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Characteristics of Ovarian Hyperstimulation Syndrome During Pregnancy Resulting from Frozen-Thawed Embryo Transfer: A Case Report and Literature Review

Nguyen-Tuong Ho

Taipei Fertility Center, Taipei, Taiwan

IVFMD, My Duc Hospital, Ho Chi Minh, Vietnam

E-mail Address: nguyentuonghnt@gmail.com

Corresponding author: Nguyen-Tuong Ho, My Duc Hospital, 4th Nui Thanh Street, Tan Binh, Ho Chi Minh City, Vietnam.

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Thi-Thanh-Thao Pham

Department of Obstetrics and Gynecology, Pham Ngoc Thach University of Medicine, Ho Chi Minh, Vietnam

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Shu-Huei Kao

Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

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, and

Chii-Ruey Tzeng

Taipei Fertility Center, Taipei, Taiwan

Department of Obstetrics and Gynecology, Taipei Medical University, Taipei, Taiwan

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https://doi.org/10.1142/S2661318224720010Cited by:0 (Source: Crossref)

Abstract

Ovarian hyperstimulation syndrome (OHSS) is a rare complication often associated with superovulation cycles for fertility treatment. This report presents a case of spontaneous OHSS (sOHSS) during a frozen-thawed embryo transfer (FET) cycle, an event rarely documented in the literature. We describe herein the case of a 37-year-old nulligravida woman who presented with features suggestive of polycystic ovarian syndrome (PCOS), underwent FET using an artificial endometrial preparation protocol, and was transferred with two frozen-thawed blastocysts, which finally resulted in a diamniotic twin pregnancy. At the 12th week of gestation, the patient developed sOHSS with hyperthyroidism, which was successfully managed conservatively, and favorable outcomes were observed at delivery. This case contributes to the limited literature on sOHSS in FET cycles, reinforcing the importance of tailored monitoring and conservative management for optimal outcomes in such infertile patients.

Keywords:

INTRODUCTION

Ovarian hyperstimulation syndrome (OHSS) is a relatively rare complication that typically occurs after a superovulation cycle for fertility treatment. The overall incidence of moderate-to-severe OHSS is approximately 1% to 10% (Li et al., 2014; Steward et al., 2014) and may reach 20% in high-risk patients (Gera et al., 2010). The predominant etiology of this condition is attributed to the elevated concentration of human chorionic gonadotropin (hCG), which stimulates the release of the pro-inflammatory mediator, vascular endothelial growth factor (VEGF), as well as the activation of the renin-angiotensin system. This cascade of events culminates in arteriolar vasodilation, augmented capillary permeability, and subsequent transudation of fluid, protein, and ions from the intravascular compartment into the extravascular spaces (Practice Committee of the American Society for Reproductive Medicine, 2016). Clinical manifestations such as ovarian enlargement, ascites, hemoconcentration, hypercoagulability, and electrolyte imbalances are typical (Steward et al., 2014). Excessive capillary permeability in severe OHSS can lead to profound hypovolemia, which has the potential to result in fatal outcomes (Sun et al., 2020).

A typical case of OHSS typically occurs after ovarian hyperstimulation with gonadotropins for oocyte retrieval, which is also referred to as treatment-induced or iatrogenic OHSS. The occurrence of OHSS in patients without exogenous gonadotropin administration has been very rare. However, OHSS can also develop without any external ovarian stimulation, commonly known as spontaneous OHSS (sOHSS) (Di Carlo et al., 2012; Sridev and Barathan, 2013). The incidence of this condition is sporadic in nonpregnant females (Chai et al., 2020) but notably more prevalent among pregnant individuals, especially those with polycystic ovarian syndrome (PCOS) (Daolio et al., 2023; Sridev and Barathan, 2013). In cycles involving assisted reproductive interventions, the excessive utilization of exogenous gonadotropin analogs has been associated with an increased incidence of this syndrome. In individuals with a high risk of OHSS, performing a fresh embryo transfer during the IVF cycle could elevate the occurrence and intensity of this syndrome (Henshaw et al., 2022; Lodh et al., 2014). Hence, for high responders, the ‘freeze-all’ and frozen-thawed embryo transfer (FET) strategy has been utilized, as it is deemed a safer approach. This syndrome rarely occurs in frozen embryo transfer cycles due to the absence of exposure to supraphysiological doses of gonadotropins and hCG. Thus, the characteristics of ovarian hyperstimulation after frozen embryo transfer, as well as its prognosis and appropriate treatment approach, remain subjects of considerable debate. Herein, we report a rare case of sOHSS resulting from an FET attempt, followed by successful conservative management of a twin pregnancy. Furthermore, we review the literature on OHSS in FET cycles to explore its incidence, management strategies, and outcomes in pregnant women experiencing this particular condition.

