases of twin pregnancy with CHM; ovulation induction has been administered 12 of 51 cases with available data (24 %) [32]. Another report presented 30 cases of twin pregnancy with CHM. Among these, nine cases (30 %) received ovulation induction treatment with either hMG/hCG (8 cases) or clomiphene citrate (1 case). Five of eight cases treated with hMG/hCG were also performed with assisted reproductive techniques (in vitro fertilization and embryo transfer (IVF–ET) in 3 cases, intra-cytoplasmic sperm injection and embryo transfer (ICSI–ET) in 2 cases) [33]. It is well known that treatment with hMG/hCG frequently leads to superovulation. Bruchim et al. [34] speculated that forced ovulation of more than one egg by ovulationinducing agents such as hMG/hCG treatment might increase the rate of a nuclear ‘‘empty’’ egg, which may be one of the theoretical reasons for the development of a CHM. In addition, several authors assumed that assisted reproductive techniques may be another risk factor for the development of HM, which is associated with embryo prolonged in vitro culture, higher volume and pressure of culture medium injected into the uterus, the tilt-down position of the patient at the time of embryo transfer, and advanced maternal/paternal age and poor oocyte quality of the patients who require assisted techniques to achieve a successful pregnancy [35–37].
Conclusion This is a special and rare case with two features. Firstly, the patient with panhypopituitarism due to postpartum hemorrhage of the first delivery had the second pregnancy following ovulation induction without assisted reproductive techniques. Secondly, even in the patient with SS, HM pregnancy may still occur. Conflict of interest
The authors declare no conflict of interest.
References 1. Kelestimur F (2003) Sheehan’s syndrome. Pituitary 6(4):181–188 2. Kristjansdottir HL, Bodvarsdottir SP, Sigurjonsdottir HA (2011) Sheehan’s syndrome in modern times: a nationwide retrospective study in Iceland. Eur J Endocrinol 164(3):349–354
123
1150 3. Grimes HG, Brooks MH (1980) Pregnancy in Sheehan’s syndrome. Report of a case and review. Obstet Gynecol Surv 35(8):481–488 4. Kriplani A, Goswami D, Agarwal N, Bhatla N, Ammini AC (2000) Twin pregnancy following gonadotrophin therapy in a patient with Sheehan’s syndrome. Int J Gynaecol Obstet 71(1):59–63 5. Malhotra N, Deka D, Takkar D, Kochar S, Goel S, Sharma MC (2001) Hydatiform mole with coexisting live fetus in dichorionic twin gestation. Eur J Obstet Gynecol Reprod Biol 94(2):301–303 6. Lee SW, Kim MY, Chung JH, Yang JH, Lee YH, Chun YK (2010) Clinical findings of multiple pregnancy with a complete hydatidiform mole and coexisting fetus. J Ultrasound Med 29(2):271–280 7. Massardier J, Golfier F, Journet D, Frappart L, Zalaquett M, Schott AM, Lenoir VT, Dupuis O, Hajri T, Raudrant D (2009) Twin pregnancy with complete hydatidiform mole and coexistent fetus: obstetrical and oncological outcomes in a series of 14 cases. Eur J Obstet Gynecol Reprod Biol 143(2):84–87 8. Gualandi F, Sensi A, Trabanelli C, Falciano F, Bonfatti A, Calzolari E (2000) Prenatal UPD testing survey in Robertsonian translocations. Prenat Diagn 20(6):465–468 9. Barkan AL (1989) Pituitary atrophy in patients with Sheehan’s syndrome. Am J Med Sci 298(1):38–40 10. Ozbey N, Inanc S, Aral F, Azezli A, Orhan Y, Sencer E, Molvalilar S (1994) Clinical and laboratory evaluation of 40 patients with Sheehan’s syndrome. Isr J Med Sci 30(11):826–829 11. Shahmanesh M, Ali Z, Pourmand M, Nourmand I (1980) Pituitary function tests in Sheehan’s syndome. Clin Endocrinol (Oxf) 12(3):303–311 12. Shivaprasad C (2011) Sheehan’s syndrome: Newer advances. Indian J Endocrinol Metab 15(Suppl 3(S)):203–207 13. Algun E, Ayakta H, Harman M, Topal C, Aksoy H (2003) Spontaneous pregnancy in a patient with Sheehan’s syndrome. Eur J Obstet Gynecol Reprod Biol 110(2):242–244 14. See TT, Lee SP, Chen HF (2005) Spontaneous pregnancy and partial recovery of pituitary function in a patient with Sheehan’s syndrome. J Chin Med Assoc 68(4):187–190 15. Hao J, Liu M, Mo Z (2012) The symptoms get worse after pregnancy in Sheehan’s syndrome: a case report. Case Rep Med 2012:271345 16. Jain D (2013) A ray of hope for a woman with Sheehan’s syndrome. BMJ Case Rep 17. Vieira HB, Knoepfelmacher M, Salgado LR, Wajchenberg BL, Liberman B (1995) Preservation of gonadotrophic function and pregnancy in Sheehan’s syndrome: a case report and review of the literature. Rev Assoc Med Bras 41(2):135–138 18. Cohen BL, Baillie P (1980) Sheehan’s syndrome followed by successful pregnancy: a case report. S Afr Med J 57(20):838–840 19. Briet JW (1998) Diabetes insipidus, Sheehan’s syndrome and pregnancy. Eur J Obstet Gynecol Reprod Biol 77(2):201–203 20. Barbieri RL, Randall RW, Saltzman DH (1985) Diabetes insipidus occurring in a patient with Sheehan’s syndrome during a gonadotropin-induced pregnancy. Fertil Steril 44(4):529–531 21. Kilicli F, Dokmetas HS, Acibucu F (2013) Sheehan’s syndrome. Gynecol Endocrinol 29(4):292–295
