Maternal complications of fetal triploidy: a case report

Abstract

A 32-year-old woman underwent a medical termination in the second trimester of a spontaneously conceived triploid pregnancy after developing early-onset preeclampsia with subsequent haemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. Placental histology was normal (non-molar) and unusually, she developed ovarian hyperstimulation syndrome (OHSS) 4 weeks later. She was managed conservatively following multidisciplinary team input to exclude malignant pathology. The rarity of late-onset spontaneous OHSS could have resulted in inappropriate surgical management. In the absence of supportive treatment there is also a risk of the condition progressing to a critical stage. Follow-up ultrasonography after termination of pregnancy should be considered for women with evidence of ovarian hyperstimulation, particularly if other risk factors for OHSS are present. Delayed-onset OHSS should be considered in women presenting with bilateral cystic ovarian enlargement after triploid pregnancy.

Background

A triploid pregnancy is an abnormal pregnancy that contains a complete extra set of haploid chromosomes (either maternal or paternal) and is not compatible with life, usually self terminating within the first trimester. The progression of a triploid pregnancy into the late second trimester is extremely rare estimated at 1 in 300 000.¹ This case demonstrates two rare maternal complications associated with a triploid pregnancy progressing into the second trimester: severe early onset preeclampsia and haemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome - both are obstetric emergencies that require immediate treatment. In severe cases, prompt delivery of the fetus and placenta (regardless of the presence or absence of known abnormalities) are recommended to improve maternal outcomes, albeit at the demise of the pregnancy if below the gestation of viability (22–24 weeks). This case is especially interesting because, despite prompt termination of the pregnancy, the woman re-presented 4 weeks later with delayed-onset ovarian hyperstimulation syndrome (OHSS). This very rare occurrence, not previously reported in the literature, may have resulted in severe morbidity from both the underlying disease pathogenesis as well as potential inappropriate surgical management due to diagnostic uncertainty. This case is of additional interest as the vast majority of reported maternal complications in triploid pregnancies are associated with an abnormal (molar) placenta² and the histology of the placenta in our case was non-molar.

Case presentation

A 32-year-old-nulliparous woman with no significant medical history had a spontaneous conception of a singleton pregnancy. Her routine dating scan at 11 weeks’ gestation was normal, with a nuchal translucency measurement of 1.9 mm and no concerns regarding the maternal ovaries. Her combined screening test showed an elevated serum beta human chorionic gonadotropin (βhCG) measurement of 9.810 MoM and a high adjusted risk for trisomy 21 of 1:113. She underwent a specialist scan in the fetal medicine unit at 16+1 weeks gestation which revealed a small for gestational age and hydropic fetus with pericardial effusion, abdominal ascites, polyhydramnios and anomalies, including cystic hygroma and short femurs. The placenta was grossly oedematous, enlarged and uniformly filled with lacunae (figure 1). The maternal ovaries were moderately enlarged (ovarian volumes: left 99 mL and right 49 mL), with multiple segmented cysts (figure 2). Amniocentesis was performed for DNA microarray and showed a female sex with triploidy (69, XXX) explaining the anomalies noted. PCR for toxoplasma, parvovirus and cytomegalovirus was negative. Routine assessment at the time of the scan found severe hypertension with a blood pressure of 160/100 mmHg, and significant proteinuria with a raised urinary protein:creatinine ratio of 1586. The woman denied associated symptoms of headache, upper abdominal pain, worsening oedema or visual disturbance. A diagnosis of early-onset preeclampsia was made and she was admitted for treatment with antihypertensives.

Figure 1.

Ultrasound scan at 16+1 week of gestation showing a small for gestational age and hydropic fetus with short femurs and cystic hygromas. The placenta is enlarged with multiple lacunae.

Figure 2.

Enlarged multicystic maternal ovaries: left 82×35×66 mm and right 41×51×46 mm.

Due to fetal anomalies and severe maternal preeclampsia, the patient opted for a medical termination of the pregnancy at 16+2 weeks gestation. She required a manual removal of placenta and despite minimal blood loss, her haemoglobin decreased from 96 g/L to 65 g/L, requiring a blood transfusion. Alanine aminotransferase was elevated at 122 U/L and she was hypoalbuminemic (serum albumin of 14 g/L). In addition, there was an acute decrease in platelets from 302×10⁹/L to 189×10⁹/L. These investigations, in the context of her preeclampsia, were in keeping with a diagnosis of HELLP syndrome. Her biochemistry and blood pressure normalised with antihypertensive management and she was discharged 2 days post medical termination of pregnancy with advice for outpatient blood pressure monitoring and βhCG level follow-up. Histology of the placenta demonstrated hydropic villous tissue but no evidence of gestational trophoblastic disease.