METHODOLOGY

Ovarian stimulation, oocyte retrieval, embryo vitrification, thawing, and transfer

The patient had been indicated for IVF using an ultrashort GnRH agonist protocol, as extensively described elsewhere (Mauries et al., 2022). Ovarian stimulation was conducted for 10 days with a total dose of 1,500 units of Pergoveris^® (containing follitropin alfa and lutropin alfa in a 2:1 ratio, Merck KGaA, Darmstadt, Germany), divided into 150 international units (IU) administered subcutaneously each day. When at least two follicles reached a mean diameter of 18mm or greater, a dual trigger of 3,500 IU hCG (Pregnyl^®, Organon, Oss, The Netherlands) in combination with 0.2mg of triptorelin acetate (Decapeptyl^®, Ipsen, Paris, France) was employed to induce final oocyte maturation. Oocyte retrieval was performed 36 hours after the trigger. Embryo morphology was assessed and graded on Day 3 and Day 5 according to the Gardner and Schoolgraft’s criteria (Gardner et al., 2000). The vitrification and thawing procedures followed standard protocols using the Kitazato Freeze Kit (Kitazato Corporation, Japan).

Endometrial preparation was done using a fixed-dose exogenous hormone protocol. The embryo transfer was scheduled once the endometrial thickness exceeded 7mm, and luteal phase support was provided using injectable progesterone and vaginal gel. Embryo transfer was performed in the lithotomy position using a Wallace^® Trial Transfer Catheter (CooperSurgical, Connecticut, USA). Pregnancy testing was conducted 10 days post-transfer. Upon confirmation of pregnancy, patients were scheduled for follow-up visits every 2 weeks.

Laboratory tests and imaging diagnostics

All laboratory tests, including anti-Müllerian hormone (AMH, measured in nanograms per milliliter—ng/mL), serum estradiol (E2, picogram per milliliter—pg/mL), luteinizing hormone (LH, IUs per liter—IU/L), progesterone (P4, nanograms per milliliter—ng/ mL), free thyroxine (fT4, nanograms per deciliter—ng/dL), thyroid-stimulating hormone (TSH, micro-IUs per milliliter— $μ$ $μ$ IU/mL), and beta-hCG( $β$ $β$ -hCG, milli-internationalunitspermilliliter—mIU/mL), were measured using automated Elecsys^® kits (Roche Diagnostics, Basel, Switzerland), applied on a clinically validated platform (Cobas e 411, e 601, e 170, Roche Diagnostics). In accordance with the manufacturer’s instructions, samples were processed within 4 hours before the test or cryopreservation. All assays were calibrated and quality-controlled using the manufacturer’s reagents. Gynecological and fetal ultrasounds during treatment were performed utilizing the GE Voluson E8 Ultrasound system (GE HealthCare Technologies, Illinois, USA).

Ethical approval

Clinical data for this case report was approved for publication by the Institutional Review Board (Tri-Service General Hospital, Taipei, Taiwan) with A202205161 as the approval number.

CASE PRESENTATION

A 37-year-old nulligravida woman, with a body mass index (BMI) of 18.8kg/m², presented at the clinic after 3 years of primary infertility. She exhibited features suggestive of PCOS, including oligomenorrhea coupled with intermittent dysmenorrhea and a serum AMH value of 8.02ng/mL. A controlled ovarian stimulation cycle was conducted, utilizing an ultrashort GnRH agonist protocol, a low-dose gonadotropin regimen, and dual trigger, resulting in 28 oocytes, 22 of which were successfully fertilized using intracytoplasmic sperm injection (ICSI). To mitigate the risk of OHSS, a freeze-all strategy was implemented.

An FET was conducted 6 months post-oocyte retrieval, employing an 8mg fixed-dose artificial cycle for endometrial preparation. A daily dose of 8mg E2 (Estrace^® Tablet 2mg, Warner Chilcot, New Jersey, USA). As the endometrial thickness reached 8.6mm, embryo transfer was scheduled, and progesterone supplementation was prescribed using one Crinone 8% (Merck KGaA, Darmstadt, Germany) applicator BID and an HP 250mg (McGuff Pharmaceuticals, California, USA) injection every 5 days. On the day of the transfer, blood tests revealed an appropriate hormonal profile, with serum E2, P4, and LH levels at 239pg/mL, 13.3ng/mL, and 0.545mIU/mL, respectively. The patient underwent FET with two blastocysts of adequate quality (4AA according to Garner’s criteria). Two weeks post-transfer, transvaginal ultrasonography (TVS) reported two intrauterine gestation sacs with heartbeat activity, alongside ovaries of average size. During the time of follow-up, there was a prominent rise in serum E2 concentration from 239pg/mL on FET day to 9,453pg/mL at 9-week gestation ( Table 1).

