Effect of early intake versus known standard intake of cabergoline in prevention of development of OHSS in ICSI cycles

Introduction

Ovarian hyperstimulation syndrome (OHSS) is a dangerous iatrogenic compli-cation of ovulation induction⁽¹⁾. Though it is a rare ⁽²⁾ or an uncommon⁽³⁾ condition its true incidence is difficult to delineate as a strict consensus definition is lacking⁽³⁾ . The incidence ranges from of 33% in mild cases to 3-6% in moderate cases while reaching only 1-2% in severe cases^(4,5). These severe cases are life-threatening conditions that could be fatal. Furthermore, the pathophy-siology of this condition is not fully clear, understanding it helps identifying preventive and treating modalities ^(6).

The syndrome almost always presents either up to 8 days after hCG administration in susceptible patients (early onset) or during early pregnancy, 9 or more days  after hCG administration related to pregnancy induced hCG production(late onset⁽⁷⁾. Early OHSS can to some extent be predicted by pre-ovulatory indices of ovarian response, in time to institute preventive measures such as cancellation ^(8). Late OHSS does not relate strongly to pre-ovulatory ovarian response, making it difficult for clinicians to identify the cycles in which it is likely to occur ^(2,9).

Clinical features of OHSS include a spectrum of findings, such as ovarian enlargement, ascites, haemoconcentration, hyper-coagulability, and electrolyte imba-lances. Pleural effusion, acute renal insufficiency, and venous thrombo-embo-lism occur in severe cases. A classification of OHSS symptoms was adopted by ASRM.^(3). Human chronic gonadotropine hCG administration for the final follicular maturation and ovulation triggering is the knock-out stimulus for OHSS. This leads to over expression of vascular endothelial growth factor VEGF in the ovary, and release of vasoactive angiogenic substances or mediators that increase capillary permeability.  Subsequently, fluid shift from the intra- to the extravascular spaces with acute third-space fluid sequestration occurs. This causes hemoconcentration with reduced organ perfusion, alterations in blood coagulation and the resulting risk of thromboembolism and leakage of fluid into the peritoneal cavity and lungs ^{(3,6 ,10,11).}

The most important of these mediators is vascular endothelial growth factor (VEGF). VEGF is a vasoactive mediator which increases capillary permeability. VEGF has been found to be expressed in human ovaries and is expressed at a higher level in the granulosa cells ^(12). It has been observed that VEGF mRNA levels increases after human chorionic gonadotropin (hCG) administration in granulosa cells and the elevated levels of the secreted proteins have been detected in serum, plasma, and peritoneal fluids in women at risk or with OHSS. VEGF stimulates new blood vessel development and vascular hyperpermeability by interacting with its VEGF receptor 2 (VEGFR2)^(13,14). Other factors that have been implicated include angotensin II, interleukin-6, insulin like growth factor 1 IGF-1, epidermal growth factor, transforming growth factor a and b, basic fibroblast growth factor, platelet driven growth factor interleukin 1b and others which can act directly or indirectly via VEGF ^(3).

No definite cure for this syndrome ⁽¹⁵⁾, prevention is considered as an essential and vital issue. Every attempt should be done to identify those at high risk. Two types of prevention have been suggested; primary prevention (before ovarian stimulation) and secondary prevention after ovarian stimulation^.(2).  Many preventive approaches have been used for its prevention including using antagonist rather than agonists for ovulation induction, triggering ovulation with agonist, metformin administration, intravenous albumin, cabergoline, corticosteroids, aspirin, coasting, cryopreservation and others, but the reports are conflicting and many of them have not been critically evaluated ^(2,3).

There is growing evidence that the ergot derivative; cabergoline which is a potent dopamine receptor agonist on D2 administration reduces incidence and severity of OHSS.⁽³⁾  Dopamine agonists prevent the phosphorylation of VEGFR2 and reduce the in vitro and in vivo release of vasoactive angiogenic agents. As a result, vascular permeability is also reduced. Consequently, dopamine agonist at a daily dose of 0.5 mg has been supposed to be a potential new strategy to prevent OHSS and reduce its severity.⁽¹⁶⁾

Results obtained with animal models⁽¹⁷⁾ and the safe clinical profile of dopamine agonists, have led to studies on humans.⁽¹⁶⁾ Many studies have evaluated cabergoline as a preventive strategy to reduce the incidence of OHSS using varying doses and regimens^(2,3,10) Effectiveness of cabergoline in reduction of the incidence of OHSS was reported in a group of women with the polycystic ovarian syndrome and hyperprolactinemia⁽¹⁸⁾. Also, safety of cabergoline use during infertility treatment: fertilization,  implantation  and pregnancy rates were similar to matched controls.⁽¹⁹⁾ Four systematic reviews and meta-analyses have revealed that cabergoline reduces the incidence of moderate/severe OHSS without affecting implantation, pregnancy and  miscarriage  rates.^(20-23) Two Cochrane reviews reported that the quality of evidence regarding the use dopamine agonist versus placebo in prevention of ovarian hyperstimulation ranged from very low to moderate.^(15,24)  On the other hand,  others reported  that there is good evidence that dopamine agonist administration starting at the time of hCG trigger for several days reduce the incidence of OHSS  (grade  A)^(3).

