Luker [1] first described a twin pregnancy consisting of a complete or partial hydatidiform mole in 1914. Over the previous decades, only a few cases were reported. The combination could be a live fetus with a complete hydatidiform mole or a live fetus with a partial hydatidiform mole [2, 3, 4, 5]. Therefore, as the prognosis and management of each are different, distinguishing between both possibilities is crucial [6]. The fetus that is accompanied by a partial hydatidiform mole is malformed and usually does not survive past midpregnancy [7, 8, 9], pregnancy termination is recommended once the diagnosis is made [10]. Complete hydatidiform mole with a coexistent fetus (CHMCF) can result in a viable fetus that may survive until delivery [2, 3]. However, the management of patients with CHMCF is difficult due to its rarity and complexity [7, 10, 11, 12]. Although the fetus in CHMCF can be alive [2, 3], the pregnancy is usually terminated due to consequences that can threaten the lives of both the mother and fetus [2, 3, 13, 14, 15, 16]. Prior reports note a high risk for haemorrhage requiring uterine evacuation [17]; however, several case reports have described safe continuation of the pregnancy [18, 19, 20, 21, 22, 23, 24]. In this case report, we present a case of CHMCF that resulted in a healthy newborn with no significant maternal complications throughout the pregnancy. In this report, we first describe a case of CHMCF and then provide a review and summary of the entire literature available regarding this rare condition in pregnancy.

A healthy 32-year-old woman, who was in her third pregnancy, presented to the University Malaya Medical Centre (UMMC) at 18 weeks gestation for vaginal bleeding. She did not experience abdominal pain, excessive nausea, or vomiting.

This was a planned pregnancy and a spontaneous conception. The patient was at risk for a miscarriage due to bleeding at 11 weeks, at which point she sought advice from a private practitioner. An ultrasound scan (USS) performed at that time revealed a viable fetus, and she was given a revised expected delivery date. No abnormalities were observed at that time.

She had a history of a complete miscarriage at 7 weeks gestation that required surgical intervention 4 years earlier and one uneventful full-term spontaneous vaginal delivery of a healthy baby girl 3 years earlier.

On examination, she did not appear pale and her vitals were stable. The abdomen was soft and non-tender. The fundal height was palpable at 28 weeks gestation.

USS at 18 weeks gestation showed an active fetus with parameters corresponding to the gestational age, and no obvious structural abnormalities were seen. The placenta was posterior and did not cover the cervical os. A large cystic mass measuring 16 $\times$ 8 cm with mixed echogenicity and a honeycomb appearance was observed within the uterus, which was separated by a membrane. This led to a diagnosis of a twin pregnancy with a coexistent molar pregnancy. No theca lutein cyst was detected on ultrasound. The patient declined chromosomal analysis to determine the karyotypes of the fetus and mole. No structural anomalies or soft markers were observed that suggested aneuploidy. The hydatidiform molar tissue was distinctly separated from the fetus and placenta.

Magnetic resonance imaging (MRI) was performed to support the diagnosis and delineate the distinct junction between the myometrium and molar tissue. Blood tests revealed normal thyroid function and a beta-human chorionic gonadotropin (hCG) level of 398,800 IU/L.

MRI revealed a well-formed fetus within the amniotic sac occupying the left posteroinferior aspect of the uterine cavity and a well-defined mass measuring 7.0 $\times$ 10.3 $\times$ 15.0 cm (AP $\times$ W $\times$ CC) outside the amniotic sac of the fetus occupying the right side of the uterine cavity. Multiple cystic areas were noted within the mass, as was evidence of subacute bleeding over the inferior pole of the lesion. However, no evidence of placental invasion by the mass was observed (Fig. 1).

Fig. 1.

Abdomen MRI at 20 weeks gestation. Twin pregnancy with a complete hydatidiform mole (arrow) can be seen along with a normal fetus and a normal placenta.

The patient was informed of the possible complications of continuing the pregnancy, which included persistent vaginal bleeding, gestational trophoblastic neoplasia (GTN), preeclampsia, preterm delivery, and fetal growth restriction. At this time, pregnancy termination was discussed, but she elected to continue the pregnancy.

