Molar pregnancy

molar pregnancy..... eatiology, risk factors, management, complications......

1. MOLAR PREGNANCY DR. YOGESH PATEL MBBS, DGO DIPLOMA IN LAPAROSCOPY (D. MAS) FELLOWSHIP IN LAPAROSCOPY (F. MAS) FELLOWSHIP IN INFERTILITY (F. ART) PG DIPLOMA IN ULTRASONOGRAPHY (D. USG) EMERGENCY MEDICINE SPECIALIST FORMER CONSULTANT AIIMS NEW DELHI MEMBER OF THE WORLD ASSOCIATION OF LAPROSCOPIC SURGEONS

2. MOLAR PREGNANCY

3. A molar  pregnancy  happens when tissue that normally becomes a fetus  instead becomes an abnormal growth in   uterus . Even though it isn't an  embryo , this growth triggers  symptoms of pregnancy DEFINATION: A heterogeneous group of interrelated lesions arising from the trophoblastic epithelium of the placenta ,( tropho means nutrition, blast means early developmental cells) characterized by a distinct tumor marker – β HCG as tumor arises from gestational rather than maternal tissue. WHAT IS MOLAR PREGNANCY?

4. What is the classification of gestational trophoblastic disease?

5. It is a spectrum of trophoblastic diseases that includes: Hydatiform mole (Benign) Complete mole Partial mole Gestational trophoblastic neoplasia (Malignant) Invasive mole Choriocarcinoma Placental site trophoblastic tumour Epitheloid trophoblastic tumour Gestational Trophoblastic Disease (GTD) The last 3 may follow abortion, ectopic or normal pregnancy FIGO oncology committee; Williams Obsterics 23 rd , 2010

6. It is a spectrum of trophoblastic diseases that develops malignant sequelae . GTN includes: Invasive mole Choriocarcinoma Placental site trophoblastic tumour Epitheloid trophoblastic tumour Gestational Trophoblastic Neoplasia (GTN) =Malignant Gestational Trophoblastic Disease Disaia & Creasman Clinical Gynecological Oncology 2007 Cunningham et al Williams Obsterics 23 rd , 2010

7. What is the aetiology of MOLAR PREGNANCY ?

8. Aetiology: Immunological factors Racial factors Dietary factors

9. Risk Factors Age : extremes of age <15 yr and >40 yr Reproductive history: Prior Molar Pregnancy Previous spontaneous abortion: double the incidence Second molar: 1% - Third molar : 20%! Diet : increase incidence in high carbohydrate diet, low protein and Vit . A or carotene diet (complete mole ) Malnutrition and debilitated condition. Repetitive H. moles in women with different partners Maternal Blood Group AB and A High gamma globin in absence of hepatic disesase

10. WHAT IS THE INCIDENCE?

11. In the United States, 1 in 1,500 -2,000 pregnancies In Asian countries, The rate is 10 times higher than in Europe and North America In Saudi Arabia;, 1.48 in 1000 live births (hospital-based study; Felemban AA, et al; 1969) 1 in 200-300 pregnancies in south east asia . 1-2 in 1,000 pregnancies in China and Japan. Incidence highest in philippines i,e 1 in 80

12. WHAT IS THE CHROMOSOMAL BASIS OF DEVELOPMENT OF MOLE?

13. Pathogenesis and Cytogenetics of HM Genetic Constitution Diploid Triploid/ teraploid Patho-genesis 4% Fertilization of an empty ovum by two sperms “Diandric dispermy” 90% Triploid fertilization of a normal ovum by two sperms “Dispermic triploidy” 96% Fertilization of an empty ovum by one sperms that undergoes duplication “Diandric diploidy” 10% Tetraploid fertilization of a normal ovum by three sperms “Dispermic triploidy” Karyotype 46XX 69XXX 69YXX 69YYX 46XX 46XY Complete Partial

14. Complete Mole, Pathogenesis Duplication 46XX Empty ovum 23X Diandric diploidy Androgenesis M:F 2:0 Paternal chromosomes only

15. Complete Mole, Pathogenesis 46XX Empty ovum 23X Dispermic diploidy Paternal chromosomes only 23X 23X 23X

16. Partial Mole, Pathogenesis 69XXY Normal ovum 23X Dispermic triploidy M:F 2:1 Paternal extra set 23Y 23X 23Y 23X 23X

17. Familial biparental hydatidiform mole Familial biparental hydatidiform mole (FBHM) is inherited in an autosomal recessive pattern . Extensive mapping studies had demonstrated a defective locus at 19q13.4. this abnormality have been localised to a single gene- NALP7. This is the first causative gene defect identified in H. MOLE.

