Ovulation Induction and Controlled Ovarian Stimulation, 2st ed.

20. Ovarian Hyperstimulation Syndrome

Roy Homburg1

(1)

Homerton Fertility Centre, Homerton University Hospital, London, UK

Abstract

Ovarian hyperstimulation syndrome (OHSS) is brought about by overstimulating the ovaries with gonadotrophins, whether during ovulation induction or so-called controlled ovarian hyperstimulation before intra-uterine insemination (IUI) or IVF. It is a purely iatrogenic condition which is largely preventable and often foreseeable. Those at risk to develop OHSS are young, lean and/or have polycystic ovaries, high serum AMH concentrations and a high antral follicle count and patients who have had OHSS in a previous cycle. For ovulation induction only a low-dose gonadotrophin protocol should be used as this will eliminate the incidence of OHSS. For IVF in patients predicted to be at high risk for OHSS, a GnRH antagonist protocol is recommended with the use of a GnRH agonist trigger. OHSS does not occur if hCG is withheld and it may be classified as early, due solely to the hCG injection or late, due to the added effect of hCG secreted by the developing pregnancy. Monitoring, according to the severity of the symptoms, should include fluid and electrolyte balance with detailed recording of fluid input and output, measurement of the extent of intravascular volume decrease including frequent measurements of haematocrit and arterial pressure. Central venous pressure measurement is essential for the more severe cases. Baseline renal and liver function tests should be monitored. Treatment is supportive, according to severity, mainly re-hydration and the maintenance of intravascular fluid volume and blood volume expanders when indicated. Relief of ascites and pleural effusions may be necessary.

Keywords

Ovarian Hyperstimulation SyndromeOHSSControlled ovarian hyperstimulationMultiple pregnancyGonadotrophinsOvariesIntra-uterine insemination IUIIVFhCGTrophoblastOvulationFolliclesDominant follicleMild stimulationOvum pick-upFSHOestradiolVascular endothelial growth factorVEGFAngiotensin IIInterleukin 6Ascitic fluidIntravascular hypovolaemiaArterial hypotensionArterial vasoconstrictionHaemoconcentrationThromboembolicAMHAntral follicleLuteotrophic effectLuteal phaseEmbryosProgesteroneIntravenous albuminIn-vitro maturationCorpus luteumrecLHMetforminCarbergolineOvarian electrocautery follicular aspirationHaematocritHaemoconcentrationArterial pressureDyspneaRenal functionFrusomide

Two major complications plague ovulation induction and so-called controlled ovarian hyperstimulation (COH): ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies. Both are regarded as serious complications in their own way. OHSS can be so serious that it may even be life threatening to the patient and multiple pregnancy may also be life threatening but to the fetuses. Both are very largely preventable. Awareness of the possibilities that either may occur is the first step in their prevention. Having this awareness, steps can be taken to minimize their occurrence. The main aim of this chapter is to emphasize this awareness and preventative steps that can be taken as well as management for OHSS.

Ovarian hyperstimulation syndrome (OHSS) is brought about by overstimulating the ovaries with gonadotrophins, whether during ovulation induction or so-called controlled ovarian hyperstimulation before intra-uterine insemination (IUI) or IVF. It is a purely iatrogenic condition which is largely preventable and often foreseeable. It does not occur if hCG is withheld. OHSS may be classified as early, due solely to the hCG injection or late, due to the added effect of hCG secreted by the trophoblast of the developing pregnancy.

20.1 Aetiology and Pathophysiology

While the exact aetiology of OHSS is still unknown, clearly it is basically due to over-stimulation of the ovaries by exogenous gonadotrophins followed by hCG to trigger ovulation. This may occur during ovulation induction and during ovarian stimulation before IUI or IVF. As the aims of these three treatment modes are different, the amount of gonadotrophins administered differs, ranging from gentle stimulation to ideally produce one dominant follicle, mild stimulation to produce 2–3 large follicles and stronger stimulation to produce say, 5–15 follicles respectively. It therefore would be expected that the incidence of OHSS during IVF cycles would be the highest but this is not necessarily the case. The plausible explanation for this is that during puncture of the follicles and ovum pick-up, follicular fluid containing many of the probable aetiological ingredients of OHSS are extracted from the ovary. This is obviously not the case during ovulation induction or stimulation for IUI.