Two weeks after medical termination of pregnancy, her βhCG remained abnormally high at 3455 U/L, and at 4 weeks, she presented acutely with gross abdominal distension and pain. She was systemically well with normal observations but was found to have a large mass arising from the pelvis and extending to the xiphisternum. There was mild peripheral oedema but no evidence of pleural effusion or pulmonary oedema. Ultrasound, CT and MRI of her abdomen and pelvis were performed. All demonstrated bilateral enlarged multilocular cystic ovarian masses measuring 22 cm in diameter with a small amount of ascites (figure 3). Her βhCG had decreased to 486 U/L. Carcinoembryonic antigen, cancer antigen 19-9, Inhibin B and alpha-fetoprotein were normal. Cancer antigen 125 (CA125) was moderately raised at 95 kU/L. The patient was referred for a multidisciplinary discussion at our tertiary gynaecological oncology centre. Due to the benign feature of her cysts, it was decided to manage her conservatively. A repeat pelvic ultrasound 12 weeks post termination of pregnancy revealed that her cystic ovaries had reduced in size to 15 cm each, and her βhCG became <2 U/L at 16 weeks.

Figure 3.

MRI demonstrating the extent of bilateral cystic ovarian enlargement.

Investigations

The patient’s serum βhCG was markedly elevated from the beginning of the pregnancy, most likely due to an abnormally large placenta. Unusually, the OHSS worsened after termination of the pregnancy, when βhCG concentrations started to decrease. We suspect this may be due to another triggering mechanism for OHSS. Ludwig et al hypothesised that the placenta may release vasoactive substances with a longer half-life when a termination of pregnancy is performed.³ They recommend following up these patients for 2–3 days; however, an extended period of monitoring should be considered as our patient presented 4 weeks post termination of pregnancy with worsened symptoms. Our patient had a negative βhCG level after 16 weeks.

In view of the palpable pelvic mass, serum tumour markers were ordered as per local and national guidelines.⁴ The intention was to ‘rule out’ various ovarian malignancies, including germ cell tumours and borderline ovarian cysts, which can present bilaterally and in young women. The CA125 was moderately raised; however, it is important to stress the non-specific nature of this tumour marker which can be elevated by a plethora of benign conditions including ascites and mechanical stretching of the peritoneum by large pelvic masses.

As per local and national guidelines⁴ we performed an ultrasound as the first-line mode of imaging to investigate the pelvic mass. Although ultrasound is widely used to classify the nature of ovarian cysts, the limitation in this case was the inability to view each ovary in one or two frames. In view of the complex history, rapid enlargement of the ovaries and uncertainty regarding the diagnosis, our team felt that cross-sectional imaging was warranted. Furthermore, the presence of ascites and a multilocular adnexal mass over 10 cm in size are classified as ‘malignant features’ using the International Ovarian Tumour Analysis group’s M and B rules.⁵ As benign features were also present, this rendered the scan inconclusive overall. An abdominopelvic CT and MRI was performed with the intention of ‘ruling out’ ovarian malignancy at the tertiary gynaecological oncology multidisciplinary team meeting. The lack of suspicious features, including high vascularity, solid components, papillary projections, significant ascites or evidence of metastases concluded in a benign diagnosis.

Differential diagnosis

Following assessment at our fetal medicine unit, where the patient’s raised blood pressure and proteinuria were identified, the initial differential diagnosis was a rare obstetric condition called ‘mirror syndrome’. Mirror syndrome comprises a triad of fetal hydrops (caused by a variety of genetic and structural abnormalities), which is ‘mirrored’ by oedema in the mother, in association with preeclampsia. The maternal fluid overload can be peripheral, pulmonary or ascitic. The literature on mirror syndrome is scanty however, there is a consensus that mirror syndrome is unlikely in the presence of maternal biochemical abnormalities.⁶ The acute decline in haemoglobin and platelets in combination with raised liver function tests were highly suggestive of HELLP syndrome, although ideally, a serum lactate dehydrogenase and blood film would have confirmed haemolysis.