18. - Describe Complete Hydatidiform Mole

19. Feature Partial mole Complete mole Karyotype Most commonly 69, XXX or - XXY Most commonly 46, XX or -,XY Pathology Fetus Often present Absent Amnion, fetal RBC Usually present Absent Villous edema Variable, focal Diffuse Trophoblastic proliferation Focal, slight-moderate Diffuse, slight-severe Clinical presentation Diagnosis Missed abortion Molar gestation Uterine size Small for dates 50% large for dates Theca lutein cysts Rare 25-30% Medical complications Rare 10-25% Postmolar GTN 1-5% 15-20% Disaia & Creasman Clinical Gynecological Oncology 2007 Cunningham et al Williams Obsterics 23 rd , 2010

20. What is the pathological features of complete hydatidiform mole?

21. Complete H. Mole Microscopically Enlarged, edematous villi and abnormal trophoblastic proliferation that diffusely involve the entire villi . No fetal tissue, RBCs or amnion are produced Macroscopically , these microscopic changes transform the chorionic villi into clusters of vesicles with variable dimensions “ like bunch of grapes“. No fetal or embryonic tissue are produced Uterine enlargement in excess of gestational age . Theca- lutein cyst associated in 30%

22. 1-Trophoblastic proliferation 2-Hydropic Degeneration Complete hydatidiform mole: Microscopically Enlarged, edematous villi and abnormal trophoblastic proliferation that diffusely involve the entire placenta

23. Complete hydatidiform mole: Macroscopically , these microscopic changes transform the chorionic villi into clusters of vesicles with variable dimensions the name hydatidiform mole stems from this "bunch of grapes"

24. Complete Hydatiform Mole Uterine wall

25. CLINICAL FEATURES OF COMPLETE MOLE History of amenorrhoea of 8-12 weeks Irregular Vaginal bleeding- commonest (90%). may vary from spotting to profuse haemorrhage. Expulsion of grapes like vesicles per vaginum (50%) Lower abdominal pain - a) overstretching of uterus b) concealed haemorrhage c) uterine contraction to expel out the content d) infection e) perforation of the uterus by invasive mole.

26. Hydatidiform Mole Usually, in association with, Theca lutein cysts (25-50%) Very early onset Preeclampsia ( 26%) Markedly elevated hCG 100,000 mIU / mL Breathlessness or acute respiratory distress(2%) Hyperemesis gravidarum (25%) Hyperthyroidism (1-7%) Excessive uterine enlargement (50%)

27. Points to be noted during examination GENERAL EXAMINATION: Patient looks more ill and Pallor is out of proportion of bleeding. PR-tachycardia, RR- tachypnea /dyspnoea Features of pre eclampsia present .usually there is early onset of pre eclampsia . P/A- Uterine enlargement> than expected GA. The uterus is soft and doughy due to absence of the amniotic fluid sac. Fetal parts not felt FHS cannot be detected.

28. P/S- Cervical os may be open or close. Vuval or vaginal metastasis may appear as purple nodule. P/V- Note the uterine size. Internal ballotment cannot be elicited. Unilateral or bilateral theca lutein cyst of ovary palpable in 25-35% of cases.

29. PATHOLOGY OF PARTIAL H. MOLE

30. Partial H. Mole Microscopically: The enlarged, edematous villi and abnormal trophoblastic proliferation are slight and focal and did not involve the entire villi . There is a scalloping of chorionic villi with undulating border. Fetal or embryonic or fetal RBCs Macroscopically: The molar pattern did not involve the entire placenta. Uterine enlargement in excess of gestational age is uncommon. Theca- lutein cysts are rare Fetal or embryonic tissue or amnion

31. Scalloping of chorionic villi Partial Hydatidiform Mole Trophoblastic proliferation are slight and focal

32. Partial Hydatiform Mole Vesicles Maternal side

33. Fetal hand demonstrating syndactyly . The fetus had a triploid karyotype , and the chorionic tissues were a partial mole

34. Partial H. mole.

35. CLINICAL FEATURES OF PARTIAL MOLE History: Vaginal bleeding Usually diagnosed as missed or incomplete abortion(91%). Physical : A uterus corresponds or small for gestation age Excessive uterine size noted(4%) Toxemia of pregnancy(4%)