In addition, there is a great individual variation involved, not only in the ovarian threshold for FSH required for stimulation but also in those who will develop OHSS and those who will not, despite receiving equivalent or even greater amounts of FSH and producing more follicles and oestradiol. Although certain risk factors do predispose to the likelihood of developing OHSS and should be well heeded, accurate prediction remains elusive.

Clearly, hCG, whether exogenous or endogenous, is the trigger releasing a factor or factors which initiate the progress of the syndrome. As the syndrome is basically one principally affecting the vascular department initially, the suspected factors are naturally those that are released by hCG following ovarian stimulation with gonadotrophins. The usual suspects include oestradiol, renin and angiotensin II, interleukin 6 and, probably the most important, vascular endothelial growth factor (VEGF). All these have the property of causing vasodilatation and capilliary hyperpermiability and all are produced in much increased quantities when the ovary is stimulated and ovulation triggered by hCG. Although a high oestradiol level can affect capilliary permeability, it is not capable of producing OHSS without hCG. In contrast, angiotensin II, interleukin 6 and VEGF are all produced by the ovary, their concentrations greatly enhanced by hCG, concentrations are extremely high in OHSS and all cause important changes in the vascular system.

The changes in the vascular system at the onset of OHSS are primarily vascular dilatation and increased permeability. These changes initiate a cascade of events starting with a loss of fluid and proteins from intra- to extravascular (third) space so reducing intravascular volume. Accumulating ascitic fluid in the abdominal cavity and, more extremely, in the pleural cavity, may be the result. Changes in osmotic fluid gradient intensify the intravascular hypovolaemia and the arterial hypotension can induce arterial vasoconstriction. As a result, renal function may be affected and sodium and water are retained. Increasing haemoconcentration is the key aetiological feature of life-threatening OHSS. Oliguria, renal failure and blood hypercoagulability leading to thromboembolic phenomena, the commonest cause of death from OHSS, are to be feared.

According to the severity of these symptoms and signs, a simple classification has been proposed (Table 20.1).

Table 20.1

Classification of ovarian hyperstimulation syndrome

Mild

Abdominal bloating and discomfort

Ovarian enlargement up to 8 cm

Moderate

Criteria for Mild + nausea, vomiting or diarrhoea

Ultrasound evidence of ascites

Ovarian enlargement up to 12 cm

Severe

Criteria for Moderate +

Oliguria <500 ml/24 h

Serum creatinine 1.0–1.5 mg/dl

Haematocrit >45 %, leucocytosis >15,000/ml

Clinically evident ascites +/− pleural effusion

Critical

Tense ascites with pleural and/or pericardial effusions

Haematocrit >55 %, leukocytosis >25,000/ml

Oliguria with serum creatinine >1.5 ml/dl

Renal failure, liver dysfunction

Thromboembolic phenomena

20.2 Risk Factors

Knowing the risk factors predisposing to OHSS is an essential ingredient in the prevention of the syndrome (Table 20.2). In the first cycle, at least, gonadotrophin stimulation, i.e. dosage and rate of dose increments, should be undertaken cautiously in those patients who are at risk.

Table 20.2

Risk factors for ovarian hyperstimulation syndrome

Before starting treatment

<30 years old

Lean body habitus

Polycystic ovaries

Previous OHSS

Serum AMH >30 pmol/l

Antral follicle count >12

During treatment

Rapidly rising oestradiol concentrations

Very high oestradiol concentrations

Large number of developing follicles

Luteal support with hCG

Pregnancy, particularly multiple pregnancy

Those at risk to develop OHSS are young, lean and/or have polycystic ovaries, high serum AMH concentrations and a high antral follicle count. Patients who have had OHSS in a previous cycle should also be approached cautiously.

A suspicion of impending OHSS can also be made during gonadotrophin stimulation. Multiple follicle development is a serious warning sign. In ovulation induction and stimulation before IUI, the development of more than five to six follicles >9 mm diameter or in IVF, >30 such follicles should set the alarm bells ringing and urge a consideration of some preventive action. With or without this number of follicles, in ovulation induction (or COH for IUI) and in IVF, oestradiol concentrations of >1,500 pg/ml (5,500 pmol/l) and >3,000 pg/ml (11,000 pmol/l) respectively should provide a similar warning. These are merely pointers which urge, at the least, awareness and watchfulness. Their actual predictive value is not high. The contribution of small developing follicles is surprisingly large and this often goes unheeded. Monitoring must be more intensive than usual and same–day oestradiol measurements are needed in these cases, even if not performed routinely.

