Jean-Claude Emperaire1
(1)
Bordeaux, France
Stimulating ovulation is a formidable procedure, and as such includes risk for complications commensurate with its intensity. One must always keep in mind the balance between expected benefits and predictable hazards. All aspects should be carefully explained to the couple who are, after all, the principal role players in this plan. Essentially all of the risk can be ascribed to excessive stimulation, of which there are two basic types: predictable problems, typically uncovered during a preliminary assessment of the couple’s fertility parameters that may be considered as primary prevention, and unpredictable problems, which appear during the treatment (i.e., secondary prevention).
It is of course always possible to stop a stimulation cycle if and when conditions exceed the fixed limits. But deprogramming a cycle has a cost, at the least an emotional cost for the patient who has already committed to a number of injections, blood tests, and ultrasound examinations. Plus there is a financial cost that may vary according to the couple’s health care plan. Thus both clinician and patient tend to be reluctant to drop out of a stimulation cycle and this is how consideration of hazard tends to become a notion of reasoned risk, or a presumed risk. Whereas some complications appear to be totally unexpected, even a posteriori, most are in fact objectively foreseeable. The weight of the human factor, which is clearly the most difficult factor to manage, remains of major importance.
8.1 Multiple Pregnancies
The risk for multiple pregnancies occurs only with classical mono- or paucifollicular stimulations. In controlled ovarian hyperstimulation for IVF purposes, multiple pregnancies result from transfer policies and not from the stimulation process itself.
8.1.1 Monofollicular Stimulation
The purpose of monofollicular stimulation is to promote the development of only a single follicle, and then to trigger ovulation in the presence of a single mature follicle.
Effective primary prevention relies on the choice of the starting dose and the gonadotropin administration protocol:
8.1.1.1 Starting Dose
Even if the starting dose is incorrectly chosen, an insufficient dose remains easier to handle than an excessive dose. For this reason a lower dose (e.g., 50 IU) should be favored for starting a patient who has not previously received gonadotropins, especially when AMH levels and/or AFC are elevated. A higher dose (75 IU) may be considered for patients who are over 38 years of age or are overweight, yet it is not unreasonable to start with a lower dose even in those cases.
8.1.1.2 Administration Protocol
The classic “step up” protocol, with an initial assessment after 5 days of gonadotropin administration, is most suitable for ovulatory patients. In anovulatory patients, or in patients with elevated levels of AMH and/or AFC, lower dose increments are indicated after an initial trial of 7 days’ treatment.
Effective secondary prevention includes adjusting the gonadotropin dosage and administration protocol in response to the patient’s reactions, and with respect to appropriate triggering criteria. The initial protocol should be reconsidered after 5–7 days of administration, to be continued as a classic step-up, a step-up low dose, a chronic step-up low dose, or step-down protocol in some cases. Results of hormonal and ultrasound assessments adjust the gonadotropin doses and the number of administration days before the next assessment. The triggering criteria in monofollicular stimulation cycles are strict: a single follicle must be >15 mm diameter without other secondary follicle(s) >12 mm.
8.1.2 Bifollicular Stimulation
This strategy is used to elicit a second follicle and oocyte capable of being fertilized, to compensate for the patient’s age, because of another hypofertility factor, or even in cases of an idiopathic infertility. This type of stimulation requires particular care, because a third (or even a fourth) follicle can be developed inadvertently.
Effective primary prevention in the spontaneously ovulating patient involves development of a second follicle either by recruiting a new one with an early stimulation (CD 3–5) at a low to mid-range dose (50–75 IU), or by rescuing a spontaneous secondary follicle with later stimulation (CD 6–7) at higher doses (75–1,125 IU). In anovulatory patients, the starting dose should be slightly higher than the posology that is sufficient for a single follicle, and the administration protocol should be careful to permit only two follicles to develop.
Secondary prevention relies on the triggering criteria, including the patient’s age, the presence of secondary follicles, and the estradiol level, in order to balance the chances for conception against the risks for multiple pregnancy. A flow chart proposed by P. Barri appears to be an adequate decision strategy [1].
