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Obstetrics and Gynaecology Cases - Reviews





DOI: 10.23937/2377-9004/1410089



Aggressive Complete Hydatidiform Mole Coexistent With A Normal Fetus During Pregnancy: Is There A Correlation Between Outcome, and Serum HCG Levels? A Report on 2 Cases and Review of the Literature

Nathalie Renard1,2*, SWA Nij Bijvank2, JWB de Groot3, RHM Verheijen4, HH De Haan2, AJ Kruse5 and J van Eyck2


1Department of obstetrics and gynaecology, University Hospital Ghent, Belgium
2Department of obstetrics and gynaecology, Isala Clinic Zwolle, The Netherlands
3Department of oncology, Isala Clinic Zwolle, The Netherlands
4Department of gynaecologic oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, The Netherlands
5Department of gynaecologic oncology, Maastricht University Medical Center, The Netherlands


*Corresponding author: Nathalie Renard, Department of obstetrics and gynaecology, University Hospital Ghent De Pintelaan 185, 9000 Ghent, Belgium, Tel: +32499164439, E-mail: nathalie_renard@hotmail.com
Obstet Gynecol Cases Rev, OGCR-3-089, (Volume 3, Issue 3), Case Series; ISSN: 2377-9004
Received: February 24, 2016 | Accepted: May 20, 2016 | Published: June 01, 2016
Citation: Renard N, Nij Bijvank SWA, de Groot JWB, Verheijen RHM, De Haan HH, et al. (2016) Aggressive Complete Hydatidiform Mole Coexistent With A Normal Fetus During Pregnancy: Is There A Correlation Between Outcome, and Serum HCG Levels? A Report on 2 Cases and Review of the Literature. Obstet Gynecol Cases Rev 3:089. 10.23937/2377-9004/1410089
Copyright: © 2016 Renard N, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.



Abstract

Two cases of complete hydatidiform mole with coexisting fetus are described. In the first case, the mole of this twin pregnancy displayed an aggressive behavior with early maternal onset of severe pre-eclampsia and lung and liver metastases. The second patient opted for termination of pregnancy prior to a possible onset of complications. Existing literature on this topic is also reviewed, in particular on the role of serum hCG levels to predict a favourable fetal prognosis.

Importance: Because the combination of a viable fetus with a hydatidifom mole is a rare clinical entity, no specific guidelines are in place to help clinicians and patients confronted with this type of pregnancy.

Objective: We try to define a parameter which may be useful in counseling patients whether or not to continue their pregnancy.

Evidence acquisition: A literature search was performed in Pubmed using the search terms 'hydatidiform mole' AND 'twin' AND 'pre-eclampsia' OR 'chemotherapy'.

Results: We found a correlation between rising serum HCG in the second trimester, and fetal demise. This information can be taken into account when counseling a patient with complete hydatidiform mole with coexisting fetus as to whether or not to continue the pregnancy.

Relevance: For clinicians and patients confronted with a complete hydatidiform mole with coexistent fetus, the trend in serum HCG in the second trimester could be of great use in decision-making.


Keywords

Complete hydatidiform mole, Twin, Pre-eclampsia, Chemotherapy


Introduction

Complete hydatidiform mole coexisting with a normal fetus (CHMCF) occurs in 1/22000-1/100000 pregnancies [1]. This rare entity poses several diagnostic and management challenges. First of all, it is important to distinguish CHMCF from partial mole. CHMCF comprises two separate products of conception: a normal and theoretically viable fetus, and a complete mole. In a partial mole, molar changes occur in the placenta of a non-viable, mostly (but not always) [2] triploid fetus, that is often structurally abnormal. Due to the non-viable nature of the fetal component, a partial mole will always be evacuated after it has been diagnosed, but the management of CHMCF is not so clear-cut. A CHMCF poses a mother-versus-fetus dilemma, where the risks for the mother (excessive bleeding, pre-eclampsia, hyperthyroidism, and persistent gestational trophoblastic disease) have to be outweighed against the chance of a live birth. Previous case reports and case series have found an estimate chance of live birth of 40% [3], however all authors stress the importance of individualizing management, taking into account prognostic factors such as the development of pre-eclampsia, or massive bleeding.

