Sonographic Findings and Perinatal Outcome of Multiple Pregnancies Associating a Complete Hydatiform Mole and a Live Fetus: A Case Series Mehmet Serdar Kutuk, MD,1 Mahmut Tuncay Ozgun, MD,1 Mehmet Dolanbay, MD,1 Cem Batukan, MD,2 Semih Uludag, MD,1 Mustafa Basbug, MD,1 1 2
Erciyes University, Faculty of Medicine, Department of Obstetrics and Gynecology, Kayseri, Turkey Acıbadem University, Faculty of Medicine, Department of Obstetrics and Gynecology, Istanbul, Turkey
Received 23 May 2013; accepted 22 April 2014
ABSTRACT: Background. The aim of this case series was to present the ultrasonographic findings, clinical features, management, and outcome of multiple pregnancies with complete hydatidiform mole and coexisting fetus (CHMCF). Methods. Sonographic features and obstetrical and perinatal outcomes of seven cases with CHMCF were analyzed retrospectively. Results. A total of seven cases was included in the analysis. Six cases were twins and one case was quadruplet. The mean 6 SD maternal age was 25.3 6 1.9 years (median: 25; range: 23–29). The mean gestational age at diagnosis was 16.1 6 4.6 weeks (median: 17; range: 11–23). Two pregnancies were achieved by ovulation induction. Two couples opted for pregnancy termination. Four pregnancies resulted in fetal loss between the 11th and 23th week of gestation. One pregnancy ended with the preterm delivery of a live-born neonate at 34 weeks due to preeclampsia. One patient developed persistent trophoblastic disease, which was treated by hysterectomy. The mean 6 SD time for b-human chorionic gonadotropin clearance was 3.7 6 0.5 weeks (median: 4; range: 3–4) in the six patients without persistent trophoblastic disease. Conclusions. Spontaneous fetal loss is the most likely outcome for CHMCF. However, on the basis of our experience, we recommend carefully monitored continuation of pregnancy as long as maternal compliC 2014 cations are not present or are controllable. V Wiley Periodicals, Inc. J Clin Ultrasound 42:465–471,
Correspondence to: M. Dolanbay C 2014 Wiley Periodicals, Inc. V
VOL. 42, NO. 8, OCTOBER 2014
2014; Published online in Wiley Online Library (wileyonlinelibrary. com). DOI: 10.1002/jcu.22169 Keywords: complete mole; twin pregnancy; molar pregnancy; perinatal outcome; obstetrics
M
ultiple pregnancy consisting of a complete hydatidiform mole (CHM) and coexisting fetus (CHMCF) is a very rare entity with an incidence of one per 22,000–100,000 pregnancies.1,2 Management of antenatally diagnosed CHMCF is very challenging, as these pregnancies are usually achieved with assisted reproductive techniques and the couples are very sensitive to an abnormal perinatal outcome.3,4 Despite the fact that CHMCF may end up with a viable fetus, this condition carries a substantial risk for many serious complications, such as pre-eclampsia, fetal demise, thyrotoxicosis, hemorrhage, trophoblastic embolism, and persistent trophoblastic disease (PTD).5 This report summarizes our experience of seven patients with CHMCF treated at our institution between 2007 and 2012. MATERIALS AND METHODS
Data of patients with CHMCF seen in the Department of Obstetrics and Gynaecology, between 2007 and 2012, were retrospectively analyzed. All patients included in this study were evaluated by two of four experienced perinatal medicine specialists (M.S.K., M.T.O., C.B., 465
KUTUK ET AL
FIGURE 1. Case 3. Transabdominal sonogram at 19 weeks of pregnancy. Sagittal view of the placenta shows a lesion with multiple vesicles suspected to be molar tissue. Arrows show the demarcation between the molar tissue and normal placenta.
FIGURE 3. Case 7. Transabdominal sonogram of the placenta at the 11th week of pregnancy. Amniotic membrane separating the molar placenta from the viable fetus can be clearly seen (arrow).
essential part of the evaluation, deoxyribonucleic acid (DNA) fingerprinting was performed in two cases as a part of another study conducted by the Genetic and Oncology Departments. The placentas and fetuses were submitted to the Pathology Department for histopathological examination and autopsy. The statistical analysis was primarily descriptive. Overall data are reported as mean, SD, minimum, and maximum value.
RESULTS FIGURE 2. Case 4. Transabdominal sonogram of a twin pregnancy with complete mole at the 12th gestational week shows transverse section of the fetal abdomen (thin arrow) and the normal (thick arrow) and molar (star) placental components.
M.B.). The sonographic (US) examinations were performed transabdominally with a Voluson 730 Pro scanner equipped with a 5–8-MHz transabdominal convex transducer and a Logic 500 scanner with a multifrequency 3.5–5.0-MHz convex probe (GE Healthcare, Milwaukee, WI). Fetal blood and placental samplings were offered to all couples. The antenatal diagnosis of CHMCF was based on the following criteria: (1) presence of a vacuolar placenta adjacent to a normal-appearing placenta; (2) presence of a fetus without major congenital malformation and/or severe growth restriction; (3) normal fetal karyotype. After the US diagnosis, baseline thyroid function tests, b-human chorionic gonadotropin (b-hCG) level, and complete blood count were requested. Because it is not an 466
Of 24,024 patients examined in our department between 2007 and 2012, seven cases of CHMCF were found (19/100,000). Six cases were twin pregnancies, and one case was a quadruplet pregnancy. The mean 6 SD maternal age was 25.3 6 1.9 years (median: 25; range: 23–29). The mean 6 SD gestational age at diagnosis was 16.1 6 4.6 weeks (median: 17; range: 11–23). Two pregnancies were achieved by ovulation induction with either clomiphene citrate or human menopausal gonadotropin. The most common presenting symptoms were vaginal bleeding (two cases) and hyperemesis gravidarum (two cases). Three patients had no symptoms attributable to molar pregnancies and were diagnosed during routine US screening. In two cases, thyroid hormone levels were found to be elevated without any clinical sign of thyrotoxicosis. In all the cases, the vacuolar tissues adjacent to the normal placenta with structurally normal fetus were demonstrated (Figures 1, 2, and 3). In one case, three gestational sacs and a molar placenta were demonstrated with JOURNAL OF CLINICAL ULTRASOUND
PREGNANCIES WITH COEXISTING HYDATIDIFORM MOLE
FIGURE 4. Case 5. (A) Transabdominal sonogram of the quadruplet pregnancy shows four gestational sacs (1,2,3,4) at the end of the 10th week of pregnancy. (B) Transabdominal sonogram at the 12th week shows typical molar appearance in the fourth sac. (C) Photograph of the gross specimen after the abortion at the 14th week of pregnancy shows a fetus with normal placenta, an embryo corresponding to the second gestational sac (arrow), and molar tissue (asterisk).