8.1.3 Paucifollicular Stimulation
Triggering ovulation in the presence of three or perhaps four mature follicles should be considered only in the patients over 40 years of age, whose chances for pregnancy, and also for multiple pregnancy, are significantly reduced.
8.2 Ovarian Hyper Stimulation Syndrome (OHSS)
OHSS is a potential complication for any stimulation cycle, classical as well as COH. Aside from a few situations such as a paradoxical effect of a GnRH agonist or in some cases of hyperthyroidism, OHSS appears exclusively due to hCG influence, no matter the timing of administration (Fig. 8.1). Early (or primary) OHSS tends to occur within the week following ovulation triggering. Late (or secondary) OHSS appears a few days before the next expected menses, due to the reappearance of endogenous hCG from an implanting embryo. Furthermore, a primary OHSS may be enhanced by a secondary hyperstimulation at the beginning of a pregnancy.
Fig. 8.1
Role of hCG in the genesis of the ovarian hyperstimulation syndrome: OHSS does not occur without hCG
8.2.1 Pathophysiology
OHSS is provoked by the secretion of vasoactive substances from granulosa cells under the influence of hCG. In particular, a vascular endothelial growth factor (VEGF-A) binds to the ovarian follicles and especially to vascular endothelial cells through two receptors (VGEF-R1 and 2). VEGF production increases throughout gonadotropin stimulation and reaches a peak within 48 h following the administration of hCG. These vasoactive substances induce angiogenesis, increase the permeability of capillary endothelium, and facilitate a net hydro-electrolytic shift from plasma to extravascular spaces (Fig. 8.2). These changes result in diminished intravascular volume and hemoconcentration, enhanced risk for hypercoagulation, hepatorenal failure, and can produce a massive fluid exudation with sequestration into extravascular spaces in the pelvic, abdominal, and even the pleural and pericardial cavities. The ovaries themselves increase in volume and develop functional cysts that can be hemorrhagic (Fig. 8.3). Occurrence of OHSS may also be facilitated by polymorphisms of VEGF and VEGF-R2 [2].
Fig. 8.2
Pathophysiology of OHSS: roles of hCG and VEGF
Fig. 8.3
Appearance at laparoscopy of hyperstimulated ovaries: note the hemorrhagic cysts (Photo courtesy RB Greenblatt)
8.2.2 Grades of Ovarian Hyperstimulation
Three grades of OHSS are typically recognized, in accordance with clinical symptoms and the degree of fluid effusion (Table 8.1).
Table 8.1
The three degrees of severity of OHSS [3, 4]
Grade 1 (mild) is characterized by abdominal pain with digestive symptoms: nausea with or without vomiting and diarrhea, or possibly constipation. Ultrasonography reveals enlarged ovaries containing many cysts, in fact difficult to recognize from the picture usually seen following an oocyte harvest. Peritoneal effusion is also visible, limited to the Pouch of Douglas. Biologic parameters remain within the normal range.
Grade 2 (moderate) presents the same symptoms as Grade 1 with increased intensity and abdominal distension. Ultrasonography shows ovaries larger than 12 cm in the long axis, with ascites rising above the uterus. Common biologic alterations include a leukocytosis (WBC of 15–20,000) and a rise of hematocrit (but remaining <55 %). A possible torsion of the adnexa may be difficult to recognize in this situation.
Grade 3 (severe) encompasses increased ascites, and effusion that sometimes reaches the pleural cavity to create dyspnea. Oliguria can occur along with various abnormal lab findings, e.g., leukocytosis (>25,000), hemoconcentration (hematocrit >55 %), hyponatremia, hyperkalemia, and serum creatinine in the range of 1–1.5 mg/dl. The severity of the syndrome may lead to organ failures complicated with thrombotic events.
Mild and moderate OHSS typically recede spontaneously without after-effects, whereas severe OHSS may become life threatening and may require paracentesis. Intensive care hospitalization and anti-coagulation therapy currently provide effective management of these complications, yet it remains the case that the desire for a baby can still cost someone their life.