123
Arch Gynecol Obstet (2014) 289:1145–1150 22. Yildirim M, Noyan V, Tiras MB (2000) Estrogen-progestogen pre-treatment before HMG induction in hypogonadotropic patients. Int J Gynaecol Obstet 71(3):249–250 23. Sheehan HL (1948) Post-partum necrosis of the anterior pituitary. Ir J Med Sci 270:241–255 24. Jorgensen PI, Sele V, Buus O, Damkjoer M (1973) Detailed hormonal studies during and after pregnancy in a previously hypophysectomized patient. Acta Endocrinol (Copenh) 73(1):117–132 25. Ferraz TJ, Bartosch CM, Ramalho CM, Carvalho FA, Carvalho BC, Brandao OG, Montenegro NA (2013) Complete mole in a dichorionic twin pregnancy after intracytoplasmic sperm injection. Rev Bras Ginecol Obstet 35(1):39–43 26. Genest DR (2001) Partial hydatidiform mole: clinicopathological features, differential diagnosis, ploidy and molecular studies, and gold standards for diagnosis. Int J Gynecol Pathol 20(4):315–322 27. Sebire NJ, Foskett M, Paradinas FJ, Fisher RA, Francis RJ, Short D, Newlands ES, Seckl MJ (2002) Outcome of twin pregnancies with complete hydatidiform mole and healthy co-twin. Lancet 359(9324):2165–2166 28. Fishman DA, Padilla LA, Keh P, Cohen L, Frederiksen M, Lurain JR (1998) Management of twin pregnancies consisting of a complete hydatidiform mole and normal fetus. Obstet Gynecol 91(4):546–550 29. Vaisbuch E, Ben-Arie A, Dgani R, Perlman S, Sokolovsky N, Hagay Z (2005) Twin pregnancy consisting of a complete hydatidiform mole and co-existent fetus: report of two cases and review of literature. Gynecol Oncol 98(1):19–23 30. Aguin E, Aguin V, Cisneros L, Aguin T, Van de Ven C, BahadoSingh R (2012) Does cerclage improve neonatal outcomes in a molar pregnancy and a coexistent fetus? A case report. BMC Res Notes 5:621 31. Malinowski W, Biskup I, Dec W (1995) Sad fetus syndromegestational trophoblastic disease concurrent with a living fetus or fetuses. Acta Genet Med Gemellol (Roma) 44(3–4):193–202 32. Dolapcioglu K, Gungoren A, Hakverdi S, Hakverdi AU, Egilmez E (2009) Twin pregnancy with a complete hydatidiform mole and co-existent live fetus: two case reports and review of the literature. Arch Gynecol Obstet 279(3):431–436 33. Piura B, Rabinovich A, Hershkovitz R, Maor E, Mazor M (2008) Twin pregnancy with a complete hydatidiform mole and surviving co-existent fetus. Arch Gynecol Obstet 278(4):377–382 34. Bruchim I, Kidron D, Amiel A, Altaras M, Fejgin MD (2000) Complete hydatidiform mole and a coexistent viable fetus: report of two cases and review of the literature. Gynecol Oncol 77(1):197–202 35. Sun CJ, Zhao YP, Yu S, Fan L, Wu QQ, Li GH, Zhang WY (2012) Twin pregnancy and partial hydatidiform mole following in vitro fertilization and embryos transfer: a novel case of placental mosaicism. Chin Med J (Engl) 125(24):4517–4519 36. Huang X, Wang H, Zhao X, Xu X, Chen Q (2007) Gestational trophoblastic disease following in vitro fertilization. Arch Gynecol Obstet 275(4):291–293 37. Montes-de-Oca-Valero F, Macara L, Shaker A (1999) Twin pregnancy with a complete hydatidiform mole and co-existing fetus following in vitro fertilization: case report. Hum Reprod 14(11):2905–2907
CASE REPORT
Complete hydatidiform mole and a coexistent fetus following ovulation induction in a patient with Sheehan’s syndrome: a first case report and review of literature Xuekun Huang • Jingyao Liang • Yonghan Huang Juanhua Huang
•