**Table 1. Hormonal characteristics.**
Gestational age (weeks)	ET day	4–5 weeks	6 weeks	9 weeks	12 weeks
E2 (ng/mL)	239	268.8	2,914	9,453	15,702
P4 (ng/mL)	13.23	8.61	29.40	51.35	104.1
LH (IU/L)	0.545	¡0.1	0.448	0.421	0.187
$β$ $β$ HCG (mIU/mL)	–	9,774	–	–	185,121
TSH ( $μ$ $μ$ IU/mL)					0.04
FT4 (ng/dL)					1.96

AMH:-Müllerian hormone (measured in nanograms per milliliter—ng/mL); $β$ $β$ -hCG: beta-hCG (milli-international units per milliliter—mIU/mL); E2: serum estradiol (picogram per milliliter—pg/mL); fT4: free thyroxine (nanograms per deciliter—ng/dL); LH: luteinizing hormone (international units per liter—IU/L); P4: progesterone (nanograms per milliliter—ng/mL); TSH: thyroid-stimulating hormone (micro-IUs per milliliter— $μ$ $μ$ IU/mL).

At 12 weeks of pregnancy, the patient was hospitalized due to vomiting three to four times a day with abdominal discomfort. Clinical manifestations included normal vital signs, with a slightly increased heart rate (90–110 beats per minute), a distended abdomen, and a uterus size corresponding to 14 weeks of gestation. Pelvic examination revealed a soft pouch Douglas, a closed cervix, and two soft and fluctuant adnexal masses. Subsequent TVS confirmed a live twin-intrauterine gestation sac, accompanied by enlarged ovaries with numerous hypoechoic cysts (“spoke-wheel” form) measuring $10 \times 6 \times 7$ $10 \times 6 \times 7$ cm on the right side and $8 \times 6 \times 6$ $8 \times 6 \times 6$ cm on the opposite, accompanied by an anechoic fluid layer approximately 2cm thick in the posterior cul-de-sac. Laboratory tests indicated abnormally elevated concentrations of $β$ $β$ -hCG and E2 at 185,121mIU/mL and 15,702pg/mL, respectively. Spontaneous OHSS was suspected. Given the mild severity of the symptoms, Novamin (prochlorperazine) was prescribed, and she was discharged for self-follow-up at home.

During the subsequent check-up after 1 week, the patient experienced relief from hyperemesis gravidarum. However, mild-onset palpitations also developed and gradually became more regular. The fT4 level showed a slight increase (1.96ng/dL), while serum TSH decreased dramatically (0.04 $μ$ $μ$ IU/mL). Consequently, a diagnosis of hyperthyroidism during pregnancy was established after a normal thyroid ultrasound report, leading to the initiation of a low-dose propylthiouracil regimen with PTU^® 50mg (Par Pharmaceutical, New York, USA), one tablet per day. After 2 weeks of treatment, all symptoms were almost improved with normal serum fT4 (1.06ng/dL) and TSH (0.446 $μ$ $μ$ IU/mL). The TVS demonstrated considerably decreased ovarian sizes ( $5 \times 5 \times 6$ $5 \times 5 \times 6$ cm and $3 \times 5 \times 6$ $3 \times 5 \times 6$ cm, respectively).

The pregnant woman was discharged from the centre and continued to have routine antenatal check-ups.

At 36 weeks of gestation, the pregnant woman underwent a prescheduled and uneventful cesarean section. Both maternal and neonatal health conditions were found to be favorable, with the twin newborns weighing 2,774g and 2,628g, respectively. No abnormalities of the ovaries were reported during the cesarean surgery.

DISCUSSION

Ovarian stimulation during assisted reproductive cycles often triggers OHSS, with risk factors including prior OHSS history, PCOS, or high gonadotropin doses (Gera et al., 2010). Women at younger ages and having low BMI were also associated with a higher rate of this disorder (Namavar Jahromi et al., 2018). On the other hand, sOHSS has been extremely rare and can occur even without the stimulation of gonadotropin. While the risk factors for sOHSS are considered to be akin to those of iatrogenic OHSS, idiopathic occurrence of OHSS has been reported to be frequently linked to hypothyroidism and/or follicle-stimulating hormone receptor (FSHR) gene mutations (Chai et al., 2020; Katulande et al., 2013; Kim et al., 2017; Sridev and Barathan, 2013; Uchida et al., 2013). The case presented in this report involved a high-risk twin pregnancy with a history of PCOS. During the FET cycle, the patient underwent an artificial endometrial preparation protocol involving complete exogenous hormonal supplementation. Despite the absence of ovarian activity and corpus luteum, the extreme elevation of hCG was believed to have triggered the development of sOHSS. It is essential to diligently monitor high-risk women undergoing ART treatment to prevent the occurrence of such adverse events and ensure the well-being of both the mother and neonates after infertility management.