Although the development of OHSS is always related to the presence of hCG, the patient’s overall condition can also be a contributing factor, making outcomes variable and uncertain. Even patients with very similar ultrasound and hormonal monitoring parameters prior to hCG administration may develop disparate degrees of OHSS afterwards. I have personally encountered a severe OHSS syndrome in the presence of a single mature follicle without evidence of secondary follicles and a with a plasma estradiol level of only 175 pg/ml. Furthermore, the prognosis of a beginning OHSS remains largely unknown. Plasma levels of total VEGF-A do not correlate strongly with the developing syndrome, but free VEGF-A does seem to be modestly reliable [5]. For all these reasons, it is always preferable to discontinue the cycle rather than to risk OHSS when the stimulation protocol exceeds proper limits.
8.2.3 Prevention of Ovarian Hyperstimulation Syndrome
Detection and management of OHSS operates on four levels [6]:
8.2.3.1 Primary Prevention
Aside from those patients who have been previously stimulated and whose susceptibility to gonadotropins is already known, detection of a potential risk for OHSS should include evaluation of her ovarian reserve along with three main criteria:
Age: Although ovarian sensitivity to gonadotropins decreases with age, an unexpectedly high response may occur in a patient over 38 years of age. For this reason, age should typically be considered as a secondary parameter when assessing risk.
Antral follicular count (AFC): When the AFC exceeds 10 follicles in each ovary, whether or not other criteria for PCO are present, much greater care is required with regard to gonadotropin administration.
AMH Level: Although there is no consensus regarding the precise level of AMH that predicts ovarian hypersensitivity to FSH, it is understood that AMH levels generally correlate with the AFC. Various assay kits may still yield inconsistent results, but a reading in excess of 5 ng/l should be taken as a warning sign.
Primary prevention consists of adjusting the management of gonadotropin administration, particularly in the choices of the stimulation protocol and of the staring dose.
8.2.3.2 Secondary Prevention
Management of an unexpected risk for OHSS that arises during the ovarian stimulation is possible by either by:
· Decreasing the FSH dose, thereby allowing only the more sensitive follicle(s) to develop, or by
· Stopping gonadotropin administration altogether
In a classic stimulation protocol, stopping gonadotropin administration is possible only in spontaneously ovulating patients who already have sufficient endogenous gonadotropin secretion. When the latter fails or is too erratic, follicular development stops. During a multifollicular stimulation, a “coasting” may be attempted. Typically, after gonadotropin administration has been interrupted for one or several days, and estradiol levels begin to drop, ovulation can be triggered when it reaches the safety range. This strategy may be able to rescue some IVF stimulation cycles, but the situation requires delicate management and may result in a suboptimal oocyte quality. Thus a “coasting” approach cannot be generally recommended for rescuing cycles at risk for OHSS [3]. The situation may lead to a diminished chance of success, so all options must be discussed with the patient. Furthermore, the risk of an OHSS developing nevertheless cannot be totally excluded. Therefore, it may be best to stop the cycle altogether in most cases when OHSS appears to start, and to begin another one with different parameters.
8.2.3.3 Tertiary Prevention
This approach becomes necessary when OHSS is definitely underway. The procedure involves the triggering criteria, which are not precisely defined and can vary substantially between fertility centers or even between clinicians within the same fertility setting. Although it is well established that no ideal criterion of hormone or ultrasonic measures is able to eliminate risk for OHSS, some rules and limits should nevertheless be firmly adopted in every clinical practice. The author presents here his personal criteria for each type of stimulation protocol that may be considered an adequate starting point from which each clinician may then shift according to one’s own experiences and objectives.
Withdrawal from hCG in a situation recognized to be at risk for OHSS remains always the best decision, and possibly followed by contraceptive measures,. Unfortunately, making this consensual decision may conflict with a number of practical considerations, variously described as “the human factor,” that result in hCG triggering nevertheless.
Among the more commonly posed reasons for continuing:
· The treatment cycle has already involved a great deal of effort and personal investment of the couple, not to mention the financial cost.
· The frustration of stopping a stimulation cycle on the heels of previously failed cycles.
· OHSS did not appear in a previous cycle that showed a comparable level of risk.