FIGURE 5. Case 6. Transabdominal sonogram at the 17th week of pregnancy shows the enlarged left ovary containing multiple thecalutein cysts.
US (Figure 4A–4C). Bilateral theca-lutein cysts that caused no symptoms or complications were seen in one case (Figure 5). Prenatal diagnoses of the all cases were confirmed by postnatal examinations of the placentas (Figure 6). VOL. 42, NO. 8, OCTOBER 2014
FIGURE 6. Case 1. Postpartum view of the placenta containing both molar and normal parts. The separation between molar and normal placenta is visible (arrows).
Two couples opted for termination of pregnancy (TOP). Four pregnancies ended up in fetal losses between 11 and 23 weeks’ gestation. One pregnancy ended with the preterm delivery of a live-born neonate at the 34th week due to pre-eclampsia. One patient developed PTD after 467
468
None 11 24 7
11
VB, HT 21 6
17 26
2 3 4 5
Abbreviations: b-hCG, b-human chorionic gonadotropin; CC, clomifene citrate; hCG, human chorionic gonadotropin; HG, hyperemesis gravidarum; hMG, human menopausal gonadotropin; HT, hyperthyroidism; IUI, intrauterine insemination; OI, ovulation induction; PPRM, preterm premature rupture of membranes; PTD, persistent trophoblastic disease; TOP, termination of pregnancy; US, ultrasonography; VB, vaginal bleeding.
Term, healthy neonate None 351,660
Spontaneous
Spontaneous abortion
46,XY
46,XY
Term, healthy neonate None Spontaneous abortion Spontaneous 310,351
Spontaneous Spontaneous Spontaneous OI (hMG/hCG) 23 24 29 26
1
20 18 12 12
2313 2113 14 14
None PPRM HG, HT VB, HG
Molar placenta Molar placenta Molar placenta Multicystic, vacuolar mass, quadruplet Theca lutein cysts, molar placenta, chorioamniotic seperation Vacuolar placenta
15,774 141,720 310,270 125,220
46,XY
46,XX
None None None Present 46,XX 46,XX 46,XX 46,XX
46,XX 46,XY 46,XX 46,XY
None 46,XX 25
Case
23
34
None
Molar placenta
100,048
IUI CC/hCG
Live birth at 34 weeks TOP Spontaneous abortion TOP Spontaneous abortion
46,XX
PTD Molar Karyotype Fetal Karyotype Outcome Type of Pregnancy US Findings
b-hCG at Diagnosis (mIU/mL) Presenting Symptom At TOP At Diagnosis Maternal Age (years)
Gestational Age (weeks1days)
TABLE 1 Clinical Features, Sonographic Findings, and Karyotypes of Pregnancies with Mole and Coexisting Fetus(es)
Subsequent Pregnancy
KUTUK ET AL
quadruplet pregnancy. Due to the patient’s reluctance to use methotrexate therapy, she was treated with hysterectomy. The mean 6 SD time for b-hCG clearance was 3.7 6 0.5 weeks (median: 4; range: 3–4) in the six patients without PTD. Two patients had successful, uncomplicated pregnancies following CHMCF and gave birth to term, healthy neonates. Clinical presentations, US findings, laboratory results, and perinatal outcome of the seven patients are summarized in Table 1.
