5

Clinical presentation and management

of molar pregnancy

Shigeru Sasaki* MD, PhD

Associate Professor

Department of Obstetrics and Gynecology, Tama-Nagayama Hospital, Nippon Medical School, 1-7-1,

Nagayama, Tama City, Tokyo 206-8512, Japan

We can now detect molar pregnancy at a much earlier gestational age than before by using highresolution vaginal ultrasonography. As a result, the current clinical presentation of completehydatidiform moles has clearly changed compared to that of the classic type of mole. Thediagnosis of molar pregnancy is nearly always made by ultrasonography. Ultrasonography doesnot, however, always lead to diagnosis in the very early stages of gestation, before the chorionicvilli have attained the characteristic vesicular pattern. Therefore, a histopathological examinationof the products of conception should be required in all such cases. Hydatidiform moles should betreated by evacuating the uterus surgically as soon as possible after diagnosis. The patients mustbe followed up until their serial weekly serum human chorionic gonadotrophin (hCG) titre hasfallen to an undetectable level.

Key words: clinical presentation; hydatidiform mole; management of molar pregnancy.

CLINICAL PRESENTATION OF HYDATIDIFORM MOLE

The clinical presentation of complete hydatidiform moles (HMs) is well described inmost obstetrics and gynaecology textbooks.1,2 The classic presenting symptoms andfindings include vaginal bleeding, anaemia, excessive uterine enlargement, toxaemia ofpregnancy, hyperemesis gravidarum, hyperthyroidism, trophoblastic emboli and thecalutein cysts associated with remarkably elevated human chorionic gonadotrophin(hCG) titres.3 Since high resolution vaginal ultrasonography became available, clinicalevaluation in early pregnancy has changed markedly. We can detect a blighted ovum at amuch earlier gestational age than before, and almost all patients with molar pregnancyare diagnosed and treated before they develop the classic clinical presentation. As aresult, we now see far fewer patients with the classic clinical signs and symptoms ofmolar pregnancy in daily clinical practice.

Soto-Wright et al4 from the New England Trophoblastic Disease Centre reportedon 74 patients primarily managed at their centre from 1988 to 1993. According totheir report, the mean maternal age of patients with complete moles was 27.7 years

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(range 16–51) and the mean estimated gestational age at evaluation was 11.8 weeks(range 6–22). The mean uterine size at evaluation was 12.4 weeks (range 7–20) andthe mean level of pre-evacuation hCG was 345 415 mIU/ml (range 828–1 680 300).The most common presenting symptom was vaginal bleeding, occurring in 62 out of74 (84%) patients. Uterine size greater than that for the expected date wasobserved in 21 out of 74 (28%), anaemia in 4 out of 74 (4%), pre-eclampsia in 1(1.3%), hyperemesis in 6 (8%) and theca lutein cysts in 6 out of 69 (9%). Seven cases(9%) were asymptomatic. They noted that the presence of excessive uterine size,anaemia, pre-eclampsia, hyperemesis and hyperthyroidism was significantly lesscommon among current patients than in past cases at their centre. Gemer et al5

from Israel have also reported the changing current clinical presentation of completemolar pregnancy in 41 patients. In their paper, the mean maternal age was 30.1years and the mean gestational age at evacuation was 10 weeks with a range of 7–14 weeks. The mean uterine size was compatible with 10 weeks’ gestation. Themean pre-evacuation b-hCG was 275 901 IU/l (range 2011–919 000). The mostcommon presenting symptom was vaginal bleeding, occurring in 24 out of 41 (58%)patients. Excessive uterine size was observed in 18 (44%), anaemia in 1 (2%) andhyperemesis in 1 (2%). No pre-eclampsia or hyperthyroidism were observed.Although vaginal bleeding was the most common presenting symptom, 17 out of the41 cases (41%) were asymptomatic. Furthermore, systemic manifestations such ashyperemesis, pre-eclampsia, clinical thyrotoxicosis and respiratory distress wereexceedingly rare in this study. All ovarian cysts were small and were diagnosed onlyby ultrasonography.