The pregnancy care plan was outlined, and she was compliant. She remained well, euthyroid, and normotensive throughout the pregnancy. No additional vaginal bleeding was seen after 21 weeks gestation.

The serial hemoglobin measurement, platelet count, thyroid function tests, liver function tests, and coagulation profiles were normal throughout the pregnancy. Oral glucose tolerance tests also ruled out gestational diabetes mellitus. The beta-hCG level at 22 weeks gestation measured 170,400 IU/L, which decreased to 80,385 IU/L after 4 weeks. The beta-hCG level exhibited a decreasing trend after 2 weeks with a value of 46,067 IU/L 1 week before delivery.

Serial fetal surveillance was satisfactory according to the Doppler findings. The molar aspect remained approximately the same size. No sonographic evidence that indicated invasion of the uterine myometrium by the mass was found.

A multidisciplinary team discussion that involved obstetricians, obstetrics anesthetists, neonatologists and gynaecologic oncologists was arranged, and an elective cesarean section was performed at 32 weeks gestation. Antenatal corticosteroids for fetal lung maturity were administered prior to the cesarean section.

A lower-segment cesarean section was performed with no intraoperative complications. A normal baby girl weighing 1.98 kg was successfully delivered with an APGAR (Appearance, Pulse, Grimace, Activity, and Respiration) score of 6 at 1 minute and 10 at 5 and 10 minutes. The placenta, which was delivered via controlled cord traction, appeared grossly normal and weighed 285 grams (Fig. 2). The mass of the hydatidiform mole containing the vesicular lesion weighed 235 grams and was also delivered (Fig. 2). The operation was uneventful, and an intravenous infusion of 80 IU of oxytocin was immediately administered after delivery.

Fig. 2.

Photograph of the molar (A) and normal (B) placentas obtained after the cesarean section.

The baby girl was observed in the neonatal unit for 5 days, was then treated for congenital pneumonia and pathological jaundice, and subsequently discharged in good condition.

The histopathological examination of the molar tissues confirmed the clinical diagnosis of CHMCF. This patient had normal lochia, and a postpartum examination showed satisfactory involution of the uterus. The immediate postdelivery serum beta-hCG level was 5916 IU/L and was subsequently measured to be 123 IU/L, 12 IU/L, and less than 2 IU/L at 1, 2 and 6 weeks postpartum, respectively. Subsequent follow-up serum beta-hCG showed no sign of GTN and the patient remained clinically well up to one year after childbirth.

The diagnosis for CHMCF is clinically challenging as it may be mistaken for partial hydatidiform mole. Since the management of these two conditions differs, distinguishing between them is important. This is a rare phenomenon [7, 10, 11], and as a result, not many of us are acquainted with this condition. In cases of a partial hydatidiform mole, pregnancy termination is advised, as the fetus is chromosomally abnormal. On the contrary, the coexistent fetus in CHMCF is viable and normal [2, 3].

A systematic search of published literature in English language from January 1990 to December 2020 from PubMed and MEDLINE using the terms “complete hydatidiform mole” or “twin hydatidiform mole”. The search was limited to case reports and case series which involved complete hydatidiform mole coexisting with at least one live fetus. 167 cases were discovered and their findings were summarized in Tables 1 (Ref. [3, 5, 6, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102]) and Table 2.

The incidence of CHMCF is predicted to rise in the future, as the ultrasonographic technology used in detecting CHMCF advances and the extensive use of ovulation induction techniques increases [12, 59, 103]. 29.94% (n = 50) of the pregnancies in the present literature review were conceived with the aids of several assisted conception methods (Table 2). Extremes of maternal age (20 and $>$40 years old) has been a well-known risk factor associated with complete hydatidiform mole [104, 105, 106, 107]. 16 (9.58%) women with CHMCF pregnancies in our literature review were from these two age groups.

CHMCF should be a differential diagnosis when a pregnant woman presents with vaginal bleeding, hyperemesis gravidarum, features of hyperthyroidism, or a uterus larger than expected [2, 4, 14, 97, 103, 108, 109].