DISCUSSION
Multiple pregnancies consisting of a CHMCF represent a very rare entity. Until recently, this condition was commonly diagnosed retrospectively after delivery by the inspection of placenta and generally managed by the gynecologic oncologists. Therefore, natural history and optimal management of these pregnancies have been poorly defined.6 With the widespread use of ovulation induction, and routine use of US in the follow-up of pregnancy, the incidence of CHMCF is expected to increase. In clinical practice, the main issue in the evaluation of molar placenta and living fetus is to differentiate between the following conditions: (1) singleton pregnancy consisting of a partial hydatidiform mole with a fetus; (2) a twin gestation consisting of a CHM along with a coexisting live fetus; (3) a twin gestation consisting of partial mole and twin in one sac and a normal twin in the other; and (4) mesenchymal dysplasia.1,5 Practically, the most challenging problem is to differentiate CHMCF from a partial mole. In CHMCF, the fetus has a normal karyotype and generally has no major malformation. The placenta consists of two components: normal villous/vascular placenta with normal karyotype identical to that of the fetus and a molar component, which has usually paternal diploid chromosome constituents. In partial mole, the fetus has abnormal triploid karyotype, structural malformation, oligohydramnios, and intrauterine growth restriction that usually precede fetal demise. For definitive diagnosis, chorionic villus sampling of molar tissue can be performed, and absence of maternal alleles confirms a diandrogenic complete mole. In our series, karyotype analysis was performed in all fetuses and revealed normal karyotype. Karyotype analysis of molar tissues showed sex chromosome discordance in three fetuses. DNA fingerprinting analysis was performed only in JOURNAL OF CLINICAL ULTRASOUND
PREGNANCIES WITH COEXISTING HYDATIDIFORM MOLE
two cases and confirmed paternal origin of the molar chromosomes. Although chromosomal triploidy is diagnostic of a partial mole, a diploid karyotype that is typical of a complete mole has rarely been described in partial moles.7,8 Thus, the final diagnosis in challenging cases requires elaborate cytogenetic studies to prove the androgenetic origin of the chromosomes.9 In our experience, the typical US depiction of the molar mass adjacent to the normal-looking placenta with a structurally normal fetus has always been diagnostic of CHMCF. Of note, in our experience, the most important condition that posed a challenge for the diagnosis of CHMCF was mesenchymal dysplasia. Mesenchymal dysplasia is characterized by enlarged cystic placenta and is usually associated with abnormal screening test results, intrauterine growth restriction, and even fetal demise.10 US findings in mesenchymal dysplasia may be similar to CHCMF, especially when the dysplastic changes are distributed nonhomogenously throughout the placenta. In difficult cases, the differential diagnosis can be made with cytogenetic analysis, measurement of b-hCG levels, and pathologic examination of the placenta. In CHMCF cases, unless affected by sporadic anomalies, the fetus is usually healthy. Therefore, continuation of pregnancy can be a reasonable option as long as serious maternal complications do not develop. However, many severe pregnancy complications, such as intrauterine fetal death, pre-eclampsia, thyrotoxicosis, antepartum hemorrhage, and PTD, are frequently associated with a CHMCF. Management of such pregnancies is largely based on the severity of the symptoms, and the gestational age at which complications occur.5 Pre-eclampsia, which affects 6% of CHMCF cases, is especially indicative of a poor outcome, and early onset of pre-eclampsia is an indication for TOP.11 Recently, Kihara et al suggested that pre-eclampsia was the major determinant of the poor fetal outcome because no babies from preeclamptic women survived in their series.12 In our series, only one woman had severe preeclampsia at 33 weeks and gave birth to a preterm, healthy neonate at the 34th week. As six of our cases ended up with miscarriage or TOP before the third trimester, it is not possible to evaluate the prevalence of pre-eclampsia in CHMCF in our series. In molar pregnancies, a variety of symptoms can be seen as a consequence of stimulation of target tissues by b-hCG. Bilateral enlarged multicystic ovaries, due to theca lutein cyst, are VOL. 42, NO. 8, OCTOBER 2014
reported in about one-fourth of the cases from the end of the first trimester.13 In our series, theca lutein cysts were found in only one case, caused no symptoms, and regressed at 2 months postpartum. A case of theca lutein cysts due to CHMCF complicated with ovarian torsion has been reported previously.6 In two of our seven cases, thyrotoxicosis developed in early pregnancy without any complications. Similarly, Lee et al reported that four of their six cases developed thyrotoxicosis in early pregnancy, and one patient successfully continued pregnancy until term with a live-born neonate.6 Spontaneous abortion and intrauterine fetal demise are also very common with a CHMCF, particularly before the third trimester. Sebire et al reported 23 spontaneous second-trimester miscarriages among 53 CHMCF pregnancies (43%).11 In our series, four (57%) pregnancies resulted in a miscarriage between 11 and 21 weeks. b-hCG is secreted by the syncytiotrophoblast and can be detected in the maternal blood and urine approximately 8–10 days after fertilization. The concentration of the b-hCG dimer in maternal blood rises rapidly during early pregnancy, peaks at 9–10 weeks’ and subsequently declines to nadir at approximately the 20th week. The serum b-hCG level can be a helpful marker in the diagnosis and follow-up of the patients with CHMCF. However, its role in determining the prognosis and outcome of these patients is not proven. Lee et al showed that decreasing b-hCG levels was associated with fetal survival in one of their cases.6 In contrast, Montes-de-Oca-Valero et al reported a healthy neonate delivered at 28 weeks, despite the increasing b-hCG titers, and molar mass.3 In our series, elevated b-hCG levels according to gestational age were shown in three cases (cases 4, 5, and 6 in Table 1). One of these (case 6) also had theca lutein cysts and thyrotoxicosis. Our limited data suggest that higher levels of b-hCG are predictive of b-hCG-mediated complications, rather than of the outcome of the pregnancy. One central issue regarding CHMCF pregnancy is the risk of PTD. In the earlier reports, the incidence of PTD has been reported to be 50–63%, and higher than in the case of a single molar pregnancy.13–15 However, in the largest series ever collected, Sebire et al reported that 19.5% of 77 patients with CHMCF had PTD.11 Nieman et al in their Danish collaborative study compared the complete diploid mole and CHMCF and reported that the risk of PTD after CHMCF is similar to that of after a singleton 469
KUTUK ET AL
molar pregnancy (25% versus 17%).16 The factors that predict the development of PTD after CHMCF are very important for prenatal counseling. In the two largest series, it was shown that there was no statistical difference between the risk of PTD in patients undergoing early elective TDP and in those who preferred to continue their pregnancy.11,15 Moreover, neither the severity of clinical symptoms nor the b-hCG levels have consistent predictive values in determining whether PTD develops after CHMCF. Therefore, PTD that complicates CHMCF may develop irrespective of the time at which pregnancy is interrupted, and even when intervention occurs in early pregnancy, the risk of malignancy persists. In our series, PTD developed only in one pregnancy, which was quadruplet. Obviously, CHM in a quadruplet pregnancy is extremely rare, with only four cases have been reported in the literature.17–20 Therefore, it is hard to elucidate the natural behavior, perinatal outcome, and malignant potential of triplet and quadruplet pregnancies with CHM. In their review, Takagi et al reported that 6 of 13 cases (46%) with triplet pregnancies with complete mole had PTD and pointed to an increased risk for PTD.21 Moreover, pregnancies with triplets or quadruplets naturally carry an increased risk of preterm labor and pre-eclampsia. According to the literature, the chance of positive outcome in triplet pregnancies with complete mole is 22.5%, and not severely impaired when compared with twin pregnancies.16,21–23 However, with an accompanying mole, the longest reported gestational age in quadruplet pregnancy is 25 weeks, and no case with a surviving child has been reported.16,19 The mean time for the b-hCG to return to nonpregnant level was 3.5 weeks in our patients who did not develop PTD. In contrast to our results, Lee et al and Vaisbuch et al reported that the mean time for b-hCG to return to normal was about 13 weeks in patients with CHMCF uncomplicated with PTD.4,6 According to the literature, the mean times for the clearance of b-hCG after the second-trimester TOP and evacuation of molar pregnancy are 4 weeks and 9 weeks, respectively.24,25 As a result, our data show that the clearance pattern of b-hCG after the TOP in CHMCF is similar to that seen in secondtrimester TOP. Sebire et al assessed 77 twin pregnancies with a CHMCF. Of 53 patients who continued pregnancy, 20 gave birth to a live-born neo470
nate.11 Although pregnancy complications are not uncommon with a CHMCF, about 40 cases of viable fetuses have been reported so far. Based on our data and previous literature,11,26,27 we can speculate that the actual chance of delivering a viable fetus in CHMCF may be increased by simply providing appropriate prenatal counseling. In conclusion, we suggest that, in a pregnancy with CHMCF but without severe preeclampsia and bleeding, pregnancy may be continued under close surveillance.