36. Diagnosis: History Clinical examination Ultrasound examination Serum hCG levels Histopathological examination Cytogenetic and molecular biological examination Immunostaining of p57kip2 gene recent development in diagnostic accuracy.it is a paternally imprinted gene which is maternally expressed .positive in PHM

37. U/S is helpful in making a pre-evacuation diagnosis but the definitive diagnosis is made by histological examination. U/S: Early detection reduced from 16 weeks (passage of vesicles) to 12 wks β hCG levels > 2 multiples of the median may be of value in the diagnosis often exceeding 10 5 IU/l. RCOG Guideline No. 38 ; 2010

38. Guideline to hCG Levels During Pregnancy hCG levels in weeks from LMP (gestational age) * : 3 weeks LMP: 5 – 50 mIU /ml 4 weeks LMP: 5 – 426 mIU /ml 5 weeks LMP: 18 – 7,340 mIU /ml 6 weeks LMP: 1,080 – 56,500 mIU /ml 7 – 8 weeks LMP: 7, 650 – 229,000 mIU /ml 9 – 12 weeks LMP: 25,700 – 288,000 mIU /ml 13 – 16 weeks LMP: 13,300 – 254,000 mIU /ml 17 – 24 weeks LMP: 4,060 – 165,400 mIU /ml 25 – 40 weeks LMP: 3,640 – 117,000 mIU /ml Non-pregnant females: <5.0 mIU /ml Postmenopausal females: <9.5 mIU /ml * These numbers are just a GUIDELINE– every woman’s level of hCG can rise differently. It is not necessarily the level that matters but rather the  change in the level.

39. Complete Molar Pregnancy

40. Complete hydatidiform mole. The classic "snowstorm" appearance is created by the multiple placental vesicles.

41. In most patients with a partial mole, the clinical and U/S diagnosis is Usually missed or incomplete abortion. This emphasizes the need for a thorough histopathologic evaluation of all missed or incomplete abortions How Is Partial H .Mole Diagnosed? RCOG Guideline No. 38 ; 2010

42. Classically : A thickened, hydropic placenta with fetal or embryonic tissue Multiple soft markers, including: Cystic spaces in the placenta and Transverse to AP dimension a ratio of the gestation sac of > 1.5, is required for the reliable diagnosis of a partial molar pregnancy β hCG ≥ 10 5 U/L RCOG Guideline No. 38 ; 2010 How Is Partial H .Mole Diagnosed?

43. Partial Molar Pregnancies

44. Hydatidiform Mole Diagnosis: Histopathological examination: It should always be done as far as possible .

45. There are 2 important basic lines : 1-Evacuation of the mole 2-Regular follow-up to detect persistent trophoblastic disease If both basic lines are done appropriately, mortality rates can be reduced to zero. What Is The Plan of Management?

46. The Management Of Gestational Trophoblastic Disease RCOG Guideline No. 38 ; 2010

47. Management: Investigations: Laboratory: Pre-evacuation hCG Complete blood count Electrolytes, BUN, creatinine Liver function tests Thyroid function tests HIV Imaging: Pelvic ultrasound Chest x-ray

48. Management : The patient should be stabilized hemodynamically  Medical care: Correction of: Anemia Dehydration Hyperthyroidism Hypertension Surgical care

49. Suction Evacuation is method of choice – can be done by conventional suction curretage as well as by MVA Two MVA set should be available Cervical preparation with prostaglandins or misoprostol , should be avoided to reduce the risk of embolisation RCOG Guideline No. 38 ; 2010 What Is The Best Method Of Evacuating A Molar Pregnancy?

50. For Partial mole : It depends on the fetal parts Small fetal parts :Suction curettage Large fetal parts: Medical ( oxytocics ) In partial mole the oxytocics is safe ,as the hazard to embolise and disseminate trophoblastic tissue is very low Also, the needing for chemotherapy is 0.1- 0.5%. RCOG Guideline No. 38 ; 2010 Is That The Same For Partial Mole?