In this paper, we describe two cases of complete hydatidiform mole with a coexisting fetus. In one case the molar component displayed an aggressive behaviour with lung and liver metastases and severe pre-eclampsia, in the other the patient opted for early termination of pregnancy. We also reviewed the existing literature on this topic, with particular interest in serum hCG rate of decrease as a predictor for good fetal prognosis.


Case 1

A 33-year-old G3P2 woman presented at 14+5 weeks gestation with a complaint of ongoing vaginal blood loss and spotting during this pregnancy. Previous ultrasounds performed by her local midwife were reported to be normal. It was a spontaneous pregnancy.

Her obstetrical history was uneventful with two previous spontaneous deliveries at term. Her medical history comprised a depression, treated several years earlier. Ultrasound evaluation revealed a normal fetus consistent with 15 weeks gestation. A vaginal culture appeared negative for pathogens, and a Pap-test did not show dysplasia.

Because the spotting did not subside, she consulted again at 16 weeks gestational age. At that time, a deviant aspect of the placenta was noted, with a multicystic, vesicular component, and the suspicion of trophoblastic disease arose.

Serum hCG (Cobas, Roche diagnostics, Mannheim, Germany) at that time was 593.000 mIU/ml (peak level in normal pregnancies: 100000 mIU/ml at 10th week of gestation) [4].

Further ultrasound confirmed the molar changes (Figure 1). The molar component continued to grow, the serum hCG rose, and fundal height was too high for gestational age. Thyroid function tests were repeatedly performed and remained normal. At 19 weeks gestational age, the coexistent fetus did not show structural abnormalities or growth restriction at ultrasonography. An amniocentesis was performed to exclude lethal chromosomal abnormalities, and revealed a normal fetal karyotype (46, XY). All these findings strongly suggested that this pregnancy was indeed a twin pregnancy comprising a complete hydatidiform mole and a normal coexisting fetus. The patient and her partner were counseled regarding risks and outcome of this type of pregnancy and chose to continue the pregnancy. She remained under close surveillance in our center. Serum hCG was repeatedly measured, and continued to rise (Figure 2).


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Figure 1: Ultrasound image of patient 1 at gestational age 19 weeks, showing fetal thorax next to molar mass. View Figure 1



.




.
Figure 2: Serum hCG curve, showing a steep fall after termination of pregnancy. View Figure 2



.




However, at 21+4 weeks gestation, the mother became increasingly dyspnoeic. A chest X-ray suggested multiple lung metastases (Figure 3). This was confirmed on a CT-scan of the thorax, that was performed to differentiate the lesions shown on chest X-ray from benign granulomas. A CT-scan of the brain revealed no metastatic lesions, a CT of the abdomen showed one lesion in the liver suggestive for a mestastasis. Serum hCG by that time had risen to 1.060.000 mIU/ml (Figure 2). According to the FIGO classification, she had a high risk Gestational Trophoblastic Neoplasia (GTN) stage IV, with a WHO prognostic score of 14 [5].


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Figure 3: Chest X-ray showing multiple lung metastases (arrows). View Figure 3



.




At this point, the couple was counseled about the recommendation to terminate the pregnancy and to start multi-agent chemotherapy [6], but they sincerely wished to continue the pregnancy until a viable newborn could be delivered.

The patient started polychemotherapy, with Bleomycine, Etoposide, Cisplatinum (BEP) since the more commonly used Etoposide, Methotrexate, Actinomycin D, Cyclophosphamide and Vincristine - regimen (EMA/CO-regimen) would be harmful for the coexistent fetus. However, before clinical response could be evaluated, one week following the start of chemotherapy, she developed severe pre-eclampsia with HELLP-syndrome at 22 weeks and 6 days of gestational age, necessitating immediate termination of pregnancy.

Since the risk of massive intrapartum hemorrhage seemed high, the patient decided to have a primary hysterectomy after counselling.

