Hyperreactio luteinalis following frozen embryo transfer managed by fetal reduction

Abstract

We report a rare case of hyperreactio luteinalis (HL) which developed in association with triplet pregnancy in a 27-year-old woman who underwent assisted reproductive technology treatment for primary infertility. She had undergone frozen embryo transfer 2 months after ovarian retrieval. She presented in the first trimester with abdominal pain and distension associated with ovarian enlargement and did not respond to conservative management. Fetal reduction was done from triplets to twins which resulted in good symptomatic relief for the patient. Fetal reduction may be an effective approach in such situations when conservative strategies fail in HL.

Background

Hyperreactio luteinalis (HL) is a rare condition occurring during pregnancy, associated with multiple theca lutein cysts causing bilateral ovarian enlargement. It is caused by elevated β-human chorionic gonadotropin (β-hCG) levels or an abnormal response to normal levels due to heightened sensitivity of the ovarian tissue to β-hCG receptors.¹ HL is commonly seen in association with gestational trophoblastic disease, multiple pregnancies, fetal hydrops, fertility treatment and isoimmunisation.¹ Generally, HL is benign, typically resolving postpartum and hence managed conservatively. Rarely HL can present as acute abdomen due to ovarian torsion or haemorrhage necessitating intervention.²

We describe a rare occurrence of HL following frozen embryo transfer (FET) which required intervention in the form of fetal reduction for symptomatic relief of the patient.

Case presentation

A 27-year-old woman presented with primary infertility after 6 years of marriage. She had regular menstrual cycles, normal ovaries and uterus and normal hormonal profile (Follicle stimulating hormone (FSH): 5.4mIU/mL, LH: 4mIU/mL, Anti Mullerian hormone (AMH): 4.3mIU/mL). Her partner had severe oligoasthenozoospermia with sperm count of 2.5 million/mL and a total motility of 15%. Considering the severe male factor, they were advised artificial reproduction with intracytoplasmic sperm injection (ICSI). She reported on the second day of menstrual cycle with normal hormonal levels (E2: 2:5 pg/mL, Luteinising hormone (LH): 1.7mIU/mL; FSH: 5.4mIU/mL) and was started on 150 IU of recombinant FSH and 75 IU of human menopausal gonadotropin for ovarian stimulation. Follicle growth was monitored. She was started on a gonadotropin-releasing hormone antagonist 0.25 mg s.c from the sixth day of stimulation. She was maintained on the same dose of gonadotropins for 9 days as growth rates were normal. On the 10th day, she was triggered with recombinant human chorionic gonadotropin (Ovitrelle) 250 μg given subcutaneously. Estradiol levels on the day of trigger was 4200 pg/mL. Twenty oocytes were retrieved followed by ICSI which was done on 19 mature oocytes. This resulted in fertilisation of 15 embryos which were cryopreserved. Embryo transfer was deferred for fear of ovarian hyperstimulation. Post retrieval, she was monitored for signs of ovarian hyperstimulation and was asked to review after 2 months for FET.

Two months later, she was prepared for FET. Her hormonal assay on the second day of menstrual cycle and pelvic ultrasound was normal. She was started on oral estradiol valerate 2 mg two times a day for 14 days. Endometrial assessment on day 14 showed a triple line endometrium measuring 9 mm. Both ovaries appeared normal with follicles less than 5 mm in size. She was started on intramuscular progesterone 100 mg daily for 3 days followed by embryo transfer. Oral estradiol was maintained at 2 mg two times a day. Three embryos were transferred. After 14 days of transfer, her β-hCG was 2228 mIU/mL. Ultrasound done at 6 weeks of gestation showed triplet pregnancy with cardiac activity in all the three sacs. Both ovaries were normal in size. She was continued on intramuscular progesterone for luteal support. At 8 weeks of gestation, ultrasound showed trichorionic triamniotic pregnancy with normal cardiac activity in all sacs (figure 1A). Both ovaries were enlarged with right ovary measuring 7.4×4×4 cm and left ovary measuring 6.4×4.1×4.8 cm with multiple cysts in both ovaries (figure 1B, C).

Figure 1.

Ultrasound at 8 weeks of gestation showing triplets (A) and enlarged ovaries with multiple cysts (B and C). Ultrasound around 10 weeks showing increased enlargement of ovaries with a ‘spoke-wheel’ appearance and minimal free fluid in the pelvis (D, E and F). Both ovaries gradually decreased in size and returned back to normal size by 4 weeks of gestation (G).

Investigations

At 9 weeks, the patient developed nausea and vomiting with abdominal distension and pain. Ultrasound showed normally developing triplet gestation with bilateral enlarged ovaries (right: 15.8 cm × 7.7cm × 12.2 cm; left: 12 cm × 5.8 cm × 7.3 cm) with a ‘spoke-wheel’ appearance and minimal free fluid in the pelvis and pleural space bilaterally (figure 1D–F). At 10 weeks, her symptoms became worse and she could not sit or walk. She was admitted with a diagnosis of hyperreactio luteinalis. She had mild hypoproteinaemia and hypoalbuminaemia with no haemoconcentration (haemoglobin: 109 g/L; haematocrit: 33.7%). Her β-hCG was 200 000 mIU/mL.

