Fig. 37.1
Pathogenesis of OHSS
Numerous factors acting directly or indirectly via VEGF, including interleukins, cytokines, angiotensin II, insulin-like growth factor 1 (IGF-1), etc. may be involved [9–11]. Some studies showed a direct correlation between plasma renin activity and the severity of OHSS [12], but it could probably be the effect and not the cause of OHSS [13]. Mutation of FSH receptor gene may also predispose to OHSS because of abnormally high sensitivity to hCG [14].
The classification of OHSS is beyond the scope of this chapter, but can be found in other sources [15, 16].
37.3 OHSS Prevention: A Stepwise Strategy
37.3.1 Identification of High-Risk Cases
Prediction of high-risk cases prior to COS and individualized approach is the first step in the prevention of OHSS (Tables 37.1 and 37.2) [17–25].
Table 37.1
Predictors of OHSS
Pretreatment characteristics | |
Young age | <33 y |
Lean body weight | Insufficient evidence |
Polycystic ovaries on ultrasound/PCOS | |
High basal antral follicle count (AFC) | ≥12–14 |
Previous episodes of OHSS or hyperresponse | |
High anti-Mullerian hormone (AMH) | Cutoff level of 3.36 ng/ml |
Table 37.2
Ovarian response parameters
High doses of exogenous gonadotropins in early follicular phase | |
High number of growing follicles | >14 follicles with diameter of 11 mm >11 follicles with diameter of 10 mm |
High serum estradiol (E2) levels | 3500–6,000 pg/ml (better applicable in combination of growing follicles) |
Rapidly rising serum E2 levels | |
VEGF levels – in follicular fluid | |
Number of oocytes retrieved | >15–20 |
Higher and/or repeated dose of exogenous hCG administration | |
Follicular fluid IL-6 and IL-8 levels on the day of embryo transfer | |
Pregnancy in fresh cycle | |
Multifetal pregnancy |
37.3.2 Adjustment of FSH Starting Dose
Starting with the lowest possible dose of gonadotropins and close monitoring during COS with ultrasound and serum estradiol levels reduces the risk of OHSS.
37.3.3 Ovarian Stimulation Protocols Preferably GnRH-Antagonist Protocol
Unlike GnRHa, the GnRH antagonists directly and rapidly inhibit gonadotropin release within several hours through competitive binding to the pituitary GnRH receptors [26]. GnRH-antagonist treatment protocols are effective and easy to use, allow flexibility of treatment with fewer side effects, and appear to offer a promising alternative to the long-established GnRHa regimens for prevention of a premature LH surge during COS. Flexibility of use of GnRHa as trigger for oocyte maturation is beneficial in reducing OHSS [27]. A Cochrane review in forty-five RCTs comparing the antagonist to the long agonist protocols showed significant lower incidence of OHSS in the antagonist group (29 RCTs; OR 0.43, 95 % CI 0.33–0.57) without any statistically significant difference in rates of live births (9 RCTs; OR 0.86, 95 % CI 0.69–1.08) [28].
37.3.4 Coasting
Coasting involves withholding the gonadotropins and postponing hCG administration until the patient’s E2 levels drop to a “safer” level [29]. Prior to the use of GnRH antagonist during COS, it had been widely used in the prevention of severe OHSS. Lower gonadotropin levels increase granulosa cell inhibition and apoptosis leading to lower levels of VEGF and other vasoactive substances involved in the pathogenesis of OHSS [30]. Daily serum E2 levels are monitored in conjunction with follicle tracking until E2 levels decrease to a safe level usually below 3000 pg/ml. A recent Cochrane review showed no evidence of difference in the incidence of moderate and severe OHSS and significantly fewer oocytes retrieved in coasting groups compared with GnRHa (OR −2.44, 95 % CI −4.30 to −0.58; P = 0.01) or no coasting (OR −3.92, 95 % CI −4.47 to −3.37; P < 0.0001. But the problem with this review was that four studies which met the inclusion criteria were different as two studies compared coasting with unilateral follicular aspiration, one compared coasting vs. no coasting, and the last study compared coasting with replacement of GnRHa with GnRH antagonist [31]. There is a high risk of cycle cancelation with coasting especially if it is more than 3–4 days or there is >30 % fall in E2 levels [32, 33].