Lindholm and Flam6 from Sweden have reported on 75 patients with completemoles and 60 with partial moles. In the complete mole group, the mean gestational ageat the time of sonography was 12.4 weeks. Twelve patients had experienced nosymptoms. The three most commonly occurring symptoms were vaginal bleeding(77%), abdominal pain (23%) and hyperemesis (19%). Some of the patients experiencedseveral symptoms. Only one patient suffered from pre-eclampsia. The uterus wasconsidered to be larger than expected for a date in 20%, equal in size expected for datein 27% and smaller in 53%. In the partial mole group, the mean gestational age at thetime of sonography was 14.3 weeks. Vaginal bleeding was seen in 62% of the patients,abdominal pain in 15% and hyperemesis in 8%. As we can see from these reports, thecurrent clinical presentation of complete HMs has clearly changed compared to that ofthe classic type of mole. The clinical presentation of partial moles usually includes notypical symptoms. Rather, the signs and symptoms are those of incomplete abortion ormissed abortion.

Practice points

The current clinical presentation of hydatidiform mole includes:† vaginal bleeding† excessive uterine size† hyperemesis† abdominal pain† sometimes, presentation is asymptomatic

886 S. Sasaki

DIAGNOSIS OF MOLAR PREGNANCY

The diagnosis of molar pregnancy is nearly always made by ultrasonography becausethe chorionic villi of typical complete HMs proliferate diffusely with hydropic swellingand produce a characteristic vesicular sonographical pattern around the 11th week ofgestation or later.7 Abdominal ultrasonography brought about a kind of revolution inpelvic examinations when it was first introduced in this field about three decades ago.It clearly showed a ‘snow–storm’ pattern when applied to patients with completemoles. Since it was so impressive, many physicians may still today be under theimpression that moles show this classic sonographical pattern. Diagnostic imagingequipment, including computed tomography (CT) scans, magnetic resonance imaging(MRI) and ultrasonography, has made remarkable progress since then and is nowwidely used. In particular, today, vaginal ultrasonography, which is non-invasive, simpleand reliable, is an essential routine examination associated with manual pelvicexamination in the first trimester of pregnancy. It is no exaggeration to say that almostevery pelvic examination table has its own vaginal ultrasound machine, be it in anyhospital or private physician’s office in Japan. We can now point out to our patientsthe fetal heart beat at the end of the sixth week of gestation; if not, abnormalpregnancies are strongly indicated.

Many molar pregnancies present with vaginal bleeding and are therefore oftendiagnosed during evaluation for normal and/or threatened spontaneous abortion.

The latest high resolution ultrasonography can reveal a vesicular pattern ofcomplete moles instead of the snow storm pattern. Benson et al8 reported that themajority of first trimester complete moles demonstrated a typical sonographicalappearance of a complex, echogenic, intrauterine mass containing many small cysticspaces.

Ultrasonography does not, however, always lead to diagnosis in the very earlystages of gestation, before the chorionic villi have attained the characteristic vesicularpattern. Lindholm and Flam6 investigated what percentage of molar tissues aremissed in normal follow up after evacuation. Sonography was performed in 68patients with complete moles and the correct diagnosis had been suspected in 84%of these cases with the aid of sonography and/or macroscopy. In 53 patients withpartial moles, the correct diagnosis was suspected in only 30% of the cases. Theirconclusion was that if all the aborted materials in early pregnancy are not examinedby a pathologist, 16% of complete moles and 70% of partial moles will be missed infollow up. They concluded, especially as far as partial moles are concerned, thatdiagnosis was even more difficult to make with ultrasound and that this holds trueeven if examination is performed in the second trimester. Often there will be nosymptoms and this, together with non-specific sonographical images, will make adiagnosis of missed abortion likely. If small vesicles are observed in the abortedmaterial directly after evacuation with the naked eye, this supports a diagnosis ofHM. Lazarus et al9 reviewed the ultrasonographical reports and clinical data of 21cases of histologically diagnosed complete molar pregnancies with a mean gestationalage of 10.5 weeks at sonography. A diagnosis of molar pregnancy was madeprospectively on ultrasonography in 12 out of the 21 (57%), one on differentialdiagnosis and 8 cases were not diagnosed as molar pregnancy. Five out of the five(100%) molar pregnancies of 13 weeks or more were prospectively diagnosed, whileonly 8 cases out of 16 (50%) in earlier pregnancies were correctly diagnosedprospectively. Other diagnoses were spontaneous abortion, thickened endometriumand retained products of conception. No lutein cysts were identified prospectively.