REFERENCES 1. Bristow RE, Shumway JB, Khouzami AN, et al. Complete hydatidiform mole and surviving coexistent twin. Obstet Gynecol Surv 1996;51:705. 2. Fishman DA, Padilla LA, Keh P, et al. Management of twin pregnancies consisting of a complete hydatidiform mole and normal fetus. Obstet Gynecol 1998;91:546. 3. Montes-de-Oca-Valero F, Macara L, Shaker A. Twin pregnancy with a complete hydatidiform mole and co-existing fetus following in-vitro fertilization: case report. Hum Reprod 1999;14:2905. 4. Vaisbuch E, Ben-Arie A, Dgani R, et al. Twin pregnancy consisting of a complete hydatidiform mole and co-existent fetus: report of two cases and review of literature. Gynecol Oncol 2005;98:19. 5. Wee L, Jauniaux E. Prenatal diagnosis and management of twin pregnancies complicated by a coexisting molar pregnancy. Prenat Diagn 2005;25: 772. 6. Lee SW, Kim MY, Chung JH, et al. Clinical findings of multiple pregnancy with a complete hydatidiform mole and coexisting fetus. J Ultrasound Med 2010;29:271. 7. Ohama K, Ueda K, Okamoto E, et al. Cytogenetic and clinicopathologic studies of partial moles. Obstet Gynecol 1986;68:259. 8. Vejerslev LO, Sunde L, Hansen BF, et al. Hydatidiform mole and fetus with normal karyotype: support of a separate entity. Obstet Gynecol 1991;77: 868. 9. Ishii J, Iitsuka Y, Takano H, et al. Genetic differentiation of complete hydatidiform moles coexisting with normal fetuses by short tandem repeatderived deoxyribonucleic acid polymorphism analysis. Am J Obstet Gynecol 1998;179:628. 10. Nayeri UA, West AB, Grossetta Nardini HK, et al. Systematic review of sonographic findings of placental mesenchymal dysplasia and subsequent pregnancy outcomes. Ultrasound Obstet Gynecol 2013;41:366. 11. Sebire NJ, Foskett M, Paradinas FJ, et al. Outcome of twin pregnancies with complete hydatidiform mole and healthy co-twin. Lancet 2002;359: 2165. JOURNAL OF CLINICAL ULTRASOUND
PREGNANCIES WITH COEXISTING HYDATIDIFORM MOLE 12. Kihara M, Usui H, Tanaka H, et al. Complicating preeclampsia as a predictor of poor survival of the fetus in complete hydatidiform mole coexistent with twin fetus. J Reprod Med 2012;57:325. 13. Steller MA, Genest DR, Bernstein MR, et al. Natural history of twin pregnancy with complete hydatidiform mole and coexisting fetus. Obstet Gynecol 1994;83:35. 14. Fishman DA, Padilla LA, Keh P, et al. Management of twin pregnancies consisting of a complete hydatidiform mole and normal fetus. Obstet Gynecol 1998;91:546. 15. Matsui H, Sekiya S, Hando T, et al. Hydatidiform mole coexistent with a twin live fetus: a national collaborative study in Japan. Hum Reprod 2000; 15:608. 16. Niemann I, Sunde L, Petersen LK. Evaluation of the risk of persistent trophoblastic disease after twin pregnancy with diploid hydatidiform mole and coexisting normal fetus. Am J Obstet Gynecol 2007;197:45. 17. Hoshi K, Morimura Y, Azuma C, et al. A case of quadruplet pregnancy containing complete mole and three fetuses. Am J Obstet Gynecol 1994;170: 1372. 18. Ibarg€ uengoitia F, Lira Plascencia J, Argueta ~ iga M, et al. [Multiple (quadruple) pregnancy Z un involving complete hydatidiform mole and 3 fetuses.] Ginecol Obstet Mex 1995;63:275. 19. Chao AS, Tsai TC, Soong YK. Clinical management of a quadruplet pregnancy combining a triplet pregnancy with a classical hydatidiform mole: case report and review of literature. Prenat Diagn 1999;19:1073. 20. Amano T, Takahashi K, Kita N, et al. A case of quadruplet pregnancy with a complete hydatidiform mole. Prenat Diagn 2005;25:718.