Not only found in OHSS, enlarged polycystic ovaries during pregnancy can also be an indication of a variety of distinct disorders (Malinowski et al., 2015; Phelan and Conway, 2011). The presence of bilaterally enlarged ovaries with numerous homogenous hypoechoic cysts mostly indicates a diagnosis of OHSS and, additionally, may also point to a rarer condition known as hyperreactio luteinalis (HL). This syndrome results from a markedly elevated circulating hCG level or hypersensitivity to hCG that leads to the formation of large theca lutein cysts (Amoah et al., 2011). While sOHSS can develop early in the first trimester and has the potential of a life-threatening condition (Wang et al., 2021), HL has been reported to usually develop in the third trimester and typically resolves without specific medical management. Moreover, HL is possibly associated with hyperandrogenism (Kaňová and Bičíková, 2011; Tanaka et al., 2001) and, sometimes, hyperthyroidism. Thyroid hormone changes during pregnancy are occasional and can be a physiological phenomenon or a manifestation of a number of medical conditions that need to be treated. In normal pregnancy, the thyrotropic activity of alpha-hCG ( $\propto$ $\propto$ -hCG) results in a decreased serum TSH level and relatively high thyroxine (T4) and triiodothyronine (T3), usually postdating the serum thyroxine-binding globulin (TBG) rise. Both pregnancy and OHSS are often associated with an increase in serum TSH level. In some cases, primary hypothyroidism can lead to ovarian hyperstimulation, which is classified as type III ovarian hyperstimulation according to De Leener’s adjusted classification (Katulande et al., 2013; Kim et al., 2017; Langroudi et al., 2013). Because of its structural similarity to FSH, extremely elevated TSH binds nonspecifically to FSHRs and stimulates the formation of ovarian cysts. Severe OHSS could also be the cause of hypothyroidism (Yu and Wang, 2016). Another study also reported that TSH increases after superovulation induction for oocyte retrieval and hypothesized that ovarian overstimulation could cause hypothyroidism under an unknown mechanism and be more frequent in women with thyroid autoimmunity (Poppe et al., 2011). On the other hand, hyperthyroidism is extremely rare and tends to not occur for the first time in pregnant women without preexisting thyroid disorders (Marx et al., 2008). A new onset hyperthyroidism during pregnancy is usually associated with another rare benign syndrome, HL. This phenomenon is characterized by moderate-to-marked cystic enlargement of the ovaries due to multiple benign theca lutein cysts and is most often associated with hydatidiform mole or choriocarcinoma (Wajda et al., 1989). Typical characteristics of sOHSS and HL are described in Table 2. The case reported herein was found with polycystic ovaries occurring at the first trimester of a twin pregnancy accompanied by a history of high response to gonadotropin, thus suggesting the diagnosis of sOHSS type I or II (Kaňová and Bičíková, 2011; Tanaka et al., 2001). The limitation of the clinical case reported here is that we did not perform genetic sequencing to diagnose FSHR mutations, which prevented us from excluding sOHSS type I in this woman. Nonetheless, the occurrences of sOHSS and HL seem to be two entities in continuum, as previously reported (Haimov-Kochman et al., 2004). Differentiating between these two syndromes remains challenging and calls for further clarification.

**Table 2. Characteristics of HL and sOHSS.**
Characteristics	HL	sOHSS
Time of onset	Majority (54%) diagnosed in the third trimester and 16% in the first trimester (Mehandru et al., 2017).	First trimester (Cabar, 2016)
Risk factors	Multiple gestation and hypothyroidism (Chauhan et al., 2021; Chaverri et al., 2019); gestational trophoblastic diseases (Hashmi and Tufail, 2007; Mathew et al., 2019); hyperandrogenism (Baxi et al., 2014; Mathew et al., 2019; Wong et al., 2021); hyperthyroidism (Wong et al., 2021); and polycystic ovary syndrome and hydrops (Mehandru et al., 2017).	Multiple gestation, hypothyroidism, and polycystic ovary syndrome
Supposed pathophysiology	Exaggerated ovarian luteinization due to hyperstimulation by or hypersensitivity to hCG, characterized by marked hypertrophy followed by luteinization of the theca interna layer.	Extreme FSHR activation due to unspecific binding or mutated FSHR
Pathology	Follicular cysts with luteinization of theca interna or granulosa cells; edema of theca layer and stroma.	No specific description
Symptoms	Usually asymptomatic, the most frequent symptom is abdominal pain, with 25% virilization. Ascites, pleural effusion, or other symptoms are less frequent and severe.	Rapidly developing ascites and/or pleural effusion. Rarely virilization.
Management	Conservatively managing HL during pregnancy is the preferred approach, with surgical intervention being reserved for instances of complications like ovarian cyst torsion or rupture, which could lead to potential intra-abdominal bleeding (Grochal et al., 2008).	No consensus on specific treatment. Usually classified and treated using OHSS severity classification

FSHR: follicle-stimulating hormone receptor; HL: hyperreactio luteinalis; hCG: human chorionic gonadotropin; OHSS: ovarian hyperstimulation syndrome; sOHSS: spontaneous OHSS.