Clinical presentation and management of molar pregnancy 887

They encountered a spectrum of unusual sonographical appearances of completemoles including an intrauterine anechoic fluid collection similar to a gestational sac, afluid collection with a complex echogenic mass similar to an oedematous placenta, aheterogeneously thickened endometrium and echogenic fluid–fluid levels with theendometrium. hCG levels were not always elevated in the first trimester. They alsoconcluded that it is not always possible to make a diagnosis of early molar pregnancyby ultrasonography and that, therefore, histological examination of specimensremains important.

Sebire et al10 reported that of the 155 cases of histologically confirmed complete orpartial HMs that they examined, only 53 (34%) were suspected as molessonographically. They concluded that although molar pregnancy may be suspected onroutine first-trimester ultrasound examination, the majority of cases are sonographi-cally diagnosed as missed miscarriage and/or anembryonic pregnancy in routinepractice, and that a histopathological examination of the products of conception isrequired in all such cases.

From these reports, it can be seen that the application of high resolutionultrasonography in early abnormal pregnancies does not always give us an exactdiagnosis. If the aborted material is not sent for microscopical examination, adequatefollow ups of these patients will not be performed. Histopathological examinationsshould always be done as far as possible and samples should be kept for DNA analysisfor a final diagnosis when histology can not differentiate molar pregnancy fromabortion. Genetic marker analysis is now quite useful and has become essential indiagnosis. Polymerase chain reaction may not only be rapid but also accurate inidentifying and classifying complete and partial HMs.

Another important characteristic of molar pregnancy is its ability to produce hCGdue to trophoblastic proliferation. Without doubt, serum quantitative hCG providesvery important information for deciding on the likelihood of a molar pregnancy.Romero et al11 reported that serum hCG levels of greater than 92 000 mIU/mlassociated with absent fetal heart beat indicate a diagnosis of complete hydatidiformmoles. However, Lazaras et al9 reported that there was no association betweenelevated b-hCG and the correct diagnosis of moles in either the prospective orretrospective review of their cases in early gestation. Serum hCG, on the other hand,should be examined consecutively when abnormal pregnancies are suspected throughultrasonography.

hCG level decreases quickly if the patient has an abortion, but it does not in molarpregnancy. The measurement of serum hCG is definitely an important tool in reachinga diagnosis of molar pregnancy.

Practice points

The diagnosis of hydatidiform moles is established by:† history† clinical examination† ultrasound examination† serum hCG levels† histopathological examination† cytogenetic and molecular biological examination

888 S. Sasaki

MANAGEMENT OF HYDATIDIFORM MOLES

Evacuation

HMs should be treated by evacuating the uterus surgically as soon as possible afterdiagnosis. Evacuation should be done by suction curettage with oxytocin orprostaglandin infusion. In our protocol (Figure 1)12, a second evacuation is doneroutinely 1 week after the first evacuation to ensure no residual molar tissue in theuterine cavity. When evacuation is not carried out by an expert, as is sometimes thecase, a persistently raised hCG level can occasionally be seen in the residual. From thispoint of view, the second evacuation is effective not only to protect against this risk, butalso to educate non-experts. Although hysterectomy does not prevent trophoblasticsequelae, it may be performed with the mole in situ if the patient desires surgicalsterilization. Chest X-rays are also used routinely to rule out pulmonary lesions. Partialmoles should be treated and followed up in the same manner, because it is now wellknown that partial moles also develop trophoblastic sequelae.13,14

Management post-evacuation

Patients must be followed up until their serial weekly serum hCG titre has fallen toundetectable levels. Soto-Wright et al4 found in their study that pre-evacuation serumhCG levels of greater than 200 000 mIU/ml were significantly associated with thedevelopment of persistent gestational trophoblastic diseases. In Japan we have our ownhCG regression curve post-evacuation calculated from collected data (Figure 2).15 Thecollected data show that the hCG titre generally falls to below 1000 mIU/ml within 5weeks of the first evacuation in spontaneous resolution. Most of the patients whosehCG titres are more than 1000 mIU/ml at the 5th week after the first evacuation suffersubsequently from persistent trophoblastic disease. In more than 90% of

If patient desires

Hysterectomy First time evacuation

Second time evacuation

Weekly serum hCG

Spontaneousresolution

Persistenttrophoblastic disease

hCG regression curve post-evacuation

Second follow-up Treatment

MOLE

Figure 1. Algorithm for the management of hydatidiform moles. hCG, human chorionic gonadotrophin.