Vascular sheets were placed in the internal iliac artery bilaterally prior to the procedure, and inflated during surgery. Under general anesthesia, a hysterectomy was performed where both fetus and mole were left in utero. Both ovaries were significantly enlarged with theca lutein cysts and also bled easily during manipulation, and thus needed to be subsequently removed (Figure 4). A male fetus of 570 grams was delivered from the excised uterus, with no apparent structural abnormalities, who died postpartum due to immaturity.


.
Figure 4: Per-operative photograph of enlarged uterus and ovaries. View Figure 4



.




After surgery, the patient was switched to the EMA/CO chemotherapy regimen [6,7], with clinical improvement. HCG levels fell steadily and returned to normal after 4 cycles of EMA/CO. After 7 cycles of EMA/CO a CT-scan showed a complete remission. One year after completion of treatment there is no evidence of disease recurrence. Pathologic investigation with p57 staining of the hysterectomy specimen confirmed the diagnosis of invasive complete mole (see figure 5 for a macroscopic image of the complete mole).


.
Figure 5: Pathology photograph of the placenta, showing the typical vesicular, grape-like lesions of a hydatidiform mole. View Figure 5



.




Case 2

A 38-year old G8P7 patient was referred to our center for suspicion of a molar pregnancy on ultrasound investigation. She was 13+4 weeks along her 8th pregnancy, and experienced no bothersome symptoms other than some minimal vaginal blood loss. Her previous medical and surgical history was uneventful. The pregnancy was spontaneous. Prior ultrasound investigations were suggestive for a vanishing twin. In our center, ultrasound investigation demonstrated a vital intrauterine singleton in combination with a molar pregnancy (Figure 6).


.
Figure 6: Ultrasound image of patient 2 during the 14th week of gestation, showing a structurally normal fetus alongside a molar mass. View Figure 6



.




Serum HCG level at the time of admission was 611.000 mIU/ml. Her lab results showed hyperthyroidism, treatment was started with Thiamazol and Propranolol.

Her chest X-ray was normal, and an ultrasound scan and MRI of the liver showed no metastatic lesions. Given the very suggestive sonographic findings, biopsy was not performed.

The patient and her partner were counseled about the different options, and chose termination of pregnancy by means of abdominal hysterectomy.

Pathologic examination of the hysterectomy specimen confirmed a complete, non-invasive mole, with a concomitant normal fetus without any gross pathological abnormalities.

Postoperative hCG-levels fell rapidly. HCG two weeks post-operatively was 821 mIU/mL, 6 weeks postoperatively 4.1 mIU/ml. Hyperthyroidism subsided.


Literature Search, Materials and Methods

A literature search was performed in Pubmed using the search terms 'hydatidiform mole' AND 'twin' AND 'pre-eclampsia' OR 'chemotherapy'. This led to 55 eligible articles. Of this list, papers were selected on the basis of title and abstract. Reference lists of selected articles were searched manually to retrieve additional articles that might be of interest to our current study. The distinction between complete and partial mole was made only in the year 1977 [8,9]. Therefore, we only considered literature from 1977, until March 2016.

Statistical analysis was performed using JMP 12 (SAS Institute Inc., Cary, NC, USA). A Fisher's exact test was performed to analyze the correlation between hCG-trend in the second trimester, and fetal outcome.


Discussion and Review of the Literature

Although CHMCF remains a rare entity, with a cited incidence of 1/22000-1/100000 pregnancies [1], we found numerous case reports and case series describing this exceptional type of twin pregnancy. However, due to the small numbers, management guidelines are not yet defined. Treatment is suggested to be individualized for each single patient.

Before counseling the patient, a definite diagnosis of CHMCF is needed. A clinical suspicion of CHMCF may arise due to ultrasound findings, namely a cystic multilocular component of the placenta. Differential diagnosis of these findings include partial hydatidiform mole, molar degeneration of a normal placenta following spontaneous abortion [10], placental hematomas, focal hydropic placental changes, chorioangioma [11], mesenchymal dysplasia [2] or even a partially necrotic leiomyoma [12].