Received: 15 July 2013 / Accepted: 26 November 2013 / Published online: 8 December 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract Pregnancy in Sheehan’s syndrome (SS) is extremely rare. We present the first reported case of twin pregnancy with complete hydatiform mole (CHM) and a coexistent fetus (CHCF) in a patient with SS. A 29-yearold Chinese patient with SS became pregnant following one cycle of ovulation induction with human menopausal gonadotropin after secondary infertility. A normal live fetus and a low echogenic mass suspected hydatidiform mole (HM) were detected by ultrasound examinations at gestational week 8. The couple highly desired to continue the pregnancy because it is very hard to get pregnant for the patients with SS. However, the pregnancy was terminated for the size of the HM component increased rapidly at gestational week 15. Histological examinations confirmed CHCF. Genetic studies showed that the CHM genome was derived from paternal diploidy, and the normal fetus was from biparental genomes. Furthermore, a literature review on these topics is included. This case highlighted that even in a patient with SS, twin pregnancy with CHCF can still occur after ovulation induction. Keywords Sheehan’s syndrome Hydatiform mole Fetus Ovulation induction Twin pregnancy
X. Huang and J. Liang contributed equally to this work. X. Huang (&) Y. Huang J. Huang Reproductive Medicine Center, Department of Obstetrics and Gynaecology, The First People’s Hospital of Foshan, Foshan 528000, Guangdong, People’s Republic of China e-mail: [email protected] J. Liang Department of Neurology, Chinese PLA General Hospital, Beijing 100853, People’s Republic of China
Introduction Sheehan’s syndrome (SS) is characterized by hypopituitarism during or several years after delivery, caused by severe pregnancy-related hemorrhage and hypovolemia leading to ischemic pituitary necrosis. The prevalence of SS is estimated to be about 100–200 in 1,000,000 women [1]. A retrospective analysis carried out in Iceland reported the prevalence of 5.1 per 100,000 women in 2009 [2]. The clinical manifestation may present with lactation failure, breast atrophy, amenorrhea, sterility, loss of pubic and/or axillary hair, skin depigmentation, hypothyroidism and hypoadrenalism. Depending on the extent of pituitary destruction, varying the degrees of hypopituitarism, ranging from only selective pituitary deficiencies to panhypopituitarism, and relevant clinical manifestations are observed in patients. It is very rare for a patient with SS to get pregnant spontaneously, although it is possible in patients with partial hypopituitarism with preserved secretion of gonadotropins, and in those with selective impairment of gonadotropin secretion or panhypopituitarism by ovulation induction with exogenous gonadotropins. To date, only about 36 patients with SS have been reported to successfully become pregnant in the English language literature. Nineteen of them published before 1980 were reviewed by Grimes and Brooks [3], thirteen between 1980 and 2000 by Kriplani et al. [4] and four after 2000 by us (Table 1). Likewise, hydatiform mole (HM) and coexistent fetus (es) are rarely seen during clinical practice, with an estimated incidence of 1 in 22,000–100,000 pregnancies [5]. HM is mainly subdivided into complete hydatidiform mole (CHM) and a coexistent fetus (CHCF) and partial hydatidiform mole (PHM) and a coexistent fetus based on gross morphological, histological and cytogenetic criteria. CHM
123
1146
Arch Gynecol Obstet (2014) 289:1145–1150
Table 1 Successful pregnancy in patients with SS published after 2000 and our patient Case
Author (References)
Age (years) and parity of onset SS
Duration of SS before pregnancy (years)
Pituitary insufficient (deficient hormones)
Hormone therapy (daily dose)
Ovulation induction
Outcome
1
Algun [13]
33, P1
5
Partial (GH, TSH, PRL, LH)
Prednisolone (7.5 mg) L-thyroxin (100 mg)
None
Successful delivery (one baby)
2
See [14]
33, P2
2.5
Partial (GH, TSH, PRL)
Prednisolone (7.5 mg) L-thyroxine (100 lg) GH (0.15 mg)
None
Successful delivery (one baby)
3
Hao [15]
41, P3
2
Partial
Hydrocortisone Levothyroxine sodium
None
Successful delivery
4
Jain [16]
20, P1
3.5
Partial (PRL)
Ethinyl estradiol (4 mg) Medroxy progesterone acetate (5 mg) estrogen Progesterone
Gn
Successful delivery (37 weeks, one baby)
5
Huang (our case)
27, P1
2
Total
Prednisolone (7.5 mg) Levothyroxine sodium (100 mg) Climen (1 mg)
Gn
Abortion (15 weeks, twin pregnancy with CHM and a fetus)
pregnancy is more common than PHM, which is probably because PHM mostly coexisting with abnormal triploid fetus tends to miscarriage in the first trimester, while CHM and coexistent normal karyotype fetus dose allow for expectant management [6, 7]. The widespread application of assisted conception has been considered as one of possible risk factors for the increasing rates of HM. Here, we presented a sterile patient with SS, and twin pregnancy with CHCF following ovulation induction. To our best knowledge, this is first reported CHCF in a patient with SS.