Various cabergoline administration proto-cols were reported in different studies. Doses were ranging from 0.25 mg- 0.5 mg and were started either from day of HCG triggering or day of oocyte retrieval. ^{(16-23 & 25-28})  Cabergoline was continued form two days in one study⁽²⁷⁾ and up to 8 days in most studies^(25,28) or as long as three weeks in one study ⁽²⁶⁾ . Alveizer et al.,(²⁵⁾ gave 0.5 mg cabergoline daily for 8 days from the day of HCG injection.  Carriza et al.,⁽²⁶⁾ gave 0.5 mg cabergoline daily for 3 weeks from the day after oocyte retrieval.  Salah Edeen and Alhelou⁽²⁷⁾ used 0.5 mg cabergoline oral on 2 successive days and repeated after 1 week starting from the day of HCG. Shaltout et al.,⁽²⁸⁾ used   0.25 mg cabergoline daily for 8 days from the day of HCG injection.

The influence of timing of cabergoline initiation on prevention of OHSS is currently under study^.

Patients and Methods

This study was an interventional comparative clinical trial including eighty patients with high risk for ovarian hyperstimulation attended to the infertility clinic/center of Obstetrics and Gynae-cology department, El Minia University Maternity hospital, El Minia, Egypt and in private centers and undergoing ovulation induction using GnRH agonist down regulation protocol for ICSI cycles. Patients were divided into two groups according to the drug regimen used for OHSS risk prevention.  The study was conducted between April 2019 and April 2020 after approval of the study protocol by the Ethical Committee of and all participants will sign an informed written consent form.

Inclusion criteria: (high risk for OHSS)

1. Female less than 35 years old.
2. Previous history of sever OHSS.
3. Patient undergoing ovulation induction by GnRH Agonist down regulation protocol
4. Presence of >18 oocytes11 mm or more in diameter at any day of the stimulation cycle before HCG trigger.
5. Ovary size >10cm.
6. Serum estradiol >3500 pg/ml on the day of HCG administration.

Exclusion criteria: (low risk for OHSS)

1. Female more than 35 years old
2. Patient with single ovary.
3. Patient undergoing ovulation induction by antagonist protocol.
4. Presence of < 18 oocytes during oocyte retrieval or at any time before HCG trigger.
5. Ovary size <10cm.
6. Serum estradiol <3500 pg/ml on the day of HCG administration.

All patients will be subjected to:

1. History taking (name, age, duration of infertility, type of infertility male or female factor, previous history of OHSS)
2. Clinical examination.
3. Ultrasound scanning.
4. Investigations (CBC, HCT value, liver and kidney functions, E2 level)
5. β-hCG was checked 15 days after embryos transfer.

A long protocol was used for ovulation induction starting with subcutaneous daily injections of triptorelin acetate 300 micrograms decapeptyle, on Day 21 of the preceding cycle. Urinary FSH (fostimon) and HMG (merional) injections were administered at the first day of the subsequent cycle, at an initial dose of 150 IU; the doses were subsequently adjusted on the basis of responses and monitoring with transvaginal scan, and serum estradiol levels. The duration of   stimulation was tailored according to the response with serial estradiol estimations and Ultrasound scans that will be performed on alternate days between Days 5 and 10 of the cycle and as necessary thereafter.

Once the decision to administer HCG was taken, patients were immediately allocated into two randomized   groups; 40 patients each   according to the drug regimen used for OHSS prevention (using computer-generated tables):

Group A (group I) (n=40) (Early adminis-tration group) The drug regimen consists of cabergoline oral tab 0.5 mg (Dostinex, Pfizer Australia Pty ltd) that was administered daily starting from the day of peak serum estradiol level and optimum follicle number that were fulfilled the criteria for successful hyperstimulation –whatever this day is -)   and continued  till the day of ovum retrieval and for more 8 days after .

Group B (group II) (n=40) (Standard  administration group). The drug regimen consists of cabergoline oral tab 0.5 mg (Dostinex, Pfizer Australia Pty ltd) that was administered daily starting from the day of ovum retrieval for 8 days after.

Follow up

Patients were followed up according to the standard protocol for ICSI. Primary outcome variables were efficacy and safety.  Efficacy of each regimen was recorded as the success in the prevention of OHSS. Safety was recorded as the presence or absence of side effects. Secondary outcome variables were pregnancy rate, live-birth rate….etc.  All patients were assessed every week after retrieval and for 8 weeks to determine early clinical or ultrasound evidence of OHSS. The occurrence and severity of OHSS was defined according to the classification described by Golan et al.,⁽⁵⁾

^.

The presence of OHSS is defined in accordance with the Golan 5 grade system and women who at least are at grade 2 of this classification (Mild) considered as OHSS cases and will experience abdominal distention and discomfort, nausea and vomiting and/or diarrhea and enlargement of ovaries(5-12cm). In Moderate forms, ultrasound evidences of ascites will be observed and severe OHSS accompany with clinical signs of ascites, hydrothorax, breathing disorders, hemoconcentration, coagulopathy and renal perfusion decrease.