· The cycle at risk is the last of a series, and/or the undertaking of a new treatment will not be possible for some time.
These uncomfortable situations lead to impatience for the couple and some guilt for the clinician, who more or less consciously senses a responsibility for successive treatment failures. Of course, every physician has days like these, and this usually helps one understand why nearly all instances of OHSS were predictable as well as preventable.
Reduction of the hCG triggering dose: In a classical stimulation, the standard dose of 5,000 IU u-hCG or 250 μg r-hCG is in fact unnecessarily high. We and others have shown that satisfactory results may be obtained with 1,500 IU u-hCG [7]. Likewise, reducing the triggering hCG dose in a COH decreases, although it does not totally eliminate, the risk for OHSS. On the other hand, if the pregnancy rate can be maintained with a dose of 3,000 IU, chances for pregnancy may be diminished with a triggering dose of 2,500 IU or even less [8, 9]. Dose reduction may also be modulated in accordance with the patient’s BMI or the estradiol levels [9, 10].
Addition of FSH to hCG: The co-administration of 450 IU rFSH with hCG may be able to lower the risk for OHSS, except in women with a low BMI. The underlying mechanism for this effect remains unresolved [11].
Substitution of LH for hCG: The principal risk for OHSS is the result of an intense, prolonged effect of hCG on the follicles and corpora lutea that does not occur with pituitary LH. Thus the use of natural LH, hLH, or rLH to trigger ovulation significantly reduces the risk for OHSS. Unfortunately this option remains unrealistic simply because of the large amount of rLH that is required and its corresponding cost [12].
Another approach, proposed by a growing number of fertility teams over the past 25 years, is to provoke an endogenous surge of FSH and LH by using a short lived GnRH agonist. There are some reports of spectacular results regarding the diminished risk for OHSS and multiple pregnancies [13]. This author has indeed observed only a few cases of twin pregnancies and/or of very modest ovarian hyperstimulation with GnRH administration in the face of a risky classic or multifollicular stimulation. A single intra-nasal or subcutaneous dose of any short acting available GnRH agonist is sufficient to trigger a maximal pituitary response, since the gonadotropin surge profile will not be greater with higher agonist doses. The compound most used at present appears to be triptorelin 0.1 mg, basically because it is packaged in seven single doses. Most other agonists are supplied in larger, more expansive packages designed for several weeks of daily doses.
Let me add a personal account at this point: More than 20 years ago I approached the French division of the concerned pharmaceutical company to request validation studies of triptorelin use as a trigger for stimulated ovulation. My motivation was a concern for patient safety that was being placed at higher risk by other triggering methods. After several discussions, the proposition failed to move forward, for two principal reasons: (1) a commercial reason, due to the relatively low price of u-hCG; and (2) a scientific reason, due to the practical and ethical difficulty at that time of conducting a double-blind prospective study comparing two groups equally at risk for OHSS. However, it would seem that randomized controlled trials should not be necessary if one can establish a clearly superior level of efficacy and safety from corroborating observational studies (see, for example, the letter by Kol drawing this analogy to proving parachute safety) [14].
Despite the absence of definitive statistical proof, the GnRH agonist approach for triggering ovulation is being adopted by ever more clinician teams who seek a “hyperstimulation-free clinic.” The method is especially effective in cases of COH treated with antagonist protocols, but is of course impossible with long agonist protocols because of pituitary desensitization already created by earlier GnRH treatment. The usual triggering dose appears to be triptorelin 0.1 mg for classical stimulations, or 0.2 mg in COH antagonist protocols. Why is this higher dose preferred in COH, as no comparative studies have been conducted? Evidence suggests that the gonadotropin surge profiles provoked by both doses are identical. Undoubtedly those promoting the method for COH initially chose the 0.2 mg dosage, perhaps because higher numbers of mature follicles are available in a COH stimulation, and also because there is in fact no established risk for GnRH agonist overdosing.
On important caveat, however: whereas the method of GnRH agonist triggering extensively reduces, yet fails to eliminate, all risk for primary (early) OHSS, it is much less preventive of a secondary (late) OHSS in case of pregnancy, that can be equally serious. Management of the latter problem in COH requires a “freeze all” strategy that includes no embryo transfer.