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21. Takagi K, Unno N, Hyodo HE, et al. Complete hydatidiform mole in a triplet pregnancy coexisting two viable fetuses: case report and review of the literature. J Obstet Gynaecol Res 2003;29:330. 22. Amr MF, Fisher RA, Foskett MA, et al. Triplet pregnancy with hydatidiform mole. Int J Gynecol Cancer 2000;10:76. 23. Bovicelli L, Ghi T, Pilu G, et al. Prenatal diagnosis of a complete mole coexisting with a dichorionic twin pregnancy: case report. Hum Reprod 2004;19: 1231. 24. Marrs RP, Kletzky OA, Howard WF, et al. Disappearance of human chorionic gonadotropin and resumption of ovulation following abortion. Am J Obstet Gynecol 1979;135:731. 25. Genest DR, LaBorde O, Berkowitz RS, et al. A clinicopathologic study of 153 cases of complete hydatidiform mole (1980–1990): histologic grade lacks prognostic significance. Obstet Gynecol 1991;78: 402. 26. Piura B, Rabinovich A, Hershkovitz R, et al. Twin pregnancy with a complete hydatidiform mole and surviving co-existent fetus. Arch Gynecol Obstet 2008;278:377. 27. Massardier J, Golfier F, Journet D, et al. 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 2009;143:84. 28. Moini A, Ahmadi F, Eslami B, et al. Dizygotic twin pregnancy with a complete hydatidiform mole and a coexisting viable fetus. Iran J Radiol 2011;8:249. 29. Vimercati A, de Gennaro AC, Cobuzzi I, et al. Two cases of complete hydatidiform mole and coexistent live fetus. J Prenat Med 2013;7:1.
471
Erciyes University, Faculty of Medicine, Department of Obstetrics and Gynecology, Kayseri, Turkey Acıbadem University, Faculty of Medicine, Department of Obstetrics and Gynecology, Istanbul, Turkey
Received 23 May 2013; accepted 22 April 2014
ABSTRACT: Background. The aim of this case series was to present the ultrasonographic findings, clinical features, management, and outcome of multiple pregnancies with complete hydatidiform mole and coexisting fetus (CHMCF). Methods. Sonographic features and obstetrical and perinatal outcomes of seven cases with CHMCF were analyzed retrospectively. Results. A total of seven cases was included in the analysis. Six cases were twins and one case was quadruplet. The mean 6 SD maternal age was 25.3 6 1.9 years (median: 25; range: 23–29). The mean gestational age at diagnosis was 16.1 6 4.6 weeks (median: 17; range: 11–23). Two pregnancies were achieved by ovulation induction. Two couples opted for pregnancy termination. Four pregnancies resulted in fetal loss between the 11th and 23th week of gestation. One pregnancy ended with the preterm delivery of a live-born neonate at 34 weeks due to preeclampsia. One patient developed persistent trophoblastic disease, which was treated by hysterectomy. The mean 6 SD time for b-human chorionic gonadotropin clearance was 3.7 6 0.5 weeks (median: 4; range: 3–4) in the six patients without persistent trophoblastic disease. Conclusions. Spontaneous fetal loss is the most likely outcome for CHMCF. However, on the basis of our experience, we recommend carefully monitored continuation of pregnancy as long as maternal compliC 2014 cations are not present or are controllable. V Wiley Periodicals, Inc. J Clin Ultrasound 42:465–471,
Correspondence to: M. Dolanbay C 2014 Wiley Periodicals, Inc. V
VOL. 42, NO. 8, OCTOBER 2014
2014; Published online in Wiley Online Library (wileyonlinelibrary. com). DOI: 10.1002/jcu.22169 Keywords: complete mole; twin pregnancy; molar pregnancy; perinatal outcome; obstetrics
M
ultiple pregnancy consisting of a complete hydatidiform mole (CHM) and coexisting fetus (CHMCF) is a very rare entity with an incidence of one per 22,000–100,000 pregnancies.1,2 Management of antenatally diagnosed CHMCF is very challenging, as these pregnancies are usually achieved with assisted reproductive techniques and the couples are very sensitive to an abnormal perinatal outcome.3,4 Despite the fact that CHMCF may end up with a viable fetus, this condition carries a substantial risk for many serious complications, such as pre-eclampsia, fetal demise, thyrotoxicosis, hemorrhage, trophoblastic embolism, and persistent trophoblastic disease (PTD).5 This report summarizes our experience of seven patients with CHMCF treated at our institution between 2007 and 2012. MATERIALS AND METHODS
Data of patients with CHMCF seen in the Department of Obstetrics and Gynaecology, between 2007 and 2012, were retrospectively analyzed. All patients included in this study were evaluated by two of four experienced perinatal medicine specialists (M.S.K., M.T.O., C.B., 465
KUTUK ET AL
FIGURE 1. Case 3. Transabdominal sonogram at 19 weeks of pregnancy. Sagittal view of the placenta shows a lesion with multiple vesicles suspected to be molar tissue. Arrows show the demarcation between the molar tissue and normal placenta.
FIGURE 3. Case 7. Transabdominal sonogram of the placenta at the 11th week of pregnancy. Amniotic membrane separating the molar placenta from the viable fetus can be clearly seen (arrow).
essential part of the evaluation, deoxyribonucleic acid (DNA) fingerprinting was performed in two cases as a part of another study conducted by the Genetic and Oncology Departments. The placentas and fetuses were submitted to the Pathology Department for histopathological examination and autopsy. The statistical analysis was primarily descriptive. Overall data are reported as mean, SD, minimum, and maximum value.
RESULTS FIGURE 2. Case 4. Transabdominal sonogram of a twin pregnancy with complete mole at the 12th gestational week shows transverse section of the fetal abdomen (thin arrow) and the normal (thick arrow) and molar (star) placental components.