With the recent advances in ultrasonography, CHMCF can even be incidentally detected starting late in the first trimester [103, 108]. In this condition, the complete mole typically presents with a classical snowstorm appearance together with the presence of a normal placenta and a viable fetus [4, 7, 12, 103, 110]. Occasionally, a theca lutein cyst is detected on ultrasound due to a significantly elevated level of serum beta-hCG, suggesting a higher probability of CHMCF [45, 103, 109, 111, 112]. Ultrasound is sufficient for a clinical diagnosis. When the physician is experienced, this condition can be diagnosed as soon as the end of the first trimester. In these patients, MRI supports the diagnosis, differentiates it from placental mesenchymal dysplasia, and also assesses invasion of the myometrium by the molar tissue [113, 114, 115].

Fetal karyotyping has been advocated to compare the normal chromosome number in CHMCF compared with the triploidy seen in a partial mole [2, 4, 6, 10, 39, 45, 109, 116, 117]. Complete mole is exclusively diploid and paternal in origin, occurring when an “empty” ovum is being fertilized by a single haploid sperm that duplicates (46, XX) or by two haploid sperms (46, XX or 46, XY) [2, 4, 5, 45]. Cytogenetic studies in the literature review have shown that majority (37.13% versus 5.99%) of CHMCF have a 46, XX karyotype (Table 2).

Histopathological examination of the trophoblastic tissue after delivery will confirm the final diagnosis of CHMCF [103, 118].

Immediate pregnancy termination upon diagnosis has typically been recommended in the past due to the potentially fatal complications that can occur if the pregnancy is continued [3, 14, 118]. GTN, which is one of the most serious maternal conditions that can develop in patients with CHMCF [3, 11, 13, 38, 45, 103, 118, 119], has a reported incidence ranging from 19% to 50% [2, 10, 90, 97, 120, 121]. Of the reported cases in the present literature, 32.93% (n = 55) of the CHMCF pregnancies progressed to GTN (Table 3) (Ref. [15, 16, 17, 19, 21, 22, 26, 27, 31, 32, 33, 38, 41, 42, 44, 53, 55, 56, 57, 58, 60, 63, 65, 66, 67, 69, 72, 73, 77, 80, 81, 85, 87, 90, 94, 100, 102]). Among them, 15 (27.27%) of the GTN cases have progressively metastasize to distant organs, with lungs being the commonest site of metastasis. 6 (10.91%) women even required hysterectomy to cure from GTN but none of the patient in our literature review died from GTN or its complications. However, it has been demonstrated that the risk of GTN is independent of gestational age, meaning that the risk of GTN in patients who choose conservative management until delivery is the same as that in those who decide to terminate the pregnancy [2, 11, 12, 60, 118, 119]. Therefore, in the recent years, continuation of the pregnancy has become an option [2, 3, 12, 14, 116, 118], provided that the patient has access to a high standard of care under a multidisciplinary team at a tertiary hospital, does not develop any serious uncontrollable complications throughout the pregnancy, and can maintain compliance with regular follow-up during close surveillance [2, 3, 10, 12, 14, 108, 119, 122]. Comprehensive counseling involving obstetricians, gynaecologic oncologists, anesthetists and neonatologists with the couple must be performed, and they need to understand the risk of possible obstetric complications before this major decision is made [9, 10, 14, 38, 116, 118, 119]. The antenatal care included serial beta-hCG, haemoglobin and thyroid function measurements as well as monitoring of the progression of molar mass, theca lutein cysts and fetal growth [34, 41, 44, 56]. Blood pressure and urine protein should be closely evaluated to exclude pre-eclampsia [20, 56]. As with the development of any life-threatening complication, such as heavy vaginal bleeding, severe preeclampsia, GTN, or intrauterine fetal death, [2, 3, 4, 11, 14, 19, 45, 97, 109, 118, 119, 123, 124] immediate evacuation is required regardless of the gestational age [2, 14, 19, 108].

Several authors have suggested that, when a less aggressive trophoblast is noted, i.e., a smaller molar component, declining serum hCG levels in the second trimester, and a uterus that is not abnormally large for the gestational age, chances for a successful pregnancy outcome are increased, as in our patient [125]. In addition, she did not develop any serious obstetrical complications.

