Hydatidiform mole (HM) co-existing with a fetus is a rare entity with an estimated incidence of one in 22 000–100 000 pregnancies.1 Two main types exist on the basis of gross morphological, histological and cytogenetic criteria: complete hydatidiform mole (CHM) co-existing with fetus and partial hydatidiform mole (PHM) co-existing with fetus. The rarity of PHM is not entirely explained, but it is probably because the PHM leads to early miscarriage, accounting for an estimated 10%-20% early spontaneous abortion. The most common type of PHM with twin pregnancy is that one is a triploid fetus with PHM placenta and the other is a diploid fetus with a diploid placenta. The increasing proportions of pregnancies conceived following treatment using assisted reproductive technologies are one of the major etiologies for the increasing rates of twin pregnancies with HM. We present the case of PHM placental mosaicism coexisting dizygotic twins following in vitro fertilization and embryos transfer (IVF-ET). To the best of our knowledge, this is the first report of twin pregnancy complicated with mosaic PHM after IVF-ET, while survival two 46XY male infants.
The patient was a 32-year-old gravida 4 para 0 who conceived through IVF-ET. Three embryos were transferred to the uterus at 72 hours post egg collection and two embryos survived. Two weeks after ET, the result of the patient's urine human chorionic gonadotropin-beta subunit (β-hCG) test was positive. At 17 weeks' gestation, the patient consulted for intermittent vaginal bleeding in Beijing Obstetrics and Gynecology Hospital. Ultrasonographic assessment confirmed the presence of two living fetuses and no evident malformations was observed. At 22 weeks' gestation, two viable fetuses consistent with the age of gestation alongside two normal-looking placentas were observed. In addition, an echogenic mass resembling molar placenta, located at the right posterior uterine wall and very near the unremarkable placenta, was observed. A tentative diagnosis of the twin pregnancy with HM was made at this stage. After realizing the possible associated risks, the patient decided to continue the pregnancy and declined prenatal investigations to establish the fetal karyotypes. The patient was followed up weekly to detect the signs of gestational trophoblastic disease (GTD) and preeclampsia and ultrasound was carried out by the same transonic specialist at two week intervals. The patient presented to the emergency department with complaints of a vaginal watery discharge until the 30th gestational week. Except for vaginal fluid and a positive Actim® PROM test, physical examination revealed no significant findings. Serum β-hCG was 215 628 mIU/ml. Ultrasonography showed: (1) a dizygotic twin pregnancy, (2) honeycomb construction located in the right anus perineum of posterior placental wall, measured 15.9 cm × 15.2 cm × 19.1 cm, and the growth of fetus in the same amniotic cavity was less than expected; (3) the “normal” fetus matched the gestational age and was accompanied by a unremarkable placenta (Figures 1 and 2). Normal thyroid function and blood pressure were observed.
In the absence of an obvious structural abnormality, with the molar placenta growing slowly and the patient wanting to continue, we adopted a conservative therapy. To inhibit the uterine contraction, the patient was given an intravenous infusion of ritodrine in 5% dextrose at a rate of 100–350 μg/min until contractions ceased, with 50 μg/min increments every 10 minutes as required (350 μg/min maximum). When contractions ceased, the dose was decreased every 30 minutes by 50 μg/min steps. This was followed by 10 mg of ritodrine orally for 3 times a day. A 5 mg intramuscular injection dexamethasone every 12 hours (total 20 mg) was given to promote fetal lung maturity. To prevent infection 400 million units Penicillin in 250 ml of 5% glucose was prescribed and absolute bed rest was suggested. Ultrasound examination and serial measurement of serum β-hCG levels were performed every week. A continuous brown discharge presented for weeks and no obvious amniotic fluid draining was found. The PHM placenta did not significantly change, and maternal serum titres of β-hCG within the range of 23654 mIU/ml to 198 214 mIU/ml at the period of hospitalization.
Magnesium sulfate was applied to relieve spasms at 33 weeks' gestation, because the patient developed into severe preeclampsia. At 35 weeks' gestation, a low segment transverse CS was performed because of more amnionic fluid leakage and uterine contractions. A 2430-g normal male infant and a 1485-g hypospadia male infant were delivered. Both twins had normal Apgar scores and had uncomplicated neonatal courses. Details of chorioamniotic cavity with 1485g hypospadia male infant were listed as followed: (1) the amnionic fluid was kermesinus and the placenta was measured 24.0 cm ×17.0 cm ×4.5 cm; (2) The placenta was composed of normal tissue and the cystic mole. Approximately 1/3 of placenta appeared to have been invaded and merged by the HM, which measured 7 cm × 17 cm × 3 cm and filled with a diffuse cluster of vesicles of various sizes (0.5–2.0 cm); (3) There were two distinct populations of villi identified: large oedematous villi with central cisterns and trophoblast hyperplasia, and small villi that showed some degree of stromal fibrosis. (4) In gross examination, the molar tissue and normal placenta was located in the same chorioamniotic cavity. The umbilical cord was attached in the normal area of the placenta and was contained three blood vessels. The placenta of 2430 g male infant was unremarkable.