Complaints of abdominal discomfort, nausea, vomiting and ultrasound evidence of enlarged ovaries (5–12 cm) and/ or the detection of ascites defined the occurrence of moderate OHSS. The presence of clinically evident ascites and/or hydro-thorax, increased blood viscosity and coagulation abnormality or laboratory Investigation of increased hematocrite level (>45%) or decreased S. albumin (<35 g/l) defined the occurrence of severe OHSS. Patients with severe OHSS will be hospitalized. Onset of OHSS within 9 days of ovulatory trigger is defined as early onset OHSS while beyond 9 days is defined as late onset OHSS. Clinical and ultrasound examinations will be performed on the day of embryo transfer, then weekly to detect the occurrence of OHSS.

All patients will be instructed to contact us if they experi-enced difficulty in breathing, recurrent vomiting, decreased urine volume, dizziness on standing, abdominal pain, enlargement of the abdomen, and rapid weight gain and were examined as needed. Women will be monitored on an outpatient basis via phone contact and visits until menstruation occurred or until fetal heart activity was detected in pregnant patients. The primary outcome is an evaluation of the development of OHSS in the partici-pants. Implantation rate and clinical pregn-ancy rate were secondary outcomes.

Results

The study was conducted between April 2019 and April 2020 in private centers on 80 patients seeking for ICSI included in the study according to inclusion criteria.

There is no statistically significant differ-ence between early administration and standard administration groups as regard the age and BMI.

There is no statistically significant differ-ence between early administration and standard administration groups as regard cycle cancelation, clinical pregnancy and 1st time abortion. OHSS was statistically significant higher in standard adminis-tration than early administration group.

Discussion

OHSS is the most serious complication of COS and is potentially fatal, so optimization of prophylactic measures will reduce morbidity and mortality in ART clinics. Prophylactic strategies include; using the antagonist protocol, decreasing starting gonadotropin dose, metformin, coasting, cycle cancelation, cryopreser-vation of all embryos, in vitro maturation, calcium gluconate and infusion of plasma expanders ^[29].

In high responders, GnRH agonist trigger in antagonist protocol is the most effective strategy to prevent or at least significantly decrease OHSS ^[30].

However, it is associated with severe luteal phase insufficiency leading to very poor reproductive outcome ^[31].  So, to improve the reproductive outcome, options include freezing-all embryos and cycle segmen-tation or, dual trigger in which lower doses of HCG are used in addition to the GnRH agonist ^[32].

This study investigated whether the timing of cabergoline administration affects the rate of OHSS in high-risk patients.

To the best of our knowledge, this is the first study that looked specifically at when cabergoline was initiated in a cycle using agonist protocol, with the primary outcome being OHSS rates.

In 2013 a study has been done, and all women received a “long protocol,” which employs a GnRH agonist to prevent premature ovulation and necessitates the use of hCG to trigger the final oocyte maturation ^[33].

Also in our study we used “long protocol,” and trigger with (5,000-10,000) IU hCG) for final oocyte maturations. To avoid luteal phase insufficiency in these cycles ^[34].

Cabergoline was found to decrease the risk of OHSS in rats via inhibition of VEGFR2-dependent vascular permeability. Another mechanism of action is via decreasing follicular fluid mediators which might have a role in OHSS ^[35].

Various studies have evaluated the efficacy of cabergoline as a preventive measure for OHSS.

A previous study reported that the higher dose of cabergoline prevents an increase in the severity of OHSS and its prolongation following the occurrence of pregnancy ⁽³⁶⁾.

Another study observed the effect of cabergoline in the prevention of OHSS in women at risk undergoing IVF/ICSI treatment cycles. It was observed that prophylactic treatment with the dopamine agonist, cabergoline, significantly reduced the incidence of OHSS in women at high risk undergoing IVF/ICSI treatment⁽³⁷⁾.

Guvendag et al., ⁽³⁸⁾ showed that caber-goline significantly decreases the follicular fluid levels of antimullarian hormone, insulin like growth factor, Inhibin B and hepatocyte growth.

A study compared cabergoline therapy to coasting concluded that, 8 days cabergoline therapy started from hCG administration is a very effective way to reduce moderate–severe OHSS without compromising pregnancy rates in patients at risk of developing OHSS ^[39].

Another study compared prophylactic cabergoline therapy to prophylactic intra-venous human albumin, concluded that cabergoline was more effective and less costly than human albumin in the prevention of OHSS in high-risk patients ^[40].

Tehraninejad et al.,⁽⁴¹⁾ in 2006 conducted a study on rats to test the effect of cabergoline on luteal progesterone levels. They found that serum progesterone levels and luteal apoptosis remained unchanged, suggesting the absence of a luteolytic effect of cabergoline.

Randomized high-risk patients for either starting cabergoline on the day of hCG or the day of oocyte retrieval. The study showed that both regimens were equally effective in prophylaxis against OHSS, meanwhile, implantation and pregnancy rates were comparable ^(42).