M.B.). The sonographic (US) examinations were performed transabdominally with a Voluson 730 Pro scanner equipped with a 5–8-MHz transabdominal convex transducer and a Logic 500 scanner with a multifrequency 3.5–5.0-MHz convex probe (GE Healthcare, Milwaukee, WI). Fetal blood and placental samplings were offered to all couples. The antenatal diagnosis of CHMCF was based on the following criteria: (1) presence of a vacuolar placenta adjacent to a normal-appearing placenta; (2) presence of a fetus without major congenital malformation and/or severe growth restriction; (3) normal fetal karyotype. After the US diagnosis, baseline thyroid function tests, b-human chorionic gonadotropin (b-hCG) level, and complete blood count were requested. Because it is not an 466
Of 24,024 patients examined in our department between 2007 and 2012, seven cases of CHMCF were found (19/100,000). Six cases were twin pregnancies, and one case was a quadruplet pregnancy. The mean 6 SD maternal age was 25.3 6 1.9 years (median: 25; range: 23–29). The mean 6 SD gestational age at diagnosis was 16.1 6 4.6 weeks (median: 17; range: 11–23). Two pregnancies were achieved by ovulation induction with either clomiphene citrate or human menopausal gonadotropin. The most common presenting symptoms were vaginal bleeding (two cases) and hyperemesis gravidarum (two cases). Three patients had no symptoms attributable to molar pregnancies and were diagnosed during routine US screening. In two cases, thyroid hormone levels were found to be elevated without any clinical sign of thyrotoxicosis. In all the cases, the vacuolar tissues adjacent to the normal placenta with structurally normal fetus were demonstrated (Figures 1, 2, and 3). In one case, three gestational sacs and a molar placenta were demonstrated with JOURNAL OF CLINICAL ULTRASOUND
PREGNANCIES WITH COEXISTING HYDATIDIFORM MOLE
FIGURE 4. Case 5. (A) Transabdominal sonogram of the quadruplet pregnancy shows four gestational sacs (1,2,3,4) at the end of the 10th week of pregnancy. (B) Transabdominal sonogram at the 12th week shows typical molar appearance in the fourth sac. (C) Photograph of the gross specimen after the abortion at the 14th week of pregnancy shows a fetus with normal placenta, an embryo corresponding to the second gestational sac (arrow), and molar tissue (asterisk).
FIGURE 5. Case 6. Transabdominal sonogram at the 17th week of pregnancy shows the enlarged left ovary containing multiple thecalutein cysts.
US (Figure 4A–4C). Bilateral theca-lutein cysts that caused no symptoms or complications were seen in one case (Figure 5). Prenatal diagnoses of the all cases were confirmed by postnatal examinations of the placentas (Figure 6). VOL. 42, NO. 8, OCTOBER 2014
FIGURE 6. Case 1. Postpartum view of the placenta containing both molar and normal parts. The separation between molar and normal placenta is visible (arrows).
Two couples opted for termination of pregnancy (TOP). Four pregnancies ended up in fetal losses between 11 and 23 weeks’ gestation. One pregnancy ended with the preterm delivery of a live-born neonate at the 34th week due to pre-eclampsia. One patient developed PTD after 467
468
None 11 24 7
11
VB, HT 21 6
17 26
2 3 4 5
Abbreviations: b-hCG, b-human chorionic gonadotropin; CC, clomifene citrate; hCG, human chorionic gonadotropin; HG, hyperemesis gravidarum; hMG, human menopausal gonadotropin; HT, hyperthyroidism; IUI, intrauterine insemination; OI, ovulation induction; PPRM, preterm premature rupture of membranes; PTD, persistent trophoblastic disease; TOP, termination of pregnancy; US, ultrasonography; VB, vaginal bleeding.
Term, healthy neonate None 351,660
Spontaneous
Spontaneous abortion
46,XY
46,XY
Term, healthy neonate None Spontaneous abortion Spontaneous 310,351
Spontaneous Spontaneous Spontaneous OI (hMG/hCG) 23 24 29 26
1
20 18 12 12
2313 2113 14 14
None PPRM HG, HT VB, HG
Molar placenta Molar placenta Molar placenta Multicystic, vacuolar mass, quadruplet Theca lutein cysts, molar placenta, chorioamniotic seperation Vacuolar placenta
15,774 141,720 310,270 125,220
46,XY
46,XX
None None None Present 46,XX 46,XX 46,XX 46,XX
46,XX 46,XY 46,XX 46,XY
None 46,XX 25
Case
23
34
None
Molar placenta
100,048
IUI CC/hCG
Live birth at 34 weeks TOP Spontaneous abortion TOP Spontaneous abortion
46,XX
PTD Molar Karyotype Fetal Karyotype Outcome Type of Pregnancy US Findings
b-hCG at Diagnosis (mIU/mL) Presenting Symptom At TOP At Diagnosis Maternal Age (years)
Gestational Age (weeks1days)
TABLE 1 Clinical Features, Sonographic Findings, and Karyotypes of Pregnancies with Mole and Coexisting Fetus(es)
Subsequent Pregnancy
KUTUK ET AL
quadruplet pregnancy. Due to the patient’s reluctance to use methotrexate therapy, she was treated with hysterectomy. The mean 6 SD time for b-hCG clearance was 3.7 6 0.5 weeks (median: 4; range: 3–4) in the six patients without PTD. Two patients had successful, uncomplicated pregnancies following CHMCF and gave birth to term, healthy neonates. Clinical presentations, US findings, laboratory results, and perinatal outcome of the seven patients are summarized in Table 1.