Since the occurrence of HL in normal pregnancy is usually accompanied by mild and self-limiting symptoms, it is advised to restrict invasive treatment interventions or termination of pregnancy (Cavoretto et al., 2014). On the other hand, sOHSS management during pregnancy is more complex due to the need to take into account both the fetal condition and OHSS symptom severity of the woman. Multifetal pregnancy reduction (MFPR) or artificial abortion has been indicated to save the mother’s life (Mor and Schenker, 2014). However, to apply such procedures in women whose pregnancies resulted from assisted reproductive treatments can be more intricate, as these women inherently face challenges in achieving pregnancy. The current literature on sOHSS after an FET cycle remains limited ( Table 3). Kim et al. first reported a case of sOHSS during pregnancy from a FET cycle. The clinical case context closely resembled our patient, wherein the patient had a BMI of 18.31kg/m², was diagnosed with PCOS, and had a twin pregnancy from an FET using an artificial cycle. The onset of symptoms in the first trimester progressed to a much higher severity, including massive ascites and severe dyspnea. The symptoms progressively worsened, eventually leading to the termination of the pregnancy at 26 weeks and 6 days of gestation. This disparity in severity could potentially be attributed to the FSHR gene mutations. Specifically, the FSHR gene in Kim et al.’s report was sequenced, revealing one intron variation (c.374+69 C $>$ $>$ T in intron 4) and two exon 10 variations (c.919 G $>$ $>$ A Ala307Thr and c.2039 G $>$ $>$ A Ser680Asn) (Kim et al., 2014). Yang et al. reported a case of severe OHSS with viable intrauterine dizygotic dichorionic diamniotic triplet pregnancy. An MFPR operation (from three to one) was required to ameliorate OHSS progression (Yang et al., 2020). A shared characteristic among these reports was that they involved high responders carrying multiple pregnancies. However, our patient had OHSS at mild-to-moderate severity, which spontaneously went into remission after the first trimester without any invasive interventions required. All three reported cases resulted in successful live births, suggesting that the severity and prognosis of sOHSS after FET may be more favorable compared to cases occurring during ovarian hyperstimulation cycles.

Fig. 1. Morphological change of the ovaries during pregnancy. (A) At the time of embryo transfer, the patient had two normal-sized ovaries with several small cysts, which are typical of a patient with PCOS. (B) Ten days after embryo transfer, the ultrasound revealed two gestational sacs in the uterine cavity. While the ovarian size remained unchanged, fluid was observed in the cul-de-sac. (C) Subsequently, the ovarian size started to increase, even though the patient remained asymptomatic. (D) The patient experienced severe lower abdominal pain, tachycardia, and restlessness. The ultrasound showed two ovaries with a “spoke-wheel” appearance, containing numerous large cysts. A diagnosis of moderate-mild OHSS and hyperthyroidism was made, and the patient received conservative treatment with PTU. (E) After 1 month of PTU treatment, the patient’s thyroid hormone levels returned to normal, and the size of the ovaries decreased. Consequently, the patient’s symptoms resolved, and she was transferred to a specialist obstetric hospital for further monitoring of the pregnancy. L: left ovary, OHSS: ovarian hyperstimulation syndrome, R: right ovary, U: uterus.

**Table 3. Literature review of sOHSS in pregnancies resulted from frozen-thawed embryo transfer cycles.**
Author, Year	Age at diagnosis (years)	Gestational age at diagnosis	Clinical manifestations	Laboratory testing at diagnosis	Ultrasound at diagnosis	Management	Outcome
Yang et al., 2020	30	8 weeks	An infertile 30-year-old woman had two blastocysts transferred using an artificial cycle, which resulted in a dichorionic diamniotic triplet gestation. Signs and symptoms: lower abdominal pain and swelling, nausea, oliguria, and dyspnea.	Serum $β$ $β$ - $hCG > 225, 000$ $hCG > 225, 000$ mIU/mL $AFP = 24.90$ $AFP = 24.90$ UI/mL $WBC = 9.56 \times 1 0^{6}$ $WBC = 9.56 \times 1 0^{6}$ /mL, neutrophils at 83%, $HCT = 41.2 %$ $HCT = 41.2 %$ $Fibrinogen = 7.3$ $Fibrinogen = 7.3$ g/L, D- $dimer = 1, 360 μ$ $dimer = 1, 360 μ$ g/L	Ascites Size of the ovaries: NR	Multifetal pregnancy reduction $(3 - 1) + IV$ $(3 - 1) + IV$ fluid therapy	Singleton live birth at the 39th week of pregnancy
Kim et al., 2014	32	11 weeks	A nulligravida female presented with PCOS (oligomenorrhea and hyperandrogenism) and 2-year primary infertility. She underwent an artificial endometrium preparation cycle and had two blastocysts transferred, which resulted in a dichorionic diamniotic twin pregnancy. Signs and symptoms: ascites and dyspnea.	$WBC = 11.25 \times 1 0^{6}$ $WBC = 11.25 \times 1 0^{6}$ /mL, $HCT = 36.6 %$ $HCT = 36.6 %$ $PLT = 320, 000$ $PLT = 320, 000$ /mL FSHR gene variations: Intron 4 c.374+69 T $>$ $>$ C Exon 10 c.919 G $>$ $>$ A, Ala307Thr Exon 10 c.2039 G $>$ $>$ A, Ser680Asn	Ascites Size of the ovaries: $27 cm \times 12 cm$ $27 cm \times 12 cm$ $26 cm \times 11 cm$ $26 cm \times 11 cm$	Supportive management with cyst aspiration and paracentesis	Preterm twin live birth at the 27th week of gestation
This study	37	12 weeks	A 37-year-old nulligravida woman, with suspected PCOS, presented at the clinic after 3 years of primary infertility. An artificial endometrium preparation cycle was performed with two good-quality blastocysts transferred, which resulted in a dichorionic diamniotic twin pregnancy. Signs and symptoms: mildly distended abdomen, tachycardia, and vomiting.	Serum $β$ $β$ - $hCG = 185, 121$ $hCG = 185, 121$ mIU/mL $TSH = 0.04 μ$ $TSH = 0.04 μ$ IU/mL $fT 4 = 1.96$ $fT 4 = 1.96$ ng/dL	Cul-de-sac fluid accumulation Size of the ovaries: $10 \times 6 \times 7$ $10 \times 6 \times 7$ cm $8 \times 6 \times 6$ $8 \times 6 \times 6$ cm	Supportive management with propylthiouracil treatment	Late-preterm twin live birth after a planned cesarean at the 36th week of gestation

