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Year : 2020  |  Volume : 3  |  Issue : 1  |  Page : 32-36

Rare occurrence of spontaneous ovarian hyperstimulation syndrome in frozen-thawed embryo transfer cycle resulting in healthy twin birth

GG Fertility Research and Women's Specialty Centre, Chennai, Tamil Nadu, India

Date of Submission08-Aug-2020
Date of Acceptance18-Dec-2020
Date of Web Publication30-Jan-2021

Correspondence Address:
Dr. Kamala Selvaraj
GG Fertility Research and Women's Specialty Centre, Chennai, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/tofj.tofj_5_20

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This article is about an incidence of spontaneous ovarian hyperstimulation syndrome (OHSS) following a frozen embryo transfer (FET) with hormone replacement therapy. OHSS, a potentially life-threatening condition, is an iatrogenic complication of controlled ovarian stimulation; therefore, it is very important to prevent and treat OHSS with calculated doses of ovulation-inducing agents. The OHSS is triggered by vasoactive mediators, which are released from hyperstimulated ovaries. The syndrome can also occur in stimulation with clomiphene and gonadotropins. The occurrence of OHSS is more common in young women (<35 years) with low body mass index (BMI) (BMI<21 kg/m2), patients with polycystic ovarian syndrome, 10 and above antral follicle count, high serum estrogen concentration, and multiple ovarian follicles at the time of surrogate luteinizing hormone surge of human chorionic gonadotropin administration and multiple pregnancies. It is mandatory to freeze all the embryos and canceling that particular cycle to avoid OHSS. However, to our surprise we found OHSS occurring in frozen-thawed hormone replacement cycle. Although spontaneous OHSS (sOHSS) remains a rare event, females with a history of OHSS may have an elevated risk for sOHSS. Usual monitoring of pregnancy following FET helps in early diagnosis of this very rare condition which can be managed conservatively.

Keywords: Cryopreservation, frozen embryo transfer, in vitro fertilization, ovarian hyperstimulation syndrome

How to cite this article:
Selvaraj K, Selvaraj P, Suganthi K, Annigeri V. Rare occurrence of spontaneous ovarian hyperstimulation syndrome in frozen-thawed embryo transfer cycle resulting in healthy twin birth. Onco Fertil J 2020;3:32-6

How to cite this URL:
Selvaraj K, Selvaraj P, Suganthi K, Annigeri V. Rare occurrence of spontaneous ovarian hyperstimulation syndrome in frozen-thawed embryo transfer cycle resulting in healthy twin birth. Onco Fertil J [serial online] 2020 [cited 2021 Feb 24];3:32-6. Available from: https://www.tofjonline.org/text.asp?2020/3/1/32/308408

  Introduction Top

Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of assisted reproduction technology. The syndrome is characterized by cystic enlargement of the ovaries and a fluid shift from the intravascular to the extravascular compartment. The events leading to fluid accumulation is due to increased capillary permeability, release of vasoactive substances such as vascular endothelial growth factor (VEGF) causing ascites and pleural effusion. Its impact on the general health of the patient can be deleterious and fatal cases have occasionally been reported. The relationship between human chorionic gonadotropin (hCG) and OHSS is thought to be mediated through the production of the angiogenic molecule VEGF. The incidence of moderate OHSS is estimated to be between 3% and 6%, while the severe form may occur in 0.1%–3% of all cycles.[1] It is characterized by massive ovarian enlargement, ascites, hydrothorax, hemoconcentration, renal and liver dysfunction, and very rarely venous thrombosis. The pathogenesis of OHSS is currently unknown.

Several strategies to manage OHSS have been proposed, which include reduction of hCG dose, cycle cancellation, continuing gonadotrophic analog, steroids, administration of intravenous (IV) albumin, hydroxyethyl starch solution, cabergoline, and low dose aspirin.[2],[3],[4],[5] Prophylactic IV albumin is supposed to interrupt OHSS development by increasing plasma oncotic pressure. IV albumin could be helpful in reducing the severity OHSS in high-risk patients. However, it does not completely eliminate the risk with possible side effect. Similarly, high protein diet also reduces the side effects of OHSS such as ascites, pleural effusion by increasing the plasma oncotic pressure.[6] GarciaVelasco[7] stated that agonist triggering combined with embryo vitrification and embryo transfer in a subsequent natural cycle prevented OHSS in a high-risk patients and resulted in excellent pregnancy outcomes. In high-risk patients, the embryo transfer should be canceled in the case of severe OHSS, freezing of all embryos should be the first measure to prevent OHSS.[8] However, to our surprise we found OHSS occurring in frozen-thawed hormone replacement cycle, however, while uncommon, can occur in normal spontaneous pregnancies.[9] Therefore, freezing all embryos would not completely prevent OHSS.