DISCUSSION
Multiple pregnancies consisting of a CHMCF represent a very rare entity. Until recently, this condition was commonly diagnosed retrospectively after delivery by the inspection of placenta and generally managed by the gynecologic oncologists. Therefore, natural history and optimal management of these pregnancies have been poorly defined.6 With the widespread use of ovulation induction, and routine use of US in the follow-up of pregnancy, the incidence of CHMCF is expected to increase. In clinical practice, the main issue in the evaluation of molar placenta and living fetus is to differentiate between the following conditions: (1) singleton pregnancy consisting of a partial hydatidiform mole with a fetus; (2) a twin gestation consisting of a CHM along with a coexisting live fetus; (3) a twin gestation consisting of partial mole and twin in one sac and a normal twin in the other; and (4) mesenchymal dysplasia.1,5 Practically, the most challenging problem is to differentiate CHMCF from a partial mole. In CHMCF, the fetus has a normal karyotype and generally has no major malformation. The placenta consists of two components: normal villous/vascular placenta with normal karyotype identical to that of the fetus and a molar component, which has usually paternal diploid chromosome constituents. In partial mole, the fetus has abnormal triploid karyotype, structural malformation, oligohydramnios, and intrauterine growth restriction that usually precede fetal demise. For definitive diagnosis, chorionic villus sampling of molar tissue can be performed, and absence of maternal alleles confirms a diandrogenic complete mole. In our series, karyotype analysis was performed in all fetuses and revealed normal karyotype. Karyotype analysis of molar tissues showed sex chromosome discordance in three fetuses. DNA fingerprinting analysis was performed only in JOURNAL OF CLINICAL ULTRASOUND
PREGNANCIES WITH COEXISTING HYDATIDIFORM MOLE
two cases and confirmed paternal origin of the molar chromosomes. Although chromosomal triploidy is diagnostic of a partial mole, a diploid karyotype that is typical of a complete mole has rarely been described in partial moles.7,8 Thus, the final diagnosis in challenging cases requires elaborate cytogenetic studies to prove the androgenetic origin of the chromosomes.9 In our experience, the typical US depiction of the molar mass adjacent to the normal-looking placenta with a structurally normal fetus has always been diagnostic of CHMCF. Of note, in our experience, the most important condition that posed a challenge for the diagnosis of CHMCF was mesenchymal dysplasia. Mesenchymal dysplasia is characterized by enlarged cystic placenta and is usually associated with abnormal screening test results, intrauterine growth restriction, and even fetal demise.10 US findings in mesenchymal dysplasia may be similar to CHCMF, especially when the dysplastic changes are distributed nonhomogenously throughout the placenta. In difficult cases, the differential diagnosis can be made with cytogenetic analysis, measurement of b-hCG levels, and pathologic examination of the placenta. In CHMCF cases, unless affected by sporadic anomalies, the fetus is usually healthy. Therefore, continuation of pregnancy can be a reasonable option as long as serious maternal complications do not develop. However, many severe pregnancy complications, such as intrauterine fetal death, pre-eclampsia, thyrotoxicosis, antepartum hemorrhage, and PTD, are frequently associated with a CHMCF. Management of such pregnancies is largely based on the severity of the symptoms, and the gestational age at which complications occur.5 Pre-eclampsia, which affects 6% of CHMCF cases, is especially indicative of a poor outcome, and early onset of pre-eclampsia is an indication for TOP.11 Recently, Kihara et al suggested that pre-eclampsia was the major determinant of the poor fetal outcome because no babies from preeclamptic women survived in their series.12 In our series, only one woman had severe preeclampsia at 33 weeks and gave birth to a preterm, healthy neonate at the 34th week. As six of our cases ended up with miscarriage or TOP before the third trimester, it is not possible to evaluate the prevalence of pre-eclampsia in CHMCF in our series. In molar pregnancies, a variety of symptoms can be seen as a consequence of stimulation of target tissues by b-hCG. Bilateral enlarged multicystic ovaries, due to theca lutein cyst, are VOL. 42, NO. 8, OCTOBER 2014
reported in about one-fourth of the cases from the end of the first trimester.13 In our series, theca lutein cysts were found in only one case, caused no symptoms, and regressed at 2 months postpartum. A case of theca lutein cysts due to CHMCF complicated with ovarian torsion has been reported previously.6 In two of our seven cases, thyrotoxicosis developed in early pregnancy without any complications. Similarly, Lee et al reported that four of their six cases developed thyrotoxicosis in early pregnancy, and one patient successfully continued pregnancy until term with a live-born neonate.6 Spontaneous abortion and intrauterine fetal demise are also very common with a CHMCF, particularly before the third trimester. Sebire et al reported 23 spontaneous second-trimester miscarriages among 53 CHMCF pregnancies (43%).11 In our series, four (57%) pregnancies resulted in a miscarriage between 11 and 21 weeks. b-hCG is secreted by the syncytiotrophoblast and can be detected in the maternal blood and urine approximately 8–10 days after fertilization. The concentration of the b-hCG dimer in maternal blood rises rapidly during early pregnancy, peaks at 9–10 weeks’ and subsequently declines to nadir at approximately the 20th week. The serum b-hCG level can be a helpful marker in the diagnosis and follow-up of the patients with CHMCF. However, its role in determining the prognosis and outcome of these patients is not proven. Lee et al showed that decreasing b-hCG levels was associated with fetal survival in one of their cases.6 In contrast, Montes-de-Oca-Valero et al reported a healthy neonate delivered at 28 weeks, despite the increasing b-hCG titers, and molar mass.3 In our series, elevated b-hCG levels according to gestational age were shown in three cases (cases 4, 5, and 6 in Table 1). One of these (case 6) also had theca lutein cysts and thyrotoxicosis. Our limited data suggest that higher levels of b-hCG are predictive of b-hCG-mediated complications, rather than of the outcome of the pregnancy. One central issue regarding CHMCF pregnancy is the risk of PTD. In the earlier reports, the incidence of PTD has been reported to be 50–63%, and higher than in the case of a single molar pregnancy.13–15 However, in the largest series ever collected, Sebire et al reported that 19.5% of 77 patients with CHMCF had PTD.11 Nieman et al in their Danish collaborative study compared the complete diploid mole and CHMCF and reported that the risk of PTD after CHMCF is similar to that of after a singleton 469
