The incidence of twin pregnancies with a coexisting complete hydatidiform mole is 1 per 22,000 to 100,000 conceptions1–3. Triplet pregnancies with a coexisting complete hydatidiform mole are even rarer, only six cases having been reported so far4–9. This entity is different from a partial hydatidiform mole as there are three separate conceptions with two normal placentas and a coexisting complete hydatidiform mole. All reported cases of triplet or quadruplet pregnancy with a hydatidiform mole so far have occurred in women following infertility treatment4–9.
We report the first case in the UK of a triplet pregnancy with a coexisting complete hydatidiform mole that was a spontaneous conception, that proceeded to 24 weeks of gestation, and that was found to be of monospermic origin by microsatellite genotyping. We describe the treatment of this case and some evidence from the literature that guided us.
A 29 year old woman with one previous child delivered by a caesarean section for breech presentation was found to have dichorionic, diamniotic twins by an early pregnancy scan. This was a spontaneous conception. She did not complain of any of the classical symptoms of a molar gestation. At 15 weeks she was seen with mild spotting of blood and an ultrasound scan revealed two live fetuses equivalent to dates with no other suspicious features.
An anomaly scan at 20 weeks of gestation revealed normal fetal anatomy. However, there was a mass from the lower edge of the posterior placenta, covering the cervical os and extending to the left of the midline, measuring 14 × 8 × 8 cm with the classical cystic spaces of a molar pregnancy. Her serum beta-HCG concentration was > 500,000 IU/L, consistent with a diagnosis of a coexisting molar gestation. Her haemoglobin was 8.8 g%. After careful counselling regarding the risks involved and prognosis, she decided to continue her pregnancy. A repeat scan at 22 weeks of gestation revealed an increase in the size of the molar tissue to 22 × 14 × 14 cm (Fig. 1). She presented with heavy vaginal bleeding requiring a blood transfusion. The bleeding settled and the twins continued to grow with twin 1 on the 3rd centile and twin 2 just below the 50th centile. Her beta-HCG level at this stage had risen to 694,050 IU/L.
At 24 weeks of gestation she was readmitted with vaginal bleeding. This was treated expectantly. Two doses of dexamethasone were administered. However, 24 h after admission she went into premature labour and rapidly passed a large piece of molar tissue that weighed 600 g (Fig. 2), followed by delivery of the twins. Twin one was a girl weighing 500 g (74% weight for her gestation) and twin two was a boy weighing 560 g (82% weight for his gestation). They were delivered in a good condition and transferred to the regional neonatal intensive care units. Unfortunately they did not survive beyond 24 hours after birth due to complications of extreme prematurity. Microscopic examination confirmed two normal placentas and a complete hydatidiform mole. She did not have any features of pre-eclampsia or hyperemesis at any stage during this pregnancy.
She was registered at the Charing Cross Hospital for follow up. In the first week post delivery her HCG levels decreased to 25,947 IU/L but then remained between 1139 and 3439 IU/L over the next two months. This indicated the possible need for chemotherapy for persistent trophoblastic disease. However, the levels have since decreased to < 50 IU/L and remained so after six months of follow up. She is currently continuing to have close surveillance, and has no symptoms.
DNA preparations were obtained from blood samples from the woman, her partner and from formalin-fixed paraffin embedded placental and molar tissue. DNA was then amplified by polymerase chain reaction with fluorescent-labelled primers for microsatellite markers on different chromosomes. Following electrophoresis in 1% agarose gel to assess the yield, the products were diluted appropriately and resolved by capillary electrophoresis using an ABI PRISM 310 Genetic Analyser (Applied Biosystems Ltd). Analysis and sizing of microsatellite polymorphisms in the different tissues was performed using the ABI PRISM Genescan software10. Examination of microsatellite markers confirmed that the placentas were genetically distinct and compatible with normal inheritance, one allele being inherited from each parent. (Fig. 3). The hydatidiform mole had only a single allele for each marker. This was found to be of paternal origin, thus confirming the mole to be an androgenetic complete hydatidiform mole. The mole was homozygous for seven polymorphic markers for which the father was heterozygous, showing this to be a monospermic rather than a dispermic complete hydatidiform mole (i.e. the fertilisation of an anuclear empty ovum by a haploid sperm, which then duplicates).
Triplet pregnancy with a coexisting mole is extremely rare with only six cases reported in the literature so far4–9. All of them occurred in women following infertility treatment. This case was unusual as it was a result of a spontaneous conception and also in that the pregnancy continued until 24 weeks'gestation. There has been only one other instance recently reported from Jordan where the pregnancy proceeded until 30 weeks with one of the fetuses surviving9. There have been two cases registered at the Charing Cross Hospital that had resulted in a spontaneous or therapeutic abortion before 18 weeks of gestation which have not been reported. There have also been two instances where evidence of a probable triplet pregnancy has come to light at the histological review at Charing Cross Hospital. It has been suggested that drugs used for induction of ovulation increase the production of immature or anuclear ‘empty’ ova which predisposes to an increased risk of molar conception5.
These pregnancies can be complicated by vaginal bleeding, pre-eclampsia, thyrotoxicosis and hypereme-sis gravidarum; therapeutic termination of pregnancy may be indicated. The estimated risk of persistent tro-phoblastic disease following a partial hydatidiform mole is 2–4%11, but in cases of singleton or multiple pregnancies with a complete hydatidiform mole a higher risk of persistent trophoblastic disease has been noted12,13. The risk of persistent trophoblastic disease has been estimated by Steller et al.14 to be much higher at 55% in multiple pregnancies compared with a 14% in singleton pregnancies with coexisting mole. A recent review of 126 cases of twin pregnancies and coexisting complete hydatidiform mole from Charing Cross Hospital has shown a live birth rate of 25%, a 20% risk of persistent gestational trophoblastic disease and a 75% rate of pregnancy loss, including spontaneous miscarriages, stillbirths or therapeutic termination13. However, the risk of persistent trophoblastic disease has been shown to be the same whether the pregnancy is terminated spontaneously, therapeutically or allowed to proceed to term. This is a key point in the treatment and counselling of these patients. The recent RCOG guideline on the treatment of gestational trophoblastic disease is largely based on these results13,15,16. Our patient has not required chemotherapy, although two of the six reported cases have required further treatment.
Complete hydatidiform moles are genetically diploid in origin but unusual in that their entire genome is paternal in origin while partial hydatidiform moles are usually triploid. Distinction between the two is important for the reasons highlighted above. In all the cases reported previously where molecular genetics has been investigated, DNA from fresh tissue has been used for fingerprint analysis to determine zygosity. In our case, as well in the case report from Jordan9, microsatellite polymorphisms which are highly polymorphic short tandem repeats have been used. Microsatellite genotyping has the advantages that it can be used on formalin fixed paraffin embedded tissue samples retrospectively, and also in providing rapid and very reliable results10,17. With the widespread use of ovulation induction regimens such triplet trophoblastic troubles may occur more often.