The present case report is of a woman with spontaneous OHSS (sOHSS) during pregnancy after a frozen embryo transfer (FET) cycle, the OHSS persisted until delivery.

  Case Report Top

A 32-year-old female, married for 8 years visited us for primary infertility, irregular menstrual cycle, oligomenorrhea, and features of hyperandrogenism suggestive of polycystic ovarian syndrome. The couple was evaluated, the husband's semen analysis showed severe oligo asthenozoospermia with few motile sperms. Transvaginal ultrasound (USG) showed polycystic ovaries and she was diagnosed with polycystic ovarian syndrome according to the Rotterdam consensus criteria (2003).[1] Her height was 162 cm, weight 54 kg, and body mass index 21 kg/m2. No other history of illness or any surgery performed. Her history revealed three failed intrauterine insemination (IUI) and one in vitro fertilization (IVF) cycle at another center.

In view of previous failed IUI/IVF cycle and male factor infertility, the couple were counseled and they opted for ART program. The couple were given a course of antibiotics prior to treatment, the spouse was able to provide two semen samples from which the pellets were frozen. Her day 2 hormonal profile of luteinizing hormone, follicle-stimulating hormone (FSH), and serum prolactin were within normal limits. The couple's karyotype was also normal. She was then initiated for IVF using long protocol with OC pills and down regulation with Injection. Zoladex, 3.6 mg (Goserelin acetate, Astrazeneca, UK) on day 20. This was followed by controlled ovarian hyperstimulation using recombinant FSH (Organon, Ireland) and human menopausal gonadotrophin (hMG) (IVF M2, 150 IU/ml, LG life sciences, Korea). Her response was good from both the ovaries. When the 3–4 follicles reached the maximum follicle size of 1.8 cm × 1.8 cm, HCG trigger was given in the form of Injection. Ovitrelle 250 mg (Merck Serona, Italy). Thirty-six h later transvaginal aspiration of oocyte was performed. Twenty-five oocytes were retrieved; 15 were normal and 10 were immature and of poor quality. Intracytoplasmic sperm injection was performed with husband's sperms on the 15 mature oocytes, of which only nine yielded fertilized embryos. Her cycle was canceled in anticipation of severe OHSS, and high E2 levels (7841 pg/mL), and enlarged ovaries. All the embryos were vitrified in separate high security vitrification cryo-straws. She was readmitted in the hospital to closely follow her vital statistics such as size of ovaries, abdominal girth, weight, and intake output chart. Relevant blood investigations such as complete blood count, liver function test, and renal function test with electrolytes were done on alternate days. She had hemoconcentration but her coagulation profile was within the normal limits. She was put on high oral protein diet (150 g/day) and was stabilized without any complications, thus did not require fluid tapping or prophylaxis for thromboembolism. She was discharged after a week. Follow-up scans were done till her next menstrual cycle.

One month later, when she came for follow-up, her USG showed normal-sized ovaries (2.8 cm × 2.4 cm and 2.9 cm × 2.5 cm), FET was planned and she was put on hormone replacement therapy. Oral estradiol valerate (4 mg/day) 2 mg twice a day was used (Progynova, Schering Korea, Seoul, Korea) beginning on day three of the cycle. On the 17th day of the cycle, her endometrial lining was 9 mm. Vaginal progesterone (800 mg/d; Utrogestan, Hanhwa Pharmaceuticals, Seoul, Korea) was prescribed. Embryos were thawed on day 17 of her cycle, 2 (8 cells) embryos of day 3 were transferred followed by segmented 1 contracted blastocyst of day 6 was transferred on day 21 [Figure 1] and [Figure 2].
Figure 1: Hyperstimulated ovaries

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Figure 2: Hyperstimulated ovaries with fluid