AFP: alpha-fetoprotein; $β$ $β$ -hCG: beta-human chorionic gonadotropin; FSHR: follicle-stimulating hormone receptor; fT4: free thyroxine; HCT: hematocrit; PCOS: polycystic ovary syndrome; PLT: platelets; TSH: thyroid-stimulating hormone; WBC: white blood cells; NR: not recorded.

This work reminds that OHSS can occur in the absence of ovarian induction or corpus luteum, especially in high responders. In addition, our observations appear to affirm that a cautious approach is advisable when managing sOHSS during pregnancy, with treatment customized based on symptom severity. Supplementary palliative treatments, in combination with management of accompanying hormonal disorders, should be undertaken as dictated by the clinical context, thus enhancing outcomes and preventing exacerbation of symptoms. The consultative support must encompass the awareness that while this condition is exceedingly rare and well known over the world, it is actually benign and will automatically resolve after childbirth (Namavar Jahromi et al., 2018). We, in concordance with previous reports, suggest that although sOHSS can occur during pregnancy from FET cycles without ovarian stimulation, its clinical presentation is generally mild, and supporting the goal of a live birth remains warranted. This report helps emphasize that sOHSS can be managed conservatively in pregnant women from FET cycles.

CONCLUSIONS

We reported a rare case of sOHSS occurring during an FET cycle with hyperthyroidism. Differential diagnosis between OHSS and HL should be considered, as they are two entities on a continuum. For pregnant women with a history of infertility, the monitoring of sOHSS should be tailored according to the severity of symptoms, prioritizing conservative treatment approaches. This case underscores the importance of vigilance in monitoring high-risk individuals undergoing assisted reproductive treatments and suggests that, in pregnancies resulting from FET cycles, sOHSS can be successfully managed without invasive interventions, ultimately leading to favorable outcomes for both the mothers and neonates.

FUNDING

This work received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

CONFLICT OF INTEREST

The authors affirm that there is no conflict of interest associated with this study.

DATA AVAILABILITY

Data is available under reasonable request.

AUTHORS’ CONTRIBUTIONS

N.-T.H. participated in data curation, formal analysis, investigation, visualization, writing—original draft, and writing—review and editing. T.-T.-T.P. participated in writing—original draft. S.-H.K. participated in conceptualization, data curation, and investigation. C.-R.T. participated in resources, supervision, and writing—review and editing.