Treatment

She was administered 20% 100 mL albumin every 4 hours and initiated on prophylactic heparin. The patient was offered medical termination of pregnancy or fetal reduction to singleton so as to decrease the β-hCG and give her symptomatic relief. After detailed counselling regarding the procedure, she opted for fetal reduction to twin gestation. Fetal reduction is beneficial in higher order multiples since it provides a reduction in the rates of miscarriages and preterm births. Reduction from triplet to a twin pregnancy in our patient would result in a reduction of pregnancy loss from 15% to 3.5%.³ All the three fetuses were screened for aneuploidy with Nuchal translucency (NT) and markers such as nasal bone, tricuspid and ductus venosus flow and structural abnormalities were ruled out. The fetus with the highest NT and the one that is farthest from the cervix was chosen for reduction. The procedure was performed at 11 weeks of gestation under local anaesthesia with the transabdominal insertion of a 20 G × 15 cm needle. Under continuous ultrasound guidance, potassium chloride was instilled into the fetal thoracic cavity and the needle withdrawn after cardiac asystole was confirmed.

Outcome and follow-up

Post reduction, she improved symptomatically and the β-hCG level dropped to less than a lakh mIU/mL in 3 days. She could sit and walk now and was discharged to home with twin pregnancy. Pregnancy was closely monitored as per protocol for twin gestation. Both ovaries gradually decreased in size and returned back to normal size by 4 weeks of gestation (figure 1G). There were no signs of virilisation. At 34 weeks of gestation, one of the fetuses had abnormal Doppler findings showing low resistance flow at middle cerebral artery with reversal of cerebroplacental ratio. In view of the abnormal Doppler, the patient underwent caesarean section and delivered a healthy baby boy and a baby girl of 2 kg weight each with Apgar scores of 9 at 1 min and 5 min.

Discussion

Our case of HL is unique in many ways. First, there are only two such reported instances in the literature of this condition developing after FET.^{4 5} Second, HL in the first trimester is very rare in contrast to its more common occurrence in the third trimester and postpartum. This makes it difficult to differentiate it from spontaneous ovarian hyperstimulation syndrome (OHSS).⁶ Third, the deviation from the more commonly advocated strategy of conservative management for HL in our patient. Progressive ovarian enlargement resulted in the patient becoming bedridden at 10 weeks. In such a scenario, conservative approach is not an option and we proceeded with fetal reduction. Ours is only second such instance in the literature of fetal reduction being employed for the management of HL.⁷

The ovarian enlargement occurring in the first trimester of pregnancy following assisted reproductive technology (ART) would make one consider OHSS as the closest differential diagnosis. The differences between the two entities are subtle rather than distinct and are detailed in table 1. Since there are many things in common between them including aetiology, clinical features and the predominantly conservative management, they may be considered as entities in continuum.⁸ More important is the other differential of HL, which is ovarian malignancy. In a review of 96 cases of HL, malignancy was suspected in 38% of patients with many inadvertently undergoing oopherectomy.⁹ The bilaterality of involvement along with morphological regularity suggests more of functional abnormality rather than malignancy. The spoke-wheel appearance suggests theca lutein cysts without solid component. The rapid resolution of ovarian enlargement and free fluid along with reduction in the β-hCG levels following fetal reduction seen in our case suggests HL due to raised β-hCG.

Table 1.

Outline of differences between hyperreactio luteinalis (HL) and ovarian hyperstimulation syndrome (OHSS)

Characteristics	OHSS	HL
Pathophysiology	Defect of the aromatase gene and FSH receptor Abnormal sensitivity to vascular endothelial growth factor	Constantly elevated hCG levels Increased β-hCG receptor sensitivity of the ovaries
Common association	Fertility treatment, commonly ovarian stimulation with exogenous gonadotrophins	Nulligravida and multigravida
Relationship to pregnancy	With or without pregnancy	Only with pregnancy
Time of occurrence	First trimester	Late trimesters and post partum
Main clinical feature	Ascites	Ovarian enlargement
Extra ovarian symptoms	Virilisation is rare	Virilisation in 25% of patients
Clinical course	More acute	More indolent
Life-threatening complications	More frequent—includes fluid shifts resulting in hypovolemia and thrombosis	Less frequent—misdiagnosis as ovarian tumour is possible
Pregnancy-related complications	Preterm labour	Pre-eclampsia and fetal growth restriction

hCG, human chorionic gonadotropin.

Following ART, HL has been reported both with ovulation induction with gonadotrphins as well as FET.^{4 5 10} Cases of HL following fresh cycles of IVF have not been reported. Increased β-hCG receptor sensitivity of the ovarian tissue may be more important than simple raise in β-hCG, since multiple pregnancies following fertility treatment, though common do not seem to predispose the individual to HL. Though majority of cases of HL are managed conservatively, more aggressive approach is suggested when the condition becomes life threatening as happened in our case. Fetal reduction may be one such approach which by decreasing the placental production of β-hCG reduces the ovarian enlargement bringing symptomatic relief to the patient. Also, it is a safe procedure since it neither interferes with the maternal health nor affects the prospects of future fertility.

Learning points.

• Hyperreactio luteinalis (HL) is a rare condition in pregnancy associated with bilateral ovarian enlargement caused by elevated β-human chorionic gonadotropin (β-hCG) levels or increased sensitivity of the ovarian tissue to β-hCG receptors and commonly seen in association with gestational trophoblastic disease, multiple pregnancies and following fertility treatment.

• HL can also be seen in association with assisted reproductive technology procedures including frozen embryo transfer.

• Ovarian hyperstimulation syndrome and ovarian malignancies are the important differential diagnoses for HL and conservative strategies are the mainstay of management.

• In selected cases of multiple pregnancies presenting with HL in the first trimester, fetal reduction can bring symptomatic relief by decreasing β-hCG levels.

• The rare self-limiting entity of HL should be remembered while encountering ovarian enlargement in pregnancy so that unnecessary surgical procedures including oopherectomy are avoided.