Case A 29-year-old patient, gravida 2, para 0, presented to our outpatient clinic in January 2012. Her chief complaint was amenorrhea over 2 years and sought medical advice for conception. She had a history of a pregnancy 2 years earlier, and the local hospital reported that she underwent a cesarean section at term for placental abruption causing severe hemorrhage and fetal death. After the operation, she failed to lactate and menstruate, and gradually had breast atrophy, loss of pubic and axillary hair, a decrease in libido and easy fatigability. The low levels of related hormones (Table 2) and failure in response to stimulation tests (thyrotrophin-releasing hormone (TRH), luteinizing hormonereleasing hormone (LHRH) and insulin tolerance test) were suggestive of panhypopituitarism. The magnetic resonance imaging (MRI) of pituitary revealed completely empty sella (Fig. 1). According to a history of secondary amenorrhoea following postpartum hemorrhage, and hormonal analysis and MRI results, a diagnosis of SS was
123
Table 2 Hormonal values of the patient Hormone
Units
Patient values
Normal values
FT3
pmol/L
3.37
FT4
pmol/L
3.84
11.4–23.2
TSH
mIU/L
0.207
0.35–5.5
PRL
ng/mL
1.08
2.8–14.6*
ACTH
pg/mL
2.14
0–46
3.54–6.47
GH
ng/mL
\0.05
0.1–10
Cortisol
lg/dL
\1
3.9–22
FSH
IU/L
1.99
4–9.3*
LH
IU/L
0.46
1.4–13.3*
E2
ng/L
5.69
35.8–157*
FT3 free triiodothyronine, FT4 free thyroxine, TSH Thyroid stimulating hormone, PRL prolactin, ACTH adrenocorticotropic hormone, GH growth hormone, FSH follicle-stimulating hormone, LH luteinising hormone, E2 estradiol * Follicular phase
made by local hospital. She received replacement therapy with prednisolone (7.5 mg/day) and levothyroxine sodium (100 mg/day). Some of her symptoms were improved about 3 months after treatment, but menstruation still did not occurred. Two years later, she visited our outpatient clinic for assisted conception. Her husband’s semen analysis was normal. A hysterosalpingogram showed that the left fallopian tube was normal, but the right fallopian tube was not patent. After the sixth cycle of hormone replacement treatment with Climen (estradiol valerate and cyproterone, 1 mg/day), follicular growth was stimulated using 150 IU of human menopausal gonadotropin (hMG) for 1 week, but ultrasonogram revealed there was no follicular
Arch Gynecol Obstet (2014) 289:1145–1150
1147
Fig. 1 The sagittal (a) and coronary (b) magnetic resonance imaging (MRI) of the brain showing a diminutive pituitary (short arrow) and an empty sella turcica (long arrow)
Fig. 2 Ultrasound picture of CHCF and a normal placenta at gestational week 12
development in bilateral ovaries. hMG was increased dose up to 225 IU for 1 week, and ultrasonogram showed two ovarian follicles (2.2 9 1.5 and 1.6 9 1.2 cm) in the left ovary and three ovarian follicles (2.3 9 1.8, 1.7 9 1.7 and 1.5 9 1.5 cm) in the right ovary, and thickness of endometrium was 0.8 cm. Ovulation was induced with 8,000 IU of human chorionic gonadotropin (hCG) intramuscular injection, followed by copulation. Ultrasonogram on the 3rd day of hCG injection revealed ovulation. Serum b-hCG level on the 11th day of ovulation was 29.0 IU/L. Progesterone (40 mg/day) and hCG (2,000 IU/day) were given to prevent miscarriage until gestational week 15. Two gestational sacs (GS) with fetal cardiac activity and an additional low echogenic mass suspected of having HM were detected on ultrasound examination at gestational week 8. The couple highly desired to continue the
pregnancy because it is very hard to get pregnant for the patients with SS and required to closely monitor the development of the mass. At gestational week 12, the appearance of low echogenic mass became multicystic (68 9 58 9 78 mm) and was suggestive of HM (Fig. 2). She had intermittently slight vaginal bleeding, but she did not have development of hypertension, generalized edema, hyperemesis, cough and dyspnea from gestational week 8–15. Successive ultrasound examination demonstrated that the mass increased rapidly in size (106 9 46 9 130 mm, at gestational week 15). Intra-amniotic administration of rivanol and repeat curettage were performed to terminate the pregnancy after counseling with the couple. Histopathologic examination showed edematous villi with frequent cistern formation and hyperplastic trophoblast (Fig. 3). Genetic studies were carried out to clarify origin
123
1148
Arch Gynecol Obstet (2014) 289:1145–1150
Fig. 3 Histopathology of CHM (original magnification 340). a, b showing edematous villi with frequent cistern formation (short arrow) and hyperplastic trophoblast (long arrow)