Later on, we considered the differential diagnosis of hyperreactio luteinalis, an uncommon benign condition of multicystic ovarian enlargement in pregnancy where theca lutein cysts develop due to increased production of βhCG. Most women will be asymptomatic with an incidental finding on routine scans; however, it can be severe and may be difficult to differentiate from OHSS due to both having similar risk factors, symptoms and ultrasonographic appearances. The two conditions have been described as entities in continuum, with the same non‐surgical expectant management.⁷ In this case, we believe the degree of ovarian enlargement, presence of ascites and low albumin levels points more towards OHSS.

As discussed, we had to consider the possibility of an ovarian malignancy. This was excluded following multidisciplinary team discussion in a tertiary gynaecological oncology centre, with review of the tumour markers and imaging. Due to the rarity of spontaneous and late-onset OHSS, we appreciate that the diagnosis can easily be confused with a malignant process, especially when it presents or progresses after termination of pregnancy. Prompt imaging and early involvement of a multidisciplinary team were essential to avoid unnecessary surgical interventions. As in our case, supportive treatments are often successful without the condition progressing to a critical stage.

Outcome and follow-up

The patient was thoroughly debriefed regarding the events surrounding her pregnancy. Due to the increased risk of recurrent preeclampsia and OHSS, it was recommended that she be closely followed up in subsequent pregnancies. We are pleased to report that she had a healthy full-term pregnancy 2 years later and maintained a normal blood pressure throughout. She did, however, have slight cystic enlargement of both her ovaries during the pregnancy which did not progress or require additional treatment.

Discussion

We present a complex and interesting case of a spontaneous triploid conception progressing into the second trimester, with associated preeclampsia and HELLP syndrome. The absence of a molar placenta and the late-onset severe OHSS makes this case extremely rare and not previously reported in the literature.

Survival of a triploid fetus in the second trimester is rare⁸ and progression to 16–20 weeks in the region of 1 in 300 000.¹ The placenta in triploid pregnancies can present with both varying genotypes (molar and non-molar) and ultrasonographic phenotypes.⁹ Unlike other common chromosomal abnormalities, triploidy may cause maternal morbidity. A review of 17 fetuses with triploidy in the second trimester found a 35% maternal risk of developing early-onset preeclampsia or hypertension without proteinuria.² We have encountered only two other published cases of preeclampsia with triploidy without molar changes on histological investigation of the placenta.^{10 11} To our knowledge, this is the first reported case of HELLP syndrome in a triploid pregnancy with a non-molar placenta.

OHSS is mostly an iatrogenic condition in patients who undergo ovulation induction with exogenous gonadotropins. It involves enlarged ovaries with fluid shift changes and biochemical derangement. It is severe in 0.1%–2% of patients with potential life threatening consequences.¹² Spontaneous OHSS is rare and there are only a few published case reports in normal singleton pregnancies without underlying risk factors.^13–16 Spontaneous OHSS usually presents at 8–14 weeks of amenorrhoea, compared with 3–5 weeks of amenorrhoea in iatrogenic OHSS.¹⁷ It is associated with highly elevated βhCG, especially in cases of multiple¹⁸ and molar pregnancies.³ It can also occur rarely in patients with high levels of thyroid-stimulating hormone (TSH), for example, hypothyroidism¹⁹ and pituitary adenomas.²⁰ βhCG and TSH cause hyperactivation of the follicle-stimulating hormone (FSH) receptor in granulosa cells of the ovary. Alternatively, some patients may have mutations in the FSH receptor gene, causing an increased sensitivity to normal levels of βhCG.²¹

The recurrence rate of triploidy in future pregnancies, with or without a molar placenta, is not increased. An argument for earlier termination of pregnancies with fetal malformations suggestive of triploid or molar pregnancy (or after diagnostic testing in stable cases) to avoid maternal morbidity can be made considering the potential life-threatening complications of severe OHSS, preeclampsia, and HELLP.

Patient’s perspective.

Thank you for contacting me and sending me the report, even though it was 3 years ago, you can imagine I remember those days same as it was yesterday. Honestly, I didn’t know what exactly happened to me and my baby, everything was confused and ‘rare’, and it didn’t answer to any particular ‘problem’. So, reading your report, I understood that indeed everything was very ‘rare’, but at least I have read carefully my case and I found a lot of details. Thank you.

Learning points.

• Unlike other common chromosomal abnormalities, triploidy may cause maternal morbidity, including preeclampsia, HELLP syndrome and OHSS.

• OHSS should be considered in women presenting with bilateral cystic ovarian enlargement following any pregnancy event.

• After termination of pregnancy, serial ultrasonography should be considered for follow-up of women with ovarian hyperstimulation.

• Debriefing of women after rare pregnancy complications is important and valued.