Clinical presentation and management of molar pregnancy 889

the spontaneous resolution cases, their hCG titres decreased to under 100 mIU/ml atthe 8th week. In some patients with persistent trophoblastic disease, their hCG titresdecreased at one point to undetectable levels and then rose again by the 20th week.These findings indicate that the hCG titres at the 5th, 8th and 20th weeks after the firstevacuation are crucial for predicting persistent trophoblastic disease. From theseobservations, we conclude that when the serial hCG titre is always below thisdiscrimination line and reaches an undetectable level by the 20th week, resolution isspontaneous. If the hCG titre shows a plateau for 3 weeks or rises for 2 weeks and thencrosses this discrimination line at any point during the follow up as far as the 20th week,trophoblastic sequelae, i.e. persistent trophoblastic disease, arise in the patient.Recently, an international consensus has been reached that it is acceptable to wait toobserve hCG regression to undetectable levels for up to 6 months (24 weeks) aftermolar evacuation (data from the IXth World Congress on Gestational TrophoblasticDiseases, Jerusalem, 1998 and the Xth World Congress on Gestational TrophoblasticDiseases, Tbilishi, 2000).

Management of spontaneous resolution

After spontaneous resolution, the patient is subsequently seen monthly for 6 months,then at 3-monthly intervals for a further 2 years and then at least once a year for as longas possible for the early detection of any recurrence of gestational trophoblastic diseaseand to ensure that hCG levels remain undetectable. If patients want to conceive, theyare generally advised not to become pregnant again until after the first 6 months offollow up and are given reliable contraception, preferably in the form of the pill.

Oral contraceptives do not appear to increase the risk of post-molar trophoblastictumours and may, therefore, be safely prescribed after molar evacuation during the entireinterval of hCG monitoring.16 A Gynecologic Oncology Group (GOG) study17 also

20 weeks

1st evacuation

106

105

104

103

102

0.5

2nd evacuation

hCG

(m

IU/m

l)

5 8

Figure 2. Serum human chorionic gonadotrophin (hCG) level regression curve post-evacuation(discrimination line). Reprinted, with permission, from The Japan Society of Obstetrics and Gynecology andthe Japanese Pathological Society15, p. 12.

890 S. Sasaki

supported the idea that oral contraceptives are the preferred method of contraceptionafter evacuation of HMs, while the Charing Cross group recommended the use of oralcontraceptives after biochemical remission.18 Palmer19 reported that the relative risk ofpersistent gestational trophoblastic tumours was increased by long-term oral contra-ceptive use before conception, although his finding was not statistically significant.Further study is needed on this point.

SUMMARY

Blighted ova can be detected at a much earlier gestational age than before and almostall patients with molar pregnancy are diagnosed and treated before they develop theclassic clinical presentation. As a result, the current clinical presentation of completehydatidiform moles (HMs) has clearly changed compared to that of the classic type ofmole. The clinical presentation of partial moles usually includes no typical symptoms.Rather, the signs and symptoms are those of incomplete abortion or missedabortion.

The latest high resolution ultrasonography can reveal a vesicular pattern of completemoles instead of the snow storm pattern. Ultrasonography does not, however, alwayslead to diagnosis in the very early stages of gestation, before the chorionic villi haveattained the characteristic vesicular pattern. If all the aborted materials in earlypregnancy are not examined by a pathologist, 16% of complete moles and 70% of partialmoles will be missed in follow up. Histopathological examinations should always bedone as far as possible. Samples should be kept for DNA analysis for a final diagnosiswhen histology cannot differentiate molar pregnancy from abortion. The measurementof serum human chorionic gonadotrophin (hCG) is definitely an important tool forreaching a diagnosis of molar pregnancy.

HMs should be treated by evacuating the uterus surgically as soon as possible afterdiagnosis. The patients must be followed up until their serial weekly serum hCG titrehas fallen to undetectable levels. In cases where the serial hCG reaches an undetectablelevel by the 24th week after molar evacuation, resolution is spontaneous. Patients aregenerally advised not to become pregnant again until after the first 6 months of followup and are given reliable contraception, preferably in the form of the pill.