of the fetus, and of the normal and HM villi of the placenta. Genomic DNA extracted from the fetus, molar tissue and parental peripheral blood leukocytes was amplified using polymerase chain reaction (PCR) with fluorescently labeled polymorphic markers from different chromosomes as previously described [8]. Analysis of the PCR products using ABI Prism GeneScan software (Applied Biosystems Ltd, UK) revealed the normal diploid fetus (46, XY) with biparental genome and HM (46, XX) with paternal diploidy. These results confirmed the clinical impression of CHCF. Her serum b-hCG level declined progressively and returned to normal at 6 weeks until today.
Discussion Sheehan’s syndrome, hypopituitarism following postpartum pituitary necrosis, may involve a deficiency of one, several or all the pituitary trophic hormones, and spontaneous amelioration may occur [9]. Prolactin (PRL) and growth hormone (GH) are often two of the hormones lost earliest in SS because PRL and GH cells are located in the lower lateral region of the pituitary gland, where they are most susceptible to be damaged by ischemic necrosis [10, 11]. PRL and GH are deficient in 90–100 % of patients, and cortisol secretion, gonadotropin and thyroid stimulating hormone (TSH) are decreased in 50–100 % of patients [12]. The hypofunction of gonad and the effect of sex hormone axis are common in SS, which may result in cessation or disorder of menses. So it is hard for the patients with SS to get pregnant. Only 36 patients (not including our 1) with SS have been reported to have pregnancy up to now [3, 4, 13–16], some of which depended on the preservation of partial gonadotrophic function after the pituitary apoplexy event [15, 17]. In the present case, SS was diagnosed based on a history of postpartum hemorrhage and failure of lactation and characteristic clinical presentation comprising of secondary amenorrhea, breast atrophy, loss of pubic and axillary hair, a decrease in libido and easy fatigability. MRI revealed
123
loss of pituitary gland mass, and low levels of pituitary hormones [PRL, GH, cortisol, adrenocorticotropic hormone (ACTH), TSH, follicle-stimulating hormone (FSH) and luteinising hormone (LH)] as well as a decrease in response to stimulation tests demonstrated panhypopituitarism. Twin pregnancy occurred following ovulation induction with gonadotropins (hMG/hCG) in this case. Since it first was reported a successful attempt to induce ovulation and subsequent pregnancy using anterior pituitary extract in 1939 [18], only ten patients with SS have been reported to have conceived following gonadotropin treatment. Four of them were reviewed by Grimes and Brooks [3], and five of them reviewed by Kriplani et al. [4] and the other one reported by Jain [16]. Furthermore, we found that, so far, only three patients with panhypopituitarism (not including our 1) have a successful pregnancy following induction of ovulation with hMG/hCG [18–20]; two of them have twin pregnancy, and all of them have a successful outcome of pregnancy. Unfortunately, twin pregnancy with HM and coexistent fetus following induction of ovulation with hMG/hCG in our patient with panhypopituitarism had to be terminated by abortion because HM increased rapidly in size. The pathogenesis and the natural history of SS have not been exactly clarified, although enlargement of pituitary gland, small sella size, disseminated intravascular coagulation and autoimmunity have been suggested to play a role in SS [21]. The general principle of treatment of SS is to replace deficient hormones, which is important not only to correct endocrine abnormalities, but also to reduce mortality caused by hypopituitarism [1]. It has been reported that inadequate hormone replacement treatment in pregnant women with SS has resulted in high fetal and maternal morbidity and mortality [3]. Better ovulation rates in patients with hypopituitarism were obtained when pretreated estrogen and progesterone before hMG induction [22]. Our patient was given pretreatment with Climen (estradiol valerate and cyproterone) for six cycles to improve the uterine size. Exactly dosage of hMG/hCG administered in the first course of therapy was followed by
Arch Gynecol Obstet (2014) 289:1145–1150
