(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).
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.
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