While the latter entities may be very rare, it is important to distinguish the former, namely partial hydatidiform mole, from CHMCF, due to the non-viable nature of the fetus in partial mole. When suspecting CHMCF, an amniocentesis should be performed to ensure a normal fetal karyotype (although non-triploid partial moles and confined mosaicism are well known pitfalls [2]). Besides, structural ultrasound is indicated to exclude fetal abnormalities, and if possible cytogenetic or immunohistochemical analysis of the molar component is performed to confirm its androgenetic origin [13-15]. If the pregnancy is indeed found to be a partial hydatidiform mole, termination of pregnancy (TOP) and evacuation of the mole should be advised. However, if by these investigations the diagnosis of CHMCF is confirmed, the patient should be counseled about the risks of continuing the pregnancy versus the chance of delivering a healthy neonate.

Large case series [3,11,16-18] have found an estimated chance of 21% [18] to 40% [3] of delivering a live infant. This chance may possibly be underestimated, because a significant portion of CHMCF pregnancies may be terminated early upon diagnosis, but might have led to the birth of a live neonate if continued.

Several authors [11,19,20] suggest that when less aggressive trophoblast is noted (i.e. decreasing size of the molar component, falling serum hCG-levels in the second trimester, uterine size that is not abnormally large for dates) chances for a successful outcome of the pregnancy, are increased.

In this perspective, Marcorelles et al. [19] suggest two types of CHMCF pregnancy: one in which the molar part becomes quiescent and even necrotic, with successful outcome, and one where the molar part grows extensively, leading to severe maternal complications and often fetal demise.

If this theory would be true, prediction of a favourable or non-favourable outcome might be provided by hCG course. We therefore decided to investigate the trend in serum hCG-levels in relation to fetal outcome. So far, we found a total of 91 live babies born after a CHMCF pregnancy described in the literature (see Table 1 for reviewed articles [2,3,10,11,16-55]). The trend in serum hCG-levels (rather than absolute numbers, since not all authors employ the same measurement units and/or measurement assays) could be correlated with fetal outcome (Table 2).



Table 1: Reviewed articles of CHMCF pregnancies. View Table 1



Table 2: Correlation of trend in serum HCG, and fetal outcome. View Table 2


This correlation was analyzed by a Fisher's exact test, resulting in a p-value of 0.0007, indicating that there is indeed a correlation between hCG-trend in the second trimester, and fetal outcome.

Limitations of our study are: a small sample size, a binary rather than continuous exposure variable, and a non-systematic literature review.

More questions need to be answered before this correlation can be translated into a definite, clear-cut guideline: at what gestational age exactly should serum hCG-levels start to decrease? Can a cutoff value be defined of hCG-level at a certain gestational age?

The chance of live birth must be outweighed against the risks for the mother, notably the development of severe bleeding, hyperthyroidism and thyroid crisis, pre-eclampsia, and post-molar Gestational Trophoblastic Neoplasia (GTN).

Previous case reports and case series have found a risk of GTN of 19-57% [3,16,17,28], which is more than after a singleton molar pregnancy.

Although the risk of developing GTN is reported to be higher in CHMCF than in singleton mole pregnancy in some series (18-57%) [11,21], the largest case series reported by Sebire et al. [3] found that the risk of GTN was equal to that in singleton moles.

Interestingly, the risk of developing GTN does not seem to increase with increasing gestational age [17]. This warrants a conservative approach in CHMCF pregnancy if there are no other indications for immediate termination. Conversely, this also means that a rigorous follow-up should be pursued also in those cases that chose early TOP.

Also a higher incidence of severe maternal complications is observed in patients who subsequently developed GTN [17]. The risk of developing GTN and other maternal complications such as pre-eclampsia is theoretically higher in those CHMCF pregnancies with rising serum hCG in the second trimester [2,33].

Absolute indications for TOP are: thyroid crisis, evidence of trophoblastic metastases, pre-eclampsia, life-threatening vaginal bleeding, and severe hyperemesis gravidarum [11,33].