ovulation and conception. This is very similar to the case reported previously [18]. Previous publications have reported that pregnancy might improve hypopituitarism due to the hypophysiotropic hormones secreted by the hypothalamus or the pituitary remnants to undergo hyperplasia stimulated by placenta in SS [23, 24]. In contrast, one recent publication reported that pregnancy might aggravate symptoms of SS by stimulating autoimmunity system or due to the long course of disease and the old age (55 years old) [15]. These different findings suggested that pregnancy may affect SS, as we all know that SS affects pregnancy. In a patient with SS, to our best knowledge, this is the first paper to report CHCF, although many series and several case reports have been published regarding HM and coexistent fetus (es). CHM are usually diploid androgenic conceptus, occurring by an ‘empty’ egg (loss of the maternal nuclear genome) with fertilization either by a single haploid sperm cell that duplicates to result in a 46, XX (monospermic) or by two sperms producing a 46, XX or 46, XY (dispermic) [25]. There are excessive trophoblastic growth and no fetal structure due to lack of genes transcribed from maternally derived genes. Most PHM are triploidy diandric conceptus (70 % 69, XXY; 27 % 69, XXX; 3 % 69, XYY), resulting from fertilization of a normal egg by two copies of the paternal genome (either a duplicated spermatozoon or two spermatozoa) [26]. There are fetal tissue, cord and normal villus structures of the placenta. Unlike PHM which is commonly associated with multiple fetal anomalies and is managed by immediate termination of pregnancy, CHM is associated with normal fetal survival and can be considered to continue pregnancy as long as serious maternal complications do not develop. In a large case series comprising 77 twin pregnancies with CHM, about 40 % of 53 continuing pregnancies were reported resulting in livebirths, but nearly 60 % had spontaneous abortion or were terminated because of severe preeclampsia [27]. The majority of series of twin pregnancies with CHM have reported a very high frequency (41–71 %) of pregnancy termination due to severe maternal and fetal complications such as persistent vaginal bleeding, spontaneous abortion, preterm delivery, thromboembolic disease, severe preeclampsia, persistent gestational trophoblastic neoplasia and intrauterine fetal death [27–29]. The management of CHCF is an enormous dilemma between termination of the pregnancy and expectant conservation, especially for the patients of highly desired pregnancy. Some authors support the option of conservative management under strict clinical observation and follow-up after providing the patients a detailed explanation about the potential risks and poor outcomes. In a recent case report, a rescue cerclage for cervical indications was considered a benefit of good outcome in the
1149
patient with CHCF [30], suggesting some potential interventions may improve outcome of some patients with CHCF. The association between HM and assisted conception has not been confirmed, because the number of reported cases is limited. However, it has been suggested that the incidence of HM in the future may increase with the wide use of ovulation-inducing agents [31]. Recent literature in 2009 reviewed 29 studies that reported 159 cases of twin pregnancy with CHM; ovulation induction has been administered 12 of 51 cases with available data (24 %) [32]. Another report presented 30 cases of twin pregnancy with CHM. Among these, nine cases (30 %) received ovulation induction treatment with either hMG/hCG (8 cases) or clomiphene citrate (1 case). Five of eight cases treated with hMG/hCG were also performed with assisted reproductive techniques (in vitro fertilization and embryo transfer (IVF–ET) in 3 cases, intra-cytoplasmic sperm injection and embryo transfer (ICSI–ET) in 2 cases) [33]. It is well known that treatment with hMG/hCG frequently leads to superovulation. Bruchim et al. [34] speculated that forced ovulation of more than one egg by ovulationinducing agents such as hMG/hCG treatment might increase the rate of a nuclear ‘‘empty’’ egg, which may be one of the theoretical reasons for the development of a CHM. In addition, several authors assumed that assisted reproductive techniques may be another risk factor for the development of HM, which is associated with embryo prolonged in vitro culture, higher volume and pressure of culture medium injected into the uterus, the tilt-down position of the patient at the time of embryo transfer, and advanced maternal/paternal age and poor oocyte quality of the patients who require assisted techniques to achieve a successful pregnancy [35–37].