51. Canula up to a maximum of 12 mm, is usually sufficient to evacuate all complete molar pregnancie s

52. Suction curettage has been performed using 10mm canula under U/S guidance : El SHERBINY HOSP El SHERBINY HOSP Canula

53. Garner UpToDate 2010 Suction Curettage Supervision of senior surgeon Blood should be cross matched and kept available Maintain two i /v line Procedure to be carried out in OT Cervical os t o be dilated up to 12mm size suction cannula . Deep insertion of suction cannula avoided Gentle curettage is performed after evacuation is complete and tissue sent for histopathology. Intraop USG , if available help to ensure the complition of procedure. The use of oxytocin infusion prior to completion of evacuation is not recommended

54. The Molar Content For Histopathological Examination

55. When Anti-D Is Required? It is required in Partial due to the presence of fetal RBCs In Complete mole because of poor vascularisation of the chorionic villi and absence of the anti-D antigen, anti-D prophylaxis is not required. Although ACOG recommend to give Anti-D in all cases. RCOG Guideline No. 38 ; 2010

56. Barrier methods – most preffered method. Oral contraceptive method -Once β hCG level have normalized: COC pill may be used.( as it may acts as growth factor for trophoblastic tissue) Low dose OCP is preffered . If oral COC was started before the diagnosis of GTD ,COC can be continue as its potential to increase risk of GTN is very low IUCD should not be used until β hCG levels are normal to reduce uterine perforation. Permanent sterilisation - prefered in those couples whose family has been completed. What Is Safe Contraception Following GTD? RCOG Guideline No. 38 ; 2010

57. Hysterectomy may be preferred to suction curettage at age ≥ 40 years with no desire for further pregnancies especially with other risk factors for GTN as : Large theca lutein cysts( >6 cm) Significant uterine enlargement Pretreatment β hCG ≥ 10 5 U/L. Although hysterectomy does not eliminate possibility of GTN, it markedly reduces its likelihood. Post hyst . GTN is observed in 3-5% of cases. Garner UpToDate 2010 Soper . Obstet Gynecol 108:176, 2006 Cunningham et al,Williams Obstetrics,23rd ,2010

58. Theca- lutein cyst associated with a complete H. mole in >30%

59. Prophylactic Chemotherapy: The long-term prognosis for women with a H. mole is not improved with prophylactic chemotherapy. Because toxicity—including death—may be significant, it is not recommended routinely * It may be useful in the high-risk cases when follow-up are unavailable or unreliable. * * Second Uterine Evacuation : not required routinely RCOG Guideline No. 38 ; 2010 American College of Obstetricians and Gynecologists, 2004 *

60. Prophylactic chemotherapy after molar pregnancy The controversial practice of prophylactic chemotherapy in GTN in women with H.mole is not recommended ( According to recent cochrane data based review 2012). Overall PC reduces the risk of GTN however researcher consider this evidence to be low quality. When GTN did occur the time to diagnosed in women received PC is longer and these women require more courses are require to cure GTN. Unnecessary exposure to toxic adverse effect.

61. Prophylactic Chemotherapy : In one randomized clinical trial, a single course of methotrexate (0.4mg/ kg/day ) and folinic acid reduced the incidence of postmolar trophoblastic disease from 47.4% to 14.3% in patients with high-risk moles: Age >40 yrs previous history of molar pregnancy β hCG levels greater than 100,000 mIU / mL , Uterine size greater than gestational age, Ovarian size greater than 6 cm All associated factors like PE, hyperthyroidism, hyperemesis . Acute respiratory distress. Post evacuation uterine haemorrhage/ subinvolution Still the gold standard is careful follow up of each and every patient and serial estimation of β H CG.

62. Post-evacuation Surveillance Why? To determine when pregnancy can be allowed To detect persistent trophoblastic disease (i.e. GTN)

63. A baseline serum β - hCG level is obtained within 48 hours after evacuation . Levels are monitored every week till a normal value is achieved. Level usually becomes normal by 8-10 weeks. Monitor HCG every month for further 6 months from the date of evacuation if HCG has to return to normal within 56 days after pregnancy event. >56 days of the pregnancy event :Follow up is 6 months from normalization of the hCG level. These levels should progressively fall to an undetectable level (<5 mu/ml). RCOG Guideline No. 38 ; 2010 The Post-evacuation Surveillance. How?

64. In resource poor setting – UPT and USG. Monthly USG 1 month after evacuation. UPT should be perfomed once monthly starting from 3 rd to 4th month untill 1 year after evacuation. The normal time for β hCG to normalise is 99 days in complete moles and 59 days in partial mole. Pelvic examination: Duration: while hCG is elevated to monitor the involution of pelvic structures and to aid in the identification of vaginal metastasis

65. Hydatidiform Mole Complications associated with molar pregnacy : Theca- lutein cysts Pre eclampsia , hyperthyroidism, Respiratory distress Hyperemesis Uterine perforation , Excessive haemorrhage, Respiratory distress syndrome. Development of persistent mole.