ORCID

Nguyen-Tuong Ho https://orcid.org/0000-0002-6561-1596

Shu-Huei Kao https://orcid.org/0000-0003-4618-0898

Chii-Ruey Tzeng https://orcid.org/0000-0002-7445-0261

References

Amoah C, Yassin A, Cockayne E, Bird A . Hyperreactio luteinalis in pregnancy. Fertil Steril. 2011; 95(7) :2429.e1–3. Crossref, Google Scholar
Baxi LV, Grossman LC, Abellar R . Hyperreactio luteinalis in pregnancy and hyperandrogenism: a case report. J Reprod Med. 2014; 59(9–10) :509–11. Google Scholar
Cabar FR . Ovarian hyperstimulation syndrome in a spontaneous singleton pregnancy. Einstein (Sao Paulo). 2016; 14(2) :231–4. Crossref, Google Scholar
Cavoretto P, Giorgione V, Sigismondi C, Mangili G, Serafini A, Dallagiovanna C, Candiani M . Hyperreactio luteinalis: timely diagnosis minimizes the risk of oophorectomy and alerts clinicians to the associated risk of placental insufficiency. Eur J Obstet Gynecol Reprod Biol. 2014; 176 :10–6. Crossref, Google Scholar
Chai W, He H, Li F, Zhang W, He C . Spontaneous ovarian hyperstimulation syndrome in a nonpregnant female patient: a case report and literature review. J Int Med Res. 2020; 48(9) :300060520952647. Crossref, Google Scholar
Chauhan YV, Dalwadi PP, Gada JV, Varthakavi PK, Bhagwat N . Unrecognized primary hypothyroidism as a possible cause of hyperreactio luteinalis. Cureus. 2021; 13(2) :e13573. Google Scholar
Chaverri AP, Solis BEA, Paulín FD , Cárdenas JEG. Hyperreactio luteinalis and hypothyroidism: a case report. Case Rep Womens Health. 2019; 21 :e00094. Google Scholar
Daolio J, Sperduti S, Casarini L, Falbo A, Materazzo C, Aguzzoli L, Villani MT . Spontaneous and iatrogenic ovarian hyperstimulation syndrome in the absence of FSHR mutations: a case report of two unexpected cases. BMC Med Genomics. 2023; 16(1) :45. Crossref, Google Scholar
Di Carlo C, Savoia F, Ferrara C, Tommaselli GA, Bifulco G, Nappi C . Case report: a most peculiar family with spontaneous, recurrent ovarian hyperstimulation syndrome. Gynecol Endocrinol. 2012; 28(8) :649–51. Crossref, Google Scholar
Gardner DK, Lane M, Stevens J, Schlenker T, Schoolcraft WB . Blastocyst score affects implantation and pregnancy outcome: towards a single blastocyst transfer. Fertil Steril. 2000; 73(6) :1155–8. Crossref, Google Scholar
Gera PS, Tatpati LL, Allemand MC, Wentworth MA, Coddington CC . Ovarian hyperstimulation syndrome: steps to maximize success and minimize effect for assisted reproductive outcome. Fertil Steril. 2010; 94(1) :173–8. Crossref, Google Scholar
Grochal F, Turner CD, Chern AL, Wilters J, Jeanty P . Sonographic detection of the ovarian hyperreactio luteinalis in pregnancy. J Diagn Med Sonogr. 2008; 24(6) :369–73. Crossref, Google Scholar
Haimov-Kochman R, Yanai N, Yagel S, Amsalem H, Lavy Y , Hurwitz Spontaneous ovarian hyperstimulation syndrome and hyperreactio luteinalis are entities in continuum. Ultrasound Obstet Gynecol. 2004; 24(6) :675–8. Crossref, Google Scholar
Hashmi H, Tufail A . Hyperreactio luteinalis in association with molar pregnancy. Pak J Surg. 2007; 24. Google Scholar
Henshaw CA, Kirschen GW, Chen L, Vaught AJ, Cameron K, Christianson M . Severe ovarian hyperstimulation syndrome requiring recurrent large-volume paracenteses until 21 weeks’ gestation: a case report. F S Rep. 2022; 3(3) :275–9. Google Scholar
Kaňová N, Bičíková M. Hyperandrogenic states in pregnancy. Physiol Res. 2011; 60(2) :243–52. Crossref, Google Scholar
Katulande P, Kariyawasam SS, Senanayake HM, Weerakkodi M . Multicystic ovaries and pituitary pseudo-adenoma associated with primary hypothyroidism. J Obstet Gynaecol. 2013; 33(1) :17–9. Crossref, Google Scholar
Kim MK, Won HJ, Shim SH, Cha DH, Yoon TK . Spontaneous ovarian hyperstimulation syndrome following a thawed embryo transfer cycle. Clin Exp Reprod Med. 2014; 41(3) :140–5. Crossref, Google Scholar
Kim SJ, Yoon JH, Kim HK, Kang HC . Spontaneous ovarian hyperstimulation syndrome in a young female subject with a lingual thyroid and primary hypothyroidism. Korean J Intern Med. 2017; 32(3) :559–62. Crossref, Google Scholar
Langroudi RM, Amlashi FG, Emami MH . Ovarian cyst regression with levothyroxine in ovarian hyperstimulation syndrome associated with hypothyroidism. Endocrinol Diabetes Metab Case Rep. 2013; 2013 :2013. Google Scholar
Li HW, Lee VC, Lau EY, Yeung WS, Ho PC, Ng EH . Cumulative live-birth rate in women with polycystic ovary syndrome or isolated polycystic ovaries undergoing in-vitro fertilisation treatment. J Assist Reprod Genet. 2014; 31(2) :205–11. Crossref, Google Scholar
Lodh M, Mukhopadhyay J, Sharma V . A case of severe ovarian hyperstimulation syndrome. Indian J Clin Biochem. 2014; 29(3) :386–9. Crossref, Google Scholar