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Patient conceived in the same cycle and her first β HCG value was 733.9 mIU/ml on the 28th day and the second value was 2020 mIU/ml on the 30th day. Her transvaginal scan on the 38th day showed a twin intrauterine gestational sac. Fetal heart pulsations were observed on the 45th day. Usual scan for adnexa was done which showed the ovaries were normal in size. She had one episode of abdominal discomfort and pain during 8–9 weeks of gestation, the USG revealed intrauterine twin viable gestational sacs corresponding to 8–9 weeks with bilateral enlarged ovaries (Rt Ovary 8.1 cm × 5.6 cm and Lt Ovary 6.9 cm × 4.8 cm) hence she was admitted in the hospital. She was treated conservatively with a high protein diet along with the regular antenatal supplements and discharged after 5 days. At 12–13 weeks of gestation, she had another episode of bleeding per vaginum and was conservatively managed for threatened miscarriage. Regular USG revealed persistently increasing the size of ovaries until 14 weeks of gestation with the right ovary measuring 9.7 cm × 5.8 cm and left ovary 8.7 cm × 8.6 cm. The size of the ovaries remained around 8 cm × 5 cm on both sides up to 28 weeks beyond which they were not imaged separately on USG [Figure 3], [Figure 4], [Figure 5], [Figure 6].
Figure 3: Both enlarged ovaries

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Figure 4: Embryos-2, 8 cells, G-II

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Figure 5: Contracted blastocyst

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Figure 6: Twin gestation 8–9 weeks

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Her antenatal period thereafter was uneventful, at 28–29 weeks of pregnancy she developed pregnancy-induced hypertension (PIH), she was evaluated for the same, and the blood parameters were within normal limits. She was put on anti-hypertensive tablet labetalol 100 mg thrice a day and was under constant obstetric care. At 30–31 weeks of gestation, she developed severe PIH with impending eclampsia, and emergency cesarean was performed. She delivered a healthy male and female baby weighing 1.27 kg and 1.16 kg. During cesarean, both the tubes were found to be normal and both ovaries slightly enlarged.

The babies were in neonatal care, after a week mother and twin babies discharged uneventfully (2/9/19). The hospital stay was uneventful. A review pelvic scan 1 month post LSCS (Lower segment Cesarean section) showed a bulky uterus and the ovaries had reduced to normal size. Now, the babies are 10 months old, alive, and healthy.

  Discussion Top

Severe OHSS is considered a life-threatening condition and occurs in 0.2%–1.2% of stimulated cycles.[2],[3],[4],[5] The incidence of OHSS continues to increase and fatal cases involving associated cerebral infarction, pulmonary thromboembolism, and massive pulmonary edema have been reported[6],[7],[8] According to the European Society of Human Reproduction and Embryology guidelines, treatment with gonadotropins should be limited in patients at high risk for OHSS. Moreover, cycle cancelation, coasting, modification of the ovulation-triggering agent, administration of macromolecules, and cryopreservation of all embryos should be considered as secondary prevention.[10] Devroey et al.[11] recommended the concept of segmentation as a strategy to prevent OHSS. This strategy consists of optimizing ovarian stimulation, including gonadotropin-releasing hormone (GnRH) agonist triggering in a GnRH antagonist cycle (Segment A), optimal cryopreservation methods for oocyte or embryo vitrification (Segment B), and embryo replacement in a receptive, nonstimulated endometrium in a natural cycle or artificial endometrial preparation (Segment C). Embryo vitrification, however, is not a definitive treatment. Although OHSS after spontaneous pregnancy is rare, it has been reported in pregnant women with hypothyroidism, in women with polycystic ovarian disease, molar pregnancies, pituitary adenomas, and in women with mutations in FSH receptors.[12] Shin et al. demonstrated that freeze-all policy for the prevention of OHSS and a later transfer of frozen embryos might guarantee an acceptable pregnancy rate.[13] We proposed that FET should be performed within 23 weeks in day 2–4 transfer cycles and within 16 weeks in day 5 transfer cycles in case of freezing all embryos to prevent OHSS.

Kim et al. concluded that females with a history of OHSS may have an elevated risk for sOHSS, but sOHSS remains a rare event. Nevertheless, a patient with a history of OHSS should be closely monitored. The study demonstrates the importance of an early diagnosis and the role of observation and supportive care in the resolution of a potentially lethal syndrome. Hence, suggests that single embryo transfer may decrease the probability of the development of severe OHSS in cases in which freezing of all embryos is used to prevent OHSS.[14]

Cambiaghi et al.[15] compared the effect of oral whey protein for preventing OHSS. He concluded that the use of whey protein for preventing OHSS in high-risk patients may be an excellent alternative, especially to avoid the severe forms.