66. Theca lutein cyst (>5-6cm) (25-35%) pain or torsion, rupture or post molar pressure bleeding GTD Require aspiration require opherectomy The mean time for theca luteal cysts to regress is approximately 8 weeks

67. RESPIRATORY DISTRESS SYNDROME (rare event) Pathophysiology : embolisation of trophoblastic tissue , pulmonary metastasis Risk factors : uterine size > 14-16 weeks high HCG level Contributing factors- anaemia, thyrotoxicosis It should resolve within 24 to 48 hours after molar evacuation

68. Hyperthyroidism: Prevalence: Clinical hyperthyroidism is seen in less than 10% of patients with molar pregnancies Management : Beta-blockers should be administered prior to molar evacuation to prevent thyroid storm that may be induced by anesthesia and surgery.

69. When can women whose last pregnancy was a complete or partial hydatidiform molar pregnancy try to conceive in the future ? Women should be advised not to conceive until their follow-up is complete. Women who undergo chemotherapy are advised not to conceive for 1 year after completion of treatment. Patient with metastatic GTN – 2 years

70. Pregnancy after Hydatidiform Mole: Risk of another molar pregnancy: (1 – 2 % incidence) Current recommendations for management of subsequent pregnancies: P/V in first trimester and ultrasound to confirm normal gestational development and dates Examination of the placenta or products of conception histologically at the time of delivery or evacuation . An hCG level should be obtained 6 weeks and 10 weeks post evacuation or delivery to confirm normalization.

71. A hydatidiform mole and a co-existent fetus: Prevalence: Rare (0.005%-0.01% pregnancies) Diagnosis : Ultrasound In diagnostic doubt , invasive testing for karyotyping to be done. E xamination of the placenta following delivery. Outcome of such pregnancies is poor live birth of 25%, increased risk of early fetal loss(40%), preterm labour (36%) ,pre eclampsia . Complications: Increased risk of medical complications Increased risk for postmolar gestational trophoblastic disease .

72. False-positive hCG values, also known as “ phantom hCG ” Cause : the presence of non-specific heterophil antibodies in the patients ’ sera. Should be suspected if hCG values plateau at relatively low levels and do not respond to therapeutic maneuvers Evaluation of patients with : Urinary hCG Serial dilutions of the serum

73. Prognosis: Post-molar gestational trophoblastic disease: Risk: Following complete mole: 20% Following partial mole: 5% Type: 70% to 90% are persistent or invasive moles 10% to 30% are choriocarcinomas . Recurrence- Risk of recurrenc with prior molar pregnancy is 1-4%

74. PERSISTENT GESTATIONAL TROPHOBLASTIC DISEASE It is defined as persistence of trophoblastic activity as evidnced by clinical ,imaging, pathological and hormonal study following initial treatment. It may be followingtreatment of hydatiform mole, invasive mole, choriocarcinoma or placental site trophoblastic tumour. INVASIVE MOLE- In which the trophoblastic tissue invade the myometrium .

75. Criteria for diagnosis of gestational trophoblastic neoplasia or post molar GTD Plateau of serum β - hcg level (+/-10%) for four measurements during a period of 3 weeks or longer – days 1,7,14,21. Rise of serum β - hcg > 10% during three weekly consecutive measurement or longer, during a period of 2 weeks or more – days 1,7,14. The serum β - hcg level remains detectable for 6 months or more after mole evacuation. Histological criteria for choriocarcinoma .

76. Low risk (score 0-6) and high risk(score ≥7)

77. Staging International staging of WHO may be summarized as follows: Ⅰ: lesion localized in uterus, no metastasis; Ⅱ: lesion extends beyond uterus, but still confined to internal genitalias ; Ⅲ: pulmonary lesion Ⅳ: metastasis to other distant sites.

78. Indication for therapy Indication for therapy after evacuation- An abnormal hcg regression pattern (10% or> rise in hcg level or plateauing hcg or 3 stables value over 2 weeks) An hcg rebound. Histological diagnosis of choriocarcinoma or placental site trophoblastic tumour. The presence of metastases. High hcg levels(.20,000miu/ml more than 4 weeks postevacuation ) Persistently elevated hcg levels 6 months post evacuation.

79. Hydatiform mole Evacuation Serial hcg level resolution GTN FIGO scoring Low risk(≤6) high risk(>6) Single agent (MTX) combination(MAC/EMACO) chemotherapy chemotherapy Serial hcg level resolution(life –long follow up) Relapse /resistant disease Second –line chemotherapy ±surgical debulking

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