37.3.5 Minimize Use of hCG
Both exogenous and endogenous hCG due to its long half-life and leutrotrophic activity play a key role in the pathophysiology of OHSS [34]. Therefore, decreasing dose of hCG for triggering oocyte maturation, replacing GnRHa for hCG trigger, and avoiding hCG in luteal phase support (LPS) are various methods to prevent delayed-onset OHSS [17].
37.3.5.1 Lowering Dose of hCG Especially in GnRHa Protocol
In high-risk cases, the lowest effective dose of hCG has been proposed, ranging from 5,000 to 2,500 IU [35]. A low dose of hCG appears to reduce the incidence of OHSS but cannot eliminate it.
37.3.5.2 GnRHa Trigger
The role of GnRHa trigger (0.2 mg triptorelin, 0.5 mg buserelin, or 1 mg leuprolide) in elimination of OHSS in high-risk patients was first suggested in 1988 [36]. GnRHa-induced surge of gonadotropins consists of 24–36 h span with resemblance to physiological mid-cycle LH surge [37]. This is in contrast to hCG-mediated LH surge which spans several days because of its long half-life leading to prolonged levels in circulation. GnRHa can replace hCG trigger in antagonist- or gonadotropin-only stimulated cycles but not in previous downregulation cycles with long-term agonist treatment [38]. In the oocyte donation model studies, avoidance of hCG exposure has been associated with complete elimination of OHSS, while recipient pregnancy rates are equivalent to those observed with hCG triggering [39, 40]. GnRHa trigger is the method of choice in oocyte donors and patients for fertility preservation. A recent Cochrane review of 11 RCTs reported no OHSS events in the GnRHa arm of the study and also concluded that GnRHa should not be routinely used to trigger oocyte maturation due to lower live birth rates and ongoing pregnancy rates, but makes an exception for women at high risk of OHSS, after appropriate counseling. It also concluded that combining GnRHa with embryo vitrification has the potential to provide a good clinical outcome [41]. In an analysis by Humaidan et al. comparing nine RCTs with fresh IVF cycles, no OHSS was reported after GnRHa triggering. Additionally, the delivery rate improved significantly after modified luteal support [6 % risk difference in favor of the hCG group (95 % CI: 20.14–0.2)] when compared with initial studies with conventional luteal phase support (LPS) [18 % risk difference (95 % CI: 20.36–0.01)]. They also reported 0 % incidence of OHSS in oocyte donation cycles (four RCTs). They concluded that GnRHa triggering with modified LPS is a valid alternative to hCG triggering, resulting in an elimination of OHSS [27]. Regarding the LPS after GnRHa triggering in fresh transfers, the majority of studies support supplementation with LH activity in addition to standard LPS with estradiol and progesterone [42]. Some studies showed beneficial effect of intensive LPS with intramuscular progesterone and estradiol patches as well as oral estradiol, but others showed lower pregnancy rates with similar LPS [43–45]. With the dual trigger – agonist followed by hCG (1000–2500 IU) and standard LPS – comparable reproductive outcome with no increased risk of OHSS is reported [44, 46]. Recombinant LH after GnRHa trigger for LPS has also been tried with similar implantation rates as compared to standard luteal progesterone protocol and no cases of OHSS [47].
37.3.6 Deciding Fate of the Stimulation Cycle
37.3.6.1 Cycle Cancelation
Termination of cycle by canceling further stimulation and trigger helps in the prevention of OHSS and associated morbidity. But due to the financial burden and psychological impact on dropout patients, it should only be reserved as a last resort for severe OHSS cases or in cases of total loss of cycle control.