Malinowski AK, Sen J, Sermer M . Hyperreactio luteinalis: maternal and fetal effects. J Obstet Gynaecol Can. 2015; 37(8) :715–23. Crossref, Google Scholar
Marx H, Amin P, Lazarus JH . Hyperthyroidism and pregnancy. BMJ 2008; 336(7645) :663–7. Crossref, Google Scholar
Mathew HM, Lee CW, Haddady S . Rapidly progressive and severe hirsutism from hyperreactio luteinalis within a background of polycystic ovary syndrome. AACE Clin Case Rep. 2019; 5(2) :e86–e90. Crossref, Google Scholar
Mauries C, Ranisavljevic N, Mollevi C, Brunet C, Hamamah S, Brouillet S, Anahory T . “Short agonist stop” protocol, an ovarian stimulation for poor responders in in vitro fertilization (IVF): a pilot study. Front Endocrinol (Lausanne). 2022; 13 :13. Crossref, Google Scholar
Mehandru N, Harris J, Kalinkin O, Liguori A . Hyperreactio luteinalis in the third trimester complicating fetal hydrops and mirror syndrome. J Clin Gynecol Obstetr. 2017; 6 :41–4. Crossref, Google Scholar
Mor YS, Schenker JG . Ovarian hyperstimulation syndrome and thrombotic events. Am J Reprod Immunol. 2014; 72(6) :541–8. Crossref, Google Scholar
Namavar Jahromi BM, Parsanezhad MM, Shomali ZM, Bakhshai PM, Alborzi MM, Moin Vaziri NMDP, Anvar ZP . Ovarian hyperstimulation syndrome: a narrative review of its pathophysiology, risk factors, prevention, classification, and management. Iran J Med Sci. 2018; 43(3) :248–60. Google Scholar
Phelan N, Conway GS . Management of ovarian disease in pregnancy. Best Pract Res Clin Endocrinol Metab. 2011; 25(6) :985–92. Crossref, Google Scholar
Poppe K, Unuane D, D’Haeseleer M, Tournaye H, Schiettecatte J, Haentjens P, Velkeniers B . Thyroid function after controlled ovarian hyperstimulation in women with and without the hyperstimulation syndrome. Fertil Steril. 2011; 96(1) :241–45. Google Scholar
Practice Committee of the American Society for Reproductive Medicine. Prevention and treatment of moderate and severe ovarian hyperstimulation syndrome: a guideline. Fertil Steril. 2016; 106(7) :1634–47. Crossref, Google Scholar
Sridev S, Barathan S . Case report on spontaneous ovarian hyperstimulation syndrome following natural conception associated with primary hypothyroidism. J Hum Reprod Sci. 2013; 6(2) :158–61. Crossref, Google Scholar
Steward RG, Lan L, Shah AA, Yeh JS, Price TM, Goldfarb JM, Muasher SJ . Oocyte number as a predictor for ovarian hyperstimulation syndrome and live birth: an analysis of 256,381 in vitro fertilization cycles. Fertil Steril. 2014; 101(4) :967–73. Crossref, Google Scholar
Sun B, Ma Y, Li L, Hu L, Wang F, Zhang Y, Dai S, Sun Y . Factors associated with Ovarian Hyperstimulation Syndrome (OHSS) severity in women with polycystic ovary syndrome undergoing IVF/ICSI. Front Endocrinol (Lausanne). 2020; 11 :11. Google Scholar
Tanaka Y, Yanagihara T, Ueta M, et al.. Naturally conceived twin pregnancy with hyperreactio luteinalis, causing hyperandrogenism and maternal virilization. Acta Obstet Gynecol Scand. 2001; 80(3) :277–8. Crossref, Google Scholar
Uchida S, Uchida H, Maruyama T, Kajitani T, Oda H, Miyazaki K, Kagami M, Yoshimura Y . Molecular analysis of a mutated FSH receptor detected in a patient with spontaneous ovarian hyperstimulation syndrome. PLoS One. 2013; 8(9) :e75478. Crossref, Google Scholar
Wajda KJ, Lucas JG, Marsh WL, Jr . Hyperreactio luteinalis. Benign disorder masquerading as an ovarian neoplasm. Arch Pathol Lab Med. 1989; 113(8) :921–5. Google Scholar
Wang N, Chen Z, Guo X, et al . Sudden death due to severe Ovarian Hyperstimulation Syndrome: an autopsy-centric case report. Am J Forensic Med Pathol. 2021; 42(1) :88–91. Crossref, Google Scholar
Wong KY, Mak MWH, Lee KM, Lee KF . A case of hyperreactio luteinalis complicated with biochemical hyperandrogenism, symptomatic hyperthyroidism and preeclampsia. J Endocr Soc. 2021 May 3; 5(Suppl 1) :A776–7. 10.1210/jendso/bvab048.1579 Crossref, Google Scholar
Yang L, Wang R, Wang F, Wang F, Zou L . Ovarian hyperstimulation syndrome in a frozen-thawed embryo transfer pregnancy: a rare case report. BMC Pregnancy Childb. 2020; 20(1) :313. Crossref, Google Scholar
Yu Q, Wang JB . Subclinical hypothyroidism in PCOS: impact on presentation, insulin resistance, and cardiovascular risk. Biomed Res Int. 2016; 2016 :2016. Crossref, Google Scholar

Vol. 06, No. 04

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Received 4 June 2024

Accepted 21 November 2024

Published: 4 January 2025

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This is an Open Access article published by World Scientific Publishing Company. It is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 (CC BY-NC-ND) License which permits use, distribution and reproduction, provided that the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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