This case resulted in ovarian enlargement till delivery, which was well controlled with oral intake of protein diet from natural sources 150 g/day and did not require any fluid tapping. The occurrence of OHSS in a pregnancy following a thawed embryo transfer cycle, in this case, the onset of OHSS was not until 8 weeks of gestation. This case highlights the fact that although occurrence of OHSS is rare in an HRT FET cycle, a twin pregnancy characterized by elevated β-hCG levels, bilaterally enlarged ovaries, ascites, and other physical findings suggestive of intravascular depletion may be the result of OHSS, and a corresponding diagnosis should be considered.


We thank Ms. Sugunaa R and Ms. Srimathi E from HR department for their inputs in editing this article.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Abramov Y, Elchalal U, Schenker JG. Severe OHSS: An 'epidemic' of severe OHSS: A price we have to pay? Hum Reprod 1999;14:2181-3.  Back to cited text no. 1
Várnagy A, Bódis J, Mánfai Z, Wilhelm F, Busznyák C, Koppán M. Low-dose aspirin therapy to prevent ovarian hyperstimulation syndrome. Fertil Steril 2010;93:2281-4.  Back to cited text no. 2
König E, Bussen S, Sütterlin M, Steck T. Prophylactic intravenous hydroxyethyle starch solution prevents moderate-severe ovarian hyperstimulation in in-vitro fertilization patients: A prospective, randomized, double-blind and placebo-controlled study. Hum Reprod 1998;13:2421-4.  Back to cited text no. 3
Venetis CA, Kolibianakis EM, Toulis KA, Goulis DG, Papadimas I, Tarlatzis BC. Intravenous albumin administration for the prevention of severe ovarian hyperstimulation syndrome: A systematic review and metaanalysis. Fertil Steril 2011;95:188-96.  Back to cited text no. 4
Soliman BS. Cabergoline vs intravenous albumin or combination of both for prevention of the early onset ovarian hyperstimulation syndrome. Middle East Fertil Soc J 2011;16:56-60.  Back to cited text no. 5
Kumar P, Sait SF, Sharma A, Kumar M. Ovarian hyperstimulation syndrome. J Hum Reprod Sci 2011;4:70-5.  Back to cited text no. 6
[PUBMED]  [Full text]  
García-Velasco JA, Zúñiga A, Pacheco A, Gómez R, Simón C, Remohí J, et al. Coasting acts through downregulation of VEGF gene expression and protein secretion. Hum Reprod 2004;19:1530-8.  Back to cited text no. 7
Papanikolaou EG, Humaidan P, Polyzos N, Kalantaridou S, Kol S, Benadiva C, et al. New algorithm for OHSS prevention. Reprod Biol Endocrinol 2011;9:147.  Back to cited text no. 8
Oztekin O, Soylu F, Tatli O. Spontaneous ovarian hyperstimulation syndrome in a normal singleton pregnancy. Taiwan J Obstet Gynecol 2006;45:272-5.  Back to cited text no. 9
Delvigne A, De Sutter P, Dhont M, Gerris J, Olivennes F, Nygren KG. Ovarian hyperstimulation syndrome guidelines [Internet] 2013. [cited 2014 Sep 20]. Available from: http://www.gynera.ro/wp-content/uploads/2013/03/OHSS-LONG_GUIDELINES.pdf.  Back to cited text no. 10
Devroey P, Polyzos NP, Blockeel C. An OHSS-free clinic by segmentation of IVF treatment. Hum Reprod 2011;26:2593-7.  Back to cited text no. 11
Borna S, Nasery A. Spontaneous ovarian hyperstimulation in a pregnant woman with hypothyroidism. Fertil Steril 2007;88:705.  Back to cited text no. 12
Shin JJ, Jeong Y, Nho E, Jee BC. Clinical outcomes of frozen embryo transfer cycles after freeze-all policy to prevent ovarian hyperstimulation syndrome. Obstet Gynecol Sci 2018;61:497-504.  Back to cited text no. 13
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;41:140-5.  Back to cited text no. 14
Cambiaghi AS, Castellotti DS. Oral whey protein for preventing ovarian hyperstimulation syndrome. Fertil Steril. 2005;84 Suppl 1:S315.  Back to cited text no. 15


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]


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