Conclusion This is a special and rare case with two features. Firstly, the patient with panhypopituitarism due to postpartum hemorrhage of the first delivery had the second pregnancy following ovulation induction without assisted reproductive techniques. Secondly, even in the patient with SS, HM pregnancy may still occur. Conflict of interest
The authors declare no conflict of interest.
References 1. Kelestimur F (2003) Sheehan’s syndrome. Pituitary 6(4):181–188 2. Kristjansdottir HL, Bodvarsdottir SP, Sigurjonsdottir HA (2011) Sheehan’s syndrome in modern times: a nationwide retrospective study in Iceland. Eur J Endocrinol 164(3):349–354
123
1150 3. Grimes HG, Brooks MH (1980) Pregnancy in Sheehan’s syndrome. Report of a case and review. Obstet Gynecol Surv 35(8):481–488 4. Kriplani A, Goswami D, Agarwal N, Bhatla N, Ammini AC (2000) Twin pregnancy following gonadotrophin therapy in a patient with Sheehan’s syndrome. Int J Gynaecol Obstet 71(1):59–63 5. Malhotra N, Deka D, Takkar D, Kochar S, Goel S, Sharma MC (2001) Hydatiform mole with coexisting live fetus in dichorionic twin gestation. Eur J Obstet Gynecol Reprod Biol 94(2):301–303 6. Lee SW, Kim MY, Chung JH, Yang JH, Lee YH, Chun YK (2010) Clinical findings of multiple pregnancy with a complete hydatidiform mole and coexisting fetus. J Ultrasound Med 29(2):271–280 7. Massardier J, Golfier F, Journet D, Frappart L, Zalaquett M, Schott AM, Lenoir VT, Dupuis O, Hajri T, Raudrant D (2009) Twin pregnancy with complete hydatidiform mole and coexistent fetus: obstetrical and oncological outcomes in a series of 14 cases. Eur J Obstet Gynecol Reprod Biol 143(2):84–87 8. Gualandi F, Sensi A, Trabanelli C, Falciano F, Bonfatti A, Calzolari E (2000) Prenatal UPD testing survey in Robertsonian translocations. Prenat Diagn 20(6):465–468 9. Barkan AL (1989) Pituitary atrophy in patients with Sheehan’s syndrome. Am J Med Sci 298(1):38–40 10. Ozbey N, Inanc S, Aral F, Azezli A, Orhan Y, Sencer E, Molvalilar S (1994) Clinical and laboratory evaluation of 40 patients with Sheehan’s syndrome. Isr J Med Sci 30(11):826–829 11. Shahmanesh M, Ali Z, Pourmand M, Nourmand I (1980) Pituitary function tests in Sheehan’s syndome. Clin Endocrinol (Oxf) 12(3):303–311 12. Shivaprasad C (2011) Sheehan’s syndrome: Newer advances. Indian J Endocrinol Metab 15(Suppl 3(S)):203–207 13. Algun E, Ayakta H, Harman M, Topal C, Aksoy H (2003) Spontaneous pregnancy in a patient with Sheehan’s syndrome. Eur J Obstet Gynecol Reprod Biol 110(2):242–244 14. See TT, Lee SP, Chen HF (2005) Spontaneous pregnancy and partial recovery of pituitary function in a patient with Sheehan’s syndrome. J Chin Med Assoc 68(4):187–190 15. Hao J, Liu M, Mo Z (2012) The symptoms get worse after pregnancy in Sheehan’s syndrome: a case report. Case Rep Med 2012:271345 16. Jain D (2013) A ray of hope for a woman with Sheehan’s syndrome. BMJ Case Rep 17. Vieira HB, Knoepfelmacher M, Salgado LR, Wajchenberg BL, Liberman B (1995) Preservation of gonadotrophic function and pregnancy in Sheehan’s syndrome: a case report and review of the literature. Rev Assoc Med Bras 41(2):135–138 18. Cohen BL, Baillie P (1980) Sheehan’s syndrome followed by successful pregnancy: a case report. S Afr Med J 57(20):838–840 19. Briet JW (1998) Diabetes insipidus, Sheehan’s syndrome and pregnancy. Eur J Obstet Gynecol Reprod Biol 77(2):201–203 20. Barbieri RL, Randall RW, Saltzman DH (1985) Diabetes insipidus occurring in a patient with Sheehan’s syndrome during a gonadotropin-induced pregnancy. Fertil Steril 44(4):529–531 21. Kilicli F, Dokmetas HS, Acibucu F (2013) Sheehan’s syndrome. Gynecol Endocrinol 29(4):292–295