The availability of GnRH agonist triggering as a means to minimize risk for OHSS should not be taken as encouragement for irresponsibility or carelessness. The art of managing a COH always requires a need to avoid overstimulation hazards and when a risk develops, the trigger must not be done. The unfortunate problem is that, for the variety of reasons discussed above, triggering may be done anyway. Thus, in cases recognized to be at risk for serious hyperstimulation and/or multiple pregnancy, hCG should be replaced by endogenous pituitary LH whenever possible.
8.2.3.4 Final Prevention
Even after hCG has been administered, it might still be possible to reduce the risk for OHSS, or to decrease its severity. Several approaches, although nonconsensual or not validated, have been suggested, that should not threaten a beginning pregnancy.
Intravenous administration of albumin or another large molecule such as hydroxylethyl starch (Hespan®, Hestar®). This has a high binding capacity for steroids and vasoactive compounds and diminishes their bioavailability. The substances also serve to increase colloid osmotic pressure and thus assist in maintaining plasma volume [15].
Glucocorticoids will diminish the effect of vascular endothelial growth factor (VEGF) on capillary smooth muscle, thereby reducing peripheral vasodilatation and capillary permeability [16].
Dopamine (D2 ) agonists that bind to capillary VEGF receptors will limit the role of VEGF in the development of hyperpermeability without compromising angiogenesis. Cabergoline is the most extensively investigated agonist, possibly because of better overall patient tolerance. Starting on the day of hCG administration, a 0.5 mg daily dose for at least one week has been shown to decrease the frequency of OHSS episodes without interfering with an imminent pregnancy [4]. Cabergoline treatment has also been shown to enhance the prevention effect for early OHSS following GnRH agonist triggering in patients with extremely high estradiol levels (>6,000 pg/ml) [17].
GnRH antagonists would appear at present to be the best early treatment for primary severe OHSS that follows a risky triggering. If all signs, clinical and ultrasound, point to a beginning OHSS, administration of 0.25 mg ganirelix sc daily for 4 days should rapidly diffuse the complication [18]. If done as part of an IVF procedure, a prolonged in vitro culture must be chosen, and an ultrasound and hormonal check-up realized on the fifth day after oocyte harvest: when there is a rising OHSS, all the embryos should be frozen for later transfer. In patients who do not show an early OHSS at this moment, continuation with a fresh transfer results in birth rates similar to those of high risk patients who do not develop severe early OHSS and who did not receive GnRH antagonist in the luteal phase [19]. This preventive effect of GnRH antagonists upon the development of OHSS seems to be mediated through a reduction of VEGF levels [20].
None of these methods is completely able to prevent the development of OHSS, inasmuch as the level of proof is weak. Furthermore, each has some potentially serious adverse effects, and must only be considered as last-chance measures.
8.2.4 Treatment of Ovarian Hyperstimulation Syndrome
Management choices for OHSS depend upon the degree of severity and must always be undertaken with great care, since any type of OHSS may suddenly worsen in case a pregnancy occurs [21].
Mild OHSS can be managed by bed rest, treatment of symptoms, and observation of weight. Problems should resolve within a few days after the onset of menses.
Moderate OHSS may require a short-term hospitalization, where a very close observation of body weight, biological parameters, and fluid input/output can be instituted. Thrombotic complications can be diminished by support stockings and administration of low molecular weight heparin.
Severe OHSS of whatever degree requires movement into intensive medical care and may require evacuation of peritoneal and sometimes pleural fluid. On the other hand, conservative management of OHSS without paracentesis has also been claimed to yield satisfactory results, along with a significant cost reduction [22].
8.3 Conclusion
Ovarian hyperstimulation, even of moderate intensity, remains a painful experience for each patient, so much so that some will abandon their quest for a pregnancy rather than risk another such incident. For this reason alone, undertaking deliberate but unjustified actions that carry a risk for development of OHSS should be strongly discouraged. Concession of the stimulation cycle remains the most appropriate, consistent decision and is always preferable over any degree of hyperstimulation.
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