20.3 Prevention (See Also Chap.​ 18)

20.3.1 Ovulation Induction and COH for IUI

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20.3.2 IVF

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20.4 Treatment

Mild OHSS is fairly common during both ovulation induction and stimulation for IUI and IVF. It does not usually require hospitalization and can be treated expectantly as OHSS is a self-limiting syndrome. When hCG levels regress, after a week in the non-pregnant and after 2–3 weeks in the pregnant, symptoms also start to regress. I always recommend a high fluid intake, even in the mildest of cases in the hope that this may prevent the progression of symptoms. Patients complaining of abdominal bloating and discomfort should never be ignored and always examined.

Moderate to severe cases of OHSS need hospitalization and intensive monitoring. Monitoring, according to the severity of the symptoms, should include fluid balance and electrolyte concentrations with detailed recording of fluid input and output, measurement of the extent of intravascular volume decrease including frequent measurements of haematocrit as a measure of haemoconcentration and arterial pressure. Central venous pressure measurement is essential for the more severe cases. Baseline renal and liver function tests should be performed on admission and repeated frequently with any deterioration in the condition.

Treatment is supportive, according to the severity until the syndrome starts to improve spontaneously with the appearance of the next menstruation or after several weeks in the presence of pregnancy. The essential feature of the supportive treatment is re-hydration and the maintenance of intravascular fluid volume. Initially, this can be done with an intravenous infusion of normal saline or Hartman’s solution, while carefully monitoring blood pressure, haemoconcentration and urinary output. Various blood volume expanders are also recommended when indicated: crystalloids are usually the first step and, if not successful, dextran, fresh frozen plasma or low-salt albumin in doses and frequency titrated against the fluid balance.

A tense ascites, especially when causing abdominal discomfort and dyspnea and associated with decreased renal function, should be relieved by paracentesis if the patient is haemodynamically stable. It may be done trans-abdominally or trans-vaginally and, in either case, should be ultrasound guided. Rapid drainage is not advised as this may induce a rapid deterioration in intravascular volume. This can be avoided by using a closed system catheter with a locking device which is also very useful for avoiding repeated punctures. Pleural effusions should be tapped if thought to be causing symptoms.

The use of diuretics is not generally advised as they will cause a further deterioration in the intravascular fluid volume. The exception to this rule is when the patient has been fully hydrated but oliguria persists. Even then, it should be given cautiously, e.g. frusomide, 10 mg intravenously, every 4–6 h, and stopped once urinary output improves.

The ultimate aim of all this supportive treatment is the prevention of deterioration into the life-threatening stage, in particular correcting a haematocrit of >55 %, electrolyte imbalance, oliguria, serum creatinine of >1.6 mg/dl, respiratory distress and the avoidance of thromboembolic phenomena involving anti-coagulant medications. If the syndrome arrives to this stage, it is not a loss of face to the treating physician if the services of experts in intensive care, renal, anaesthetic and cardiac medicine are called for, especially if they are familiar with the peculiarities of OHSS.

20.5 Conclusions

The majority of cases of moderate to severe OHSS are preventable. The possible seriousness of this condition demands a lowering of the ambition of the practitioner to achieve a pregnancy “at all costs”. The use of an antagonist protocol and an agonist trigger in predicted high responders at risk of OHSS, preferably followed by a ‘freeze-all’ strategy, should permit the ideal of an OHSS free unit. If this is not possible, an additional month of treatment is worth more than weeks or more of intense suffering and danger to maternal health.

References

1.

Humaidan P, Bredkjaer HE, Westergaard LG, Andersen CY. 1,500 IU human chorionic gonadotropin administerd at oocyte retrieval rescues the luteal phase when gonadotropin-releasing hormone agonist is used for ovulation induction: a prospective, randomized, controlled study. Fertil Steril. 2010;93:847–54.PubMedCrossRef

2.

Griesinger G, Schultz L, Bauer T, Broessner A, Frambach T, Kissler S. Ovarian hyperstimulation syndrome prevention by gonadotropin-releasing hormone agonist triggering of final oocyte maturation in a gonadotropin-releasing hormone antagonist protocol in combination with a ‘freeze-all’ strategy: a prospective multicentric study. Fertil Steril. 2011;95:2029–33.PubMedCrossRef

3.

Leitao VM, Moroni RM, Seko LM, Nastri CO, Martins WP. Carbergoline for the prevention of ovarian hyperstimulation syndrome: systematic review and meta-analysis of randomized controlled trials. Fertil Steril. 2014;101:664–75.PubMedCrossRef