Although many patients choose a conservative approach, only 35.59% (n = 63) of the pregnancies in the present literature review resulted in successful delivery of a viable live born fetus (Table 2). Many of the pregnancies still ultimately resulted in elective (42.37%, n = 75) and spontaneous (17.51%, n = 31) termination due to obstetric complications, as discussed in many reports (Table 1). According to our literature review, vaginal bleeding (64.67%, n = 108) is the most common maternal complication in CHMCF pregnancy, followed by hyperthyroidism (17.96%, n = 30) and pre-eclampsia (16.77%, n = 28) (Table 2). Lower hCG levels at presentation, later gestational age upon detection, and absence of maternal complications are favorable prognostic factors for better pregnancy outcomes [16, 125].

Cesarean section (67.74%, n = 42) is the recommended mode of delivery in patients with CHMCF, and delivery should be performed by a dedicated team of experts [9, 119]. Intensive neonatal care must be accessible since the newborns in these cases are usually very premature [119]. No consensus on the optimal gestation time for delivery has been established, but in our patient, delivery was scheduled for between 32 and 34 weeks gestation. However, a cesarean section was performed at 32 weeks gestation due to a plateau of fetal growth and because the patient had also complained of uterine contractions. Regular monitoring of the hCG levels throughout the pregnancy and postpartum period is necessary to detect GTN [116, 119, 122]. Furthermore, the patient should be treated with chemotherapy [11, 13, 38] when GTN is suspected.

In conclusion, obstetricians should bear in mind that CHMCF can be one of the possible diagnosis when performing an ultrasound in the early gestational period in women with persistent vaginal bleeding and those with excessive symptoms during early pregnancy. However, the management of this condition remains controversial. Here we report a successful pregnancy outcome despite the late presentation to a tertiary center. However, further studies are warranted to evaluate the most appropriate management strategy for these patients.

CHMCF, Complete Hydatidiform Mole with Coexistent Fetus; CS, Caesarean Section; EMA, Etoposide + Methotrexate + Actinomycin D; EMA-CO, Etoposide + Methotrexate + Actinomycin D + Cyclophosphamide + Vincristine; GA, Gestational Age; 5-FU + KSM, 5-Fluorouracil + Kengshengmycin; GIFT, Gamete Intra-Fallopian Transfer; GTN, Gestational Trophoblastic Neoplasia; hCG, Human Chorionic Gonadotropin; HELLP Syndrome, Haemolysis, Elevated Liver Enzyme And Low Platelet Count Syndrome; HG, Hyperemesis Gravidarum; HT, Hyperthyroidism; ICSI, Intra-Cytoplasmic Sperm Injection; IUI, Intra-Uterine Insemination; IVF, In Vitro Fertilization; LB, Live Birth; MRI, Magnetic Resonance Imaging; ND, Neonatal Death; OI, Ovulation Induction; PA, Placenta Accreta; PE, Pre-Eclampsia; PIH, Pregnancy Induced Hypertension; PL, Preterm Labour; PP, Placenta Praevia; PPROM, Preterm Premature Rupture of Membranes; SA, Spontaneous Abortion Before 24 Weeks Gestation; SB, Stillbirth Equal Or More Than 24 Weeks Gestation; TLC, Theca Lutein Cysts; TOP, Termination Of Pregnancy; UMMC, University of Malaya Medical Centre; USS, Ultrasound Scan; VB, Vaginal Bleeding; VD, Vaginal Delivery.

NS prepared the manuscript and is responsible for the overall content as guarantor. SS, MK, AGT reviewed the manuscript. All authors read and approved the final manuscript.

Written informed consent was obtained from the patient for the publication of this case report. Ethical approval is waived for the case report.

The authors would like to thank all colleagues from Department of Obstetrics and Gynaecology, Department of Radiology, Department of Paediatric, Department of Anaesthesiology, and Department of Pathology at the University of Malaya Medical Centre (UMMC) for their contribution in the care of this patient.

This research received no external funding.

The authors declare no conflict of interest.