Relative indications for TOP are a fundal height that is too high for dates [24], and a serum hCG that does not fall in the second trimester [11,42,44,45] .

If the patient chooses to continue CHMCF pregnancy, a thorough search for metastatic disease should be initiated and repeated serially [26], and she should be monitored closely for signs and symptoms of hyperthyroidism, pre-eclampsia, vaginal bleeding, excessive molar growth and uterine expansion, and trophoblastic metastases.

Ultrasound and serum hCG-levels should be checked on a regular basis [36].

The patient described by us in the first case developed pulmonary and liver metastases at 21 weeks gestational age, indicating indeed the aggressive nature of this mole. She was very adamant about her wish to continue the pregnancy, thus when the need for chemotherapy arose with the occurrence of metastatic disease, she was started on BEP since the more commonly used EMA/CO-regimen is teratogenic.

Despite the fact that she started with chemotherapy, she developed severe pre-eclampsia and HELLP-syndrome, and TOP could no longer be postponed.

After TOP, the signs and symptoms of the pre-eclampsia subsided and serum hCG-levels started to fall. Subsequently, chemotherapy was switched to EMA/CO, according to management guidelines [6], resulting in complete biochemical and radiological remission.

In retrospect, the rising serum hCG-level in the second trimester might have been indicative of poor fetal prognosis, and she could have been counseled towards earlier TOP with fewer consequences.


Conclusion

We found a correlation between serum hCG trend in the second trimester, and fetal outcome, albeit based on a small number of observations. We would like to encourage future authors of CHMCF case reporting to adjoin serum hCG trends in their articles, to add to the small body of evidence of this observation and to be able to formulate definite management guidelines for CHMCF pregnancies. The first case report also demonstrates several ominous findings that were associated with fetal demise, namely a fundal height that is too large for gestational age, an ongoing growth of the molar component and the development of theca lutein cysts and pre-eclampsia.

These two cases once again underline the difficult mother-versus-fetus dilemma that arises in CHMCF pregnancy, and tries to deliver suggestions for management based on previous experiences described in the literature for patients and clinicians who are confronted with this very rare type of pregnancy.


Contribution to Authorship

Nathalie Renard: Conception and writing of the article, literature search, acquisition of data, analysis and interpretation of data.

Nij Bijvank, de Groot, De Haan and Verheijen: Revision of the article.

Van Eyck: Revision of the article, and final approval of the version to be published.


Details of Ethics Approval

Both our patient have given approval for publication of this article with the images included.


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Journal of Dermatology Research and Therapy (ISSN: 2469-5750)
International Journal of Diabetes and Clinical Research (ISSN: 2377-3634)
Journal of Family Medicine and Disease Prevention (ISSN: 2469-5793)
Journal of Genetics and Genome Research (ISSN: 2378-3648)
Journal of Geriatric Medicine and Gerontology (ISSN: 2469-5858)
International Journal of Immunology and Immunotherapy (ISSN: 2378-3672)
International Journal of Medical Nano Research (ISSN: 2378-3664)
International Journal of Neurology and Neurotherapy (ISSN: 2378-3001)
International Archives of Nursing and Health Care (ISSN: 2469-5823)
International Journal of Ophthalmology and Clinical Research (ISSN: 2378-346X)
International Journal of Oral and Dental Health (ISSN: 2469-5734)
International Journal of Pathology and Clinical Research (ISSN: 2469-5807)
International Journal of Pediatric Research (ISSN: 2469-5769)
International Journal of Respiratory and Pulmonary Medicine (ISSN: 2378-3516)
Journal of Rheumatic Diseases and Treatment (ISSN: 2469-5726)
International Journal of Sports and Exercise Medicine (ISSN: 2469-5718)
International Journal of Stem Cell Research & Therapy (ISSN: 2469-570X)
International Journal of Surgery Research and Practice (ISSN: 2378-3397)
Trauma Cases and Reviews (ISSN: 2469-5777)
International Archives of Urology and Complications (ISSN: 2469-5742)
International Journal of Virology and AIDS (ISSN: 2469-567X)
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