37.3.6.2 Cryopreservation of Oocytes and Embryos
Embryo implantation and positive pregnancy can lead to late-onset OHSS or exacerbation of early OHSS. Therefore, cryopreservation of embryos or oocyte can be an option in the prevention of OHSS. Due to improvement in freezing techniques and culture media, pregnancy rates in the frozen cycles are comparable to the fresh cycles [48].
37.3.6.3 Fresh Cycle with Single Embryo Transfer (SET)
In case of decision of fresh embryo transfer, SET is preferred to decrease chance of multiple pregnancy and associated OHSS especially in younger patient. Adoption of strategies such as blastocyst transfer may permit more time for evaluation and decision regarding cryopreservation in case of aggravation of symptoms.
37.3.7 Other Preventive Regimens for OHSS
37.3.7.1 Intravenous Fluid at the Time of Oocyte Retrieval
Albumin is known to increase the plasma oncotic pressure and decrease the capillary permeability by binding to molecules like VEGF. The role of intravenous human albumin infusion at the time of oocyte retrieval for the prevention of OHSS is controversial [49, 50]. A recent Cochrane meta-analysis showed a borderline statistically significant decrease in the incidence of severe OHSS with administration of human albumin (eight RCTs, OR 0.67, 95 % CI 0.45–0.99). But with administration of hydroxyethyl starch, a plasma expander, there was a significant decrease in the incidence of severe OHSS (three RCTs, OR 0.12, 95 % CI 0.04–0.40), without any effect on the pregnancy rates [51].
37.3.7.2 Dopamine Agonist
Cabergoline, a dopamine agonist, binds to VEGF receptor-2 and inhibits its phosphorylation leading to decrease in capillary permeability [52, 53]. Oral cabergoline 0.5 mg/day can be administered for at least 8 days in high-risk patients to prevent early OHSS. Cabergoline may reduce the risk of OHSS in high-risk women, especially moderate OHSS. It is unlikely to have a clinically relevant negative impact on clinical pregnancy or on the number of retrieved oocytes [54]. However, impact on live birth, miscarriage, and congenital abnormalities is still uncertain [55]. More recently, quinagolide has been shown to reduce the incidence and severity of OHSS [56].
37.3.7.3 Insulin-Sensitizing Agents: Metformin
Insulin is known to stimulate VEGF protein expression and secretion. Metformin improves insulin sensitivity and reduction of hyperinsulinemia and decreases OHSS. In a Cochrane review on efficacy of metformin treatment in women with PCOS undergoing IVF or ICSI cycles, there was a significant reduction in the risk of OHSS (5.7 % vs. 21.2 %) [57, 58].
37.3.8 Additional Preventive Measures with Limited Evidence
37.3.8.1 In Vitro Maturation of Oocytes (IVM)
In patients with PCOS and in normoovulatory patients at high risk of developing OHSS, IVM of oocytes offers great potential for OHSS prevention. Due to technical difficulties in oocyte retrieval, lower success rate, and reports of high rates of meiotic spindle and chromosomal abnormalities, its practice is limited to very few centers [59, 60].
37.3.8.2 Glucocorticoids
37.3.8.3 Follicular Aspiration
Timed aspiration of granulosa cells from one ovary prior to hCG administration reduces the production of OHSS mediators while allowing continued contralateral ovarian development [63]. It is not recommended because of cost, invasive procedure, and limited evidence.