123
Arch Gynecol Obstet (2014) 289:1145–1150 22. Yildirim M, Noyan V, Tiras MB (2000) Estrogen-progestogen pre-treatment before HMG induction in hypogonadotropic patients. Int J Gynaecol Obstet 71(3):249–250 23. Sheehan HL (1948) Post-partum necrosis of the anterior pituitary. Ir J Med Sci 270:241–255 24. Jorgensen PI, Sele V, Buus O, Damkjoer M (1973) Detailed hormonal studies during and after pregnancy in a previously hypophysectomized patient. Acta Endocrinol (Copenh) 73(1):117–132 25. Ferraz TJ, Bartosch CM, Ramalho CM, Carvalho FA, Carvalho BC, Brandao OG, Montenegro NA (2013) Complete mole in a dichorionic twin pregnancy after intracytoplasmic sperm injection. Rev Bras Ginecol Obstet 35(1):39–43 26. Genest DR (2001) Partial hydatidiform mole: clinicopathological features, differential diagnosis, ploidy and molecular studies, and gold standards for diagnosis. Int J Gynecol Pathol 20(4):315–322 27. Sebire NJ, Foskett M, Paradinas FJ, Fisher RA, Francis RJ, Short D, Newlands ES, Seckl MJ (2002) Outcome of twin pregnancies with complete hydatidiform mole and healthy co-twin. Lancet 359(9324):2165–2166 28. Fishman DA, Padilla LA, Keh P, Cohen L, Frederiksen M, Lurain JR (1998) Management of twin pregnancies consisting of a complete hydatidiform mole and normal fetus. Obstet Gynecol 91(4):546–550 29. Vaisbuch E, Ben-Arie A, Dgani R, Perlman S, Sokolovsky N, Hagay Z (2005) Twin pregnancy consisting of a complete hydatidiform mole and co-existent fetus: report of two cases and review of literature. Gynecol Oncol 98(1):19–23 30. Aguin E, Aguin V, Cisneros L, Aguin T, Van de Ven C, BahadoSingh R (2012) Does cerclage improve neonatal outcomes in a molar pregnancy and a coexistent fetus? A case report. BMC Res Notes 5:621 31. Malinowski W, Biskup I, Dec W (1995) Sad fetus syndromegestational trophoblastic disease concurrent with a living fetus or fetuses. Acta Genet Med Gemellol (Roma) 44(3–4):193–202 32. Dolapcioglu K, Gungoren A, Hakverdi S, Hakverdi AU, Egilmez E (2009) Twin pregnancy with a complete hydatidiform mole and co-existent live fetus: two case reports and review of the literature. Arch Gynecol Obstet 279(3):431–436 33. Piura B, Rabinovich A, Hershkovitz R, Maor E, Mazor M (2008) Twin pregnancy with a complete hydatidiform mole and surviving co-existent fetus. Arch Gynecol Obstet 278(4):377–382 34. Bruchim I, Kidron D, Amiel A, Altaras M, Fejgin MD (2000) Complete hydatidiform mole and a coexistent viable fetus: report of two cases and review of the literature. Gynecol Oncol 77(1):197–202 35. Sun CJ, Zhao YP, Yu S, Fan L, Wu QQ, Li GH, Zhang WY (2012) Twin pregnancy and partial hydatidiform mole following in vitro fertilization and embryos transfer: a novel case of placental mosaicism. Chin Med J (Engl) 125(24):4517–4519 36. Huang X, Wang H, Zhao X, Xu X, Chen Q (2007) Gestational trophoblastic disease following in vitro fertilization. Arch Gynecol Obstet 275(4):291–293 37. Montes-de-Oca-Valero F, Macara L, Shaker A (1999) Twin pregnancy with a complete hydatidiform mole and co-existing fetus following in vitro fertilization: case report. Hum Reprod 14(11):2905–2907