KUTUK ET AL
molar pregnancy (25% versus 17%).16 The factors that predict the development of PTD after CHMCF are very important for prenatal counseling. In the two largest series, it was shown that there was no statistical difference between the risk of PTD in patients undergoing early elective TDP and in those who preferred to continue their pregnancy.11,15 Moreover, neither the severity of clinical symptoms nor the b-hCG levels have consistent predictive values in determining whether PTD develops after CHMCF. Therefore, PTD that complicates CHMCF may develop irrespective of the time at which pregnancy is interrupted, and even when intervention occurs in early pregnancy, the risk of malignancy persists. In our series, PTD developed only in one pregnancy, which was quadruplet. Obviously, CHM in a quadruplet pregnancy is extremely rare, with only four cases have been reported in the literature.17–20 Therefore, it is hard to elucidate the natural behavior, perinatal outcome, and malignant potential of triplet and quadruplet pregnancies with CHM. In their review, Takagi et al reported that 6 of 13 cases (46%) with triplet pregnancies with complete mole had PTD and pointed to an increased risk for PTD.21 Moreover, pregnancies with triplets or quadruplets naturally carry an increased risk of preterm labor and pre-eclampsia. According to the literature, the chance of positive outcome in triplet pregnancies with complete mole is 22.5%, and not severely impaired when compared with twin pregnancies.16,21–23 However, with an accompanying mole, the longest reported gestational age in quadruplet pregnancy is 25 weeks, and no case with a surviving child has been reported.16,19 The mean time for the b-hCG to return to nonpregnant level was 3.5 weeks in our patients who did not develop PTD. In contrast to our results, Lee et al and Vaisbuch et al reported that the mean time for b-hCG to return to normal was about 13 weeks in patients with CHMCF uncomplicated with PTD.4,6 According to the literature, the mean times for the clearance of b-hCG after the second-trimester TOP and evacuation of molar pregnancy are 4 weeks and 9 weeks, respectively.24,25 As a result, our data show that the clearance pattern of b-hCG after the TOP in CHMCF is similar to that seen in secondtrimester TOP. Sebire et al assessed 77 twin pregnancies with a CHMCF. Of 53 patients who continued pregnancy, 20 gave birth to a live-born neo470
nate.11 Although pregnancy complications are not uncommon with a CHMCF, about 40 cases of viable fetuses have been reported so far. Based on our data and previous literature,11,26,27 we can speculate that the actual chance of delivering a viable fetus in CHMCF may be increased by simply providing appropriate prenatal counseling. In conclusion, we suggest that, in a pregnancy with CHMCF but without severe preeclampsia and bleeding, pregnancy may be continued under close surveillance.
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PREGNANCIES WITH COEXISTING HYDATIDIFORM MOLE 12. Kihara M, Usui H, Tanaka H, et al. Complicating preeclampsia as a predictor of poor survival of the fetus in complete hydatidiform mole coexistent with twin fetus. J Reprod Med 2012;57:325. 13. Steller MA, Genest DR, Bernstein MR, et al. Natural history of twin pregnancy with complete hydatidiform mole and coexisting fetus. Obstet Gynecol 1994;83:35. 14. Fishman DA, Padilla LA, Keh P, et al. Management of twin pregnancies consisting of a complete hydatidiform mole and normal fetus. Obstet Gynecol 1998;91:546. 15. Matsui H, Sekiya S, Hando T, et al. Hydatidiform mole coexistent with a twin live fetus: a national collaborative study in Japan. Hum Reprod 2000; 15:608. 16. Niemann I, Sunde L, Petersen LK. Evaluation of the risk of persistent trophoblastic disease after twin pregnancy with diploid hydatidiform mole and coexisting normal fetus. Am J Obstet Gynecol 2007;197:45. 17. Hoshi K, Morimura Y, Azuma C, et al. A case of quadruplet pregnancy containing complete mole and three fetuses. Am J Obstet Gynecol 1994;170: 1372. 18. Ibarg€ uengoitia F, Lira Plascencia J, Argueta ~ iga M, et al. [Multiple (quadruple) pregnancy Z un involving complete hydatidiform mole and 3 fetuses.] Ginecol Obstet Mex 1995;63:275. 19. Chao AS, Tsai TC, Soong YK. Clinical management of a quadruplet pregnancy combining a triplet pregnancy with a classical hydatidiform mole: case report and review of literature. Prenat Diagn 1999;19:1073. 20. Amano T, Takahashi K, Kita N, et al. A case of quadruplet pregnancy with a complete hydatidiform mole. Prenat Diagn 2005;25:718.
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21. Takagi K, Unno N, Hyodo HE, et al. Complete hydatidiform mole in a triplet pregnancy coexisting two viable fetuses: case report and review of the literature. J Obstet Gynaecol Res 2003;29:330. 22. Amr MF, Fisher RA, Foskett MA, et al. Triplet pregnancy with hydatidiform mole. Int J Gynecol Cancer 2000;10:76. 23. Bovicelli L, Ghi T, Pilu G, et al. Prenatal diagnosis of a complete mole coexisting with a dichorionic twin pregnancy: case report. Hum Reprod 2004;19: 1231. 24. Marrs RP, Kletzky OA, Howard WF, et al. Disappearance of human chorionic gonadotropin and resumption of ovulation following abortion. Am J Obstet Gynecol 1979;135:731. 25. Genest DR, LaBorde O, Berkowitz RS, et al. A clinicopathologic study of 153 cases of complete hydatidiform mole (1980–1990): histologic grade lacks prognostic significance. Obstet Gynecol 1991;78: 402. 26. Piura B, Rabinovich A, Hershkovitz R, et al. Twin pregnancy with a complete hydatidiform mole and surviving co-existent fetus. Arch Gynecol Obstet 2008;278:377. 27. Massardier J, Golfier F, Journet D, et al. 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 2009;143:84. 28. Moini A, Ahmadi F, Eslami B, et al. Dizygotic twin pregnancy with a complete hydatidiform mole and a coexisting viable fetus. Iran J Radiol 2011;8:249. 29. Vimercati A, de Gennaro AC, Cobuzzi I, et al. Two cases of complete hydatidiform mole and coexistent live fetus. J Prenat Med 2013;7:1.
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