Microscopic examination of the twin placentas revealed that placental disc was dichorionic-diamniotic, with the excess trophoblast focal. At the time of delivery, chromosome analysis using standard cytogenetics and flow cytometry was completed to assess cord blood and amniotic cells. The extremely rare condition of the dizygotic twins is that the placenta of one single fertilized ovum is mosaicism, composed of two components- the major (2/3) component is normal tissue (46XY) and the minor (1/3) is partial hydatidiform mole tissue (69 XXY). The placental mosaicism co-existing with a normal diploid new-born (46XY) in the same chorioamniotic cavity. The other twin was a diploid fetus with normal placenta (46XY) in another chorioamniotic cavity.
The level of serum β-hCG demonstrated a steady fall and serum β-hCG remained normal (<7 mIU/ml) out to 6 months post delivery. The pelvic cavity chest X-ray were normal.
The patient was counseled not to get pregnant for at least 1 year and has remained normal with no sign of recurrence or molar invasion.
Molar pregnancy can be classified on the basis of gross morphological, histological and cytogenetic criteria as either CHM or PHM. Clinical manifestation of PHM coexistent with fetus is usually a PHM with an abnormal triploid fetus. The majority of PHM fetuses (93%) that survive are structurally abnormal.2 Possible maternal complications such as early-onset preeclampsia, hyperthyroidism, and persistent GTD rarely presented in PHM patients. The diagnosis of PHM is generally considered only after histologic review of the pathological specimens.
Some studies advocate that flow cytometry can be used to distinguish a CHM from a PHM. DNA polymorphism analysis to prove paternal origin of molar placenta. The positive immunoreactivity of p57KIP2 gene was in accord with PHM. Whereas, in the case of CHM, the immunoreactivity of p57KIP2 gene was absent.
A twin pregnancy with mosaic PHM and two viable twins after IVF-ET is a rare condition. In our case, the outcome (survival of two fetuses) was excellent compared with that reported previously. In this case, karyotyping analysis and flow cytometry can be used to confirm mosaic PHM placenta (triploid placenta + diploid placenta). Diagnosis of mosaicism can be challenging, since the triploid cells have usually been selected out from the peripheral white blood cells, the starting point for karyotype analysis. Karyotyping flow sorted amniotic cells will aid the diagnosis of mosaicism. In the case described above gross morphological, histological and cytogenetic criteria, that diploid fetus with normal placenta (46XY) attached to a mosaic partial hydatidiform mole placenta (69XXY) in one sac were used.
The exact mechanism of mosaic PHM after IVF-ET is not clear, but there might be an association between blastocyte transfer, the concentrations of inseminating spermatozoa per oocyte, prolonged in vitro culture and the transfer of multiple embryos in PHM patients who had undergone IVF-ET. Huang et al3 speculated that higher volume and pressure of culture medium injected into the uterus or the tilt-down position of the patient at the time of ET could be contributory factors for the development of HM.
The expectant treatment of a twin pregnancy with mosaic PHM is little mentioned. Without obvious fetus abnormity and mosaic PHM limited in little scope placenta, the mother diagnosed with PHM should be managed with expectant management, especially the patient previously infertile suddenly bear with PHM should be carefully selected. It is necessary to careful monitoring of serum β-hCG levels and regular ultrasound. Detailed examination followed by daily scrutiny for clinical findings such as headache, visual disturbances, epigastric pain, pulmonary edema, and rapid weight gain to prevent preeclampsia and heart failure. Frequent measurements of plasma or serum creatinine, hematocrit, platelets, serum liver enzymes, evaluation of fetal size and amnionic fluid volume either clinically or with sonography. And thyroid function test, C-reactive protein and cervical secretions were also needed to be performed as early as possible in pregnancy. Once serious hemorrhage loses more than menstrual blood volume, active treatment entails termination of pregnancy. Regardless of the methods of termination, overhaul placenta, histopathological analysis and close follow-up with serial β-hCG titers are essential for every patient because of the incidence of malignant diseases. The pathologic presentation of this case was dizygotic twins combined mosaic PHM placenta. Histopathological features were the stroma of mosaic PHM in well-preserved villi, which caused one fetus having IUGR and hypospadia in this case.
AUTHORS PERSONAL OPINIONS
The conservative management for patients with mosaic PHM was possible. Gynecologists should be aware of the development of HM after IVF-ET and close observation for signs of progression or metastatic gestational trophoblastic disease after delivery is required.
1. Niemann I, Sunde L, Petersen LK. Evaluation of the risk of persistent trophoblastic disease after twin pregnancy
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2. Jauniaux E. Ultrasound diagnosis and follow-up of gestational trophoblastic disease. Ultrasound Obstet Gynecol 1998; 11: 367-377.
3. Huang X, Wang H, Zhao X, Xu X, Chen Q. Gestational trophoblastic disease following in vitro fertilization. Arch Gynecol Obstet 2007; 275: 291-293.