Practice points

Required investigations for patients with hydatidiform moles include:† clinical examination† chest X-ray† blood cell count with platelet, blood urea nitrogen (BUN), creatinine and liver

function tests on admission† blood group† thyroid function tests if necessary† Prothrombin time (PT), partial thromboplastin time(PTT), prothrombin and

fibrinogen, if clinically indicated† serum human chorionic gonadotrophin (hCG) immunoassay: a specimen of

serum for hCG should be obtained prior to and one day after the evacuation† digital oximetry, blood gases and lung scan if necessary

Clinical presentation and management of molar pregnancy 891

REFERENCES

1. Berkowitz RS & Goldstein DP. Gestational trophoblastic disease. In Breck JS, Adashi EY & Hillard PA (eds)Novak’s Gynecology, 12th edn. Baltimore: Williams & Wilkins, 1996, pp 1261–1282.

2. Cunningham FG, Gant NF, Leveno KJ et al. Gestational trophoblastic disease, In Williams Obstetrics, 21stedn. New York: McGraw-Hill, 2001. pp. 835–849.

3. Goldstein DP & Berkowitz RS. Gestational Trophoblastic Neoplasms, Clinical Principles of Diagnosis andManagement. Major Problems in Obstetrics and Gynecology, vol. 14. Philadelphia: W.B. Saunders Co, 1982.pp. 145–154.

* 4. Soto-Wright V, Bernstein M, Goldstein DP & Berkowitz RS. The changing clinical presentation ofcomplete molar pregnancy. Obstetrics and Gynecology 1995; 86: 775–779.

* 5. Gemer O, Segal S, Kopmar A & Sassoon E. The current clinical presentation of complete molar pregnancy.Archives of Gynecology and Obstetrics 2000; 264: 33–34.

* 6. Lindholm H & Flam F. The diagnosis of molar pregnancy by sonography and gross morphology. ActaObstetricia et Gynecologica Scandinavica 1999; 78: 6–9.

* 7. Jauniaux E & Nicholaides KH. Early ultrasound diagnosis and follow-up of molar pregnancy. Ultrasound inObstetrics and Gynecology 1997; 9: 17–21.

* 8. Benson CB, Genest DR, Bernstein MR et al. Sonographic appearance of first trimester completehydatidiform moles. Ultrasound in Obstetrics and Gynecology 2000; 16: 188–191.

* 9. Lazarus E, Hulka CA, Siewert B & Levine D. Sonographic appearance of early complete molar pregnancies.Journal of Ultrasound in Medicine 1999; 18: 589–593.

* 10. Sebire NJ, Rees H, Paradinas F et al. The diagnostic implications of routine ultrasound examination inhistologically confirmed early molar pregnancies. Ultrasound in Obstetrics and Gynecology 2001; 18:662–665.

* 11. Romero R, Horgan JG, Kohorn EI et al. New criteria for the diagnosis of gestational trophoblastic disease.Obstetrics and Gynecology 1985; 66: 533–538.

* 12. Sasaki S. The management of gestational trophoblastic diseases in Japan—a review. Placenta 2003;24(Suppl. A): S28–S32.

13. Matsui H, Iizuka Y & Sekiya S. Incidence of invasive mole and choriocarcinoma following partialhydatidiform mole. International Journal of Gynecology and Obstetrics 1996; 53: 63–64. (Letter).

14. Seckl MJ, Fisher RA, Salerno G et al. Choriocarcinoma and partial hydatidiform moles. Lancet 2000; 356:36–39.

15. The Japan Society of Obstetrics and Gynecology and The Japanese Pathologocal Society, The General Rulesfor Clinical and Pathological Management of Trophoblastic Disease, 2nd edn. Tokyo: Igaku-shoin, 1995.

16. Berkowitz RS, Goldstein DP, Marean AR & Bernstein M. Oral contraceptives and postmolar trophoblasticdisease. Obstetrics and Gynecology 1981; 58: 474–477.

17. Curry SL, Schlaerth JB, Kohorn EL et al. Hormonal contraception and trophoblastic sequelae afterhydatidiform mole. (A Gynecologic Oncology Group study). American Journal of Obstetrics and Gynecology1989; 160: 805–811.

* 18. Newlands ES. Presentation and management of persistent trophoblastic disease and gestationaltrophoblastic tumours in the UK. In Hancock BW, Newlands ES & Berkowitz RS (eds) GestationalTrophoblastic Diseases. London: Chapman and Hall, 1997, pp 143–156.

19. Palmer JR. Oral contraceptive use and gestational choriocarcinoma. Cancer Detection and Prevention 1991;15: 45–48.

Research agenda

† further study on the effect of long-term oral contraceptive use on the relativerisk of persistent gestational trophoblastic disease is needed

892 S. Sasaki