37.3.8.4 Aromatase Inhibitors
37.3.8.5 Nonsteroidal Anti-inflammatory Drugs
37.3.8.6 GnRH-Antagonist Salvage
37.4 Segmentation for OHSS-Free Clinic by Freeze-All Policy
As stated by Devroey, the strategy to obtain an OHSS-free clinic is closely related to the segmentation concept (Fig. 37.2) [1]. With the advent of vitrification techniques, there has been a major improvement in the embryo survival and subsequent pregnancy rates [70, 71]. For couples who do not desire embryo cryopreservation, oocyte vitrification is another option. In a proof-of-concept study by Greisinger et al., 20 high-risk patients (≥20 follicles of ≥10 mm or estradiol ≥4000 pg/ml on trigger day) with GnRHa trigger and cryopreservation of all two pronucleate oocytes reported no case of OHSS and 29.2 % ongoing pregnancy rate in subsequent thaw cycle [38, 72]. Excellent embryo or oocyte survival rates after vitrification support the use of cryopreservation as a routine approach [70]
Fig. 37.2
Segmentation of IVF
Advantages of segmentation:
(a)
Minimizes late-onset OHSS.
(b)
No need of intensive LPS.
(c)
No embryo transfer in out-of-phase endometrium, which is common in high responder patients.
(d)
Allows embryo transfer in a natural cycle where applicable. With effective cryopreservation that results in little or no damage to embryos, cumulative birth rates per retrieval should, in theory, be highest when embryos are transferred individually [73].
(e)
Decrease in multiple pregnancy rate and perinatal and maternal morbidity and mortality associated with it.
37.5 Various Proposals for Decision Making Between Fresh Embryo Transfer or Freeze-All Policy
Although the use of a GnRH-agonist trigger can dramatically reduce the risk of OHSS in high-risk patients, for some patients segmentation of the cycle would still be better option. At present, the optimal threshold for performing a freeze-all after a GnRH-agonist trigger is not clear. Following are the various proposals by different studies (Fig. 37.3):
Fig. 37.3
Stepwise approach to be individualized and combined to reach the goal of eliminating OHSS
1.
Griffin et al. stratified patients according to their estradiol concentration on the day of triggering final oocyte maturation to add 1000 IU of hCG and GnRHa for patients with peak estradiol <4000 pg/ml and GnRHa alone if peak estradiol is ≥4000 pg/ml [74].
2.
In a protocol by Orvieto et al., in patients in whom <20 oocytes were retrieved in the first IVF cycle attempt, and in low responders or patients >40 years old, the COH protocol is individually tailored. In the latter groups, if the tailored COH protocols yield 20 oocytes, or 10 embryos develop, the patient is followed for 5 days after oocyte retrieval for signs of early OHSS (ultrasonographic signs of ascites, hematocrit levels for the degree of hemoconcentration). If early signs develop, ET is withheld and all resulting embryos cryopreserved. If it does not appear, they transferred one blastocyst, with 1500 IU of hCG with the consequent decrease in the risk of multiple pregnancy to almost zero, thereby eliminating the risk of late OHSS [75, 76].
37.6 Investigation and Monitoring of an OHSS Patient
37.6.1 General Condition
General condition is monitored by regular charting of vital signs, weight charts, abdominal girth measurement, and a strict fluid balance record.
37.6.2 Biochemical Tests
A complete biochemical assessment includes hematocrit, electrolytes, liver function tests, kidney function tests, and coagulation profile. Blood gases and acid-base balance are required if there is a respiratory or renal compromise. Serum β-hCG is done to rule out pregnancy. Serum and urinary osmolarity and urinary electrolytes may be needed in more severe forms of the disease. The frequency of these tests is guided by the severity of the disease.
37.6.3 Ultrasonographic Examination
Ultrasound gives important information on ovarian size, amount of ascites, presence of hydrothorax or pericardial effusion, and detection of pregnancy, whether single or multiple.
37.6.4 Chest X-Ray
A chest X-ray can rule out pleural effusion.
37.6.5 Serum ß-hCG
It is done to confirm pregnancy making the women at a high risk for developing severe disease.
37.6.6 Invasive Hemodynamic Monitoring
When OHSS becomes critical, monitoring of pulmonary artery pressure and central venous pressure may be required.
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