!DOCTYPE html>
Complications of Ovulation Induction: Ovarian Hyperstimulation Syndrome
Introduction
Ovarian hyperstimulation syndrome (OHSS) is a condition inherently related to controlled ovarian stimulation.
It can, however, occur in a spontaneous ovulatory cycle. The underlying mechanism of this rarity is believed to be related to a mutation in the FSH receptor (1). Typically, OHSS occurs as an iatrogenic complication in women undergoing IVF/ICSI due to the supra-physiological doses of gonadotrophins, which are used to induce multifollicular growth. OHSS is a clinical diagnosis based on symptoms. The majority of these symptoms are a result of increased vascular permeability of the gonadotropin-primed ovaries. The syndrome can be best characterized by bilaterally enlarged ovaries due to multiple fol-licular and thecal lutein ovarian cysts. In addition to the physical enlargement of ovaries, an acute shift of intravascular fluid distribution occurs, causing clinical ascites, leading to serious complications and, ultimately, death (2–5).
The accurate incidence of OHSS is difficult to state because of the different classifications used in the literature. The incidence varies between patient groups and treatments used. In IVF, up to 33% of cycles develop mild OHSS. Although they are considered clinically less significant, they still have the potential to develop into the severe form, which is estimated to occur in 3.1%–8.0% of cycles (6).
The development of OHSS with ovulation induction using gonadotropins or clomiphene citrate is even less well studied. Anecdotal cases can be found in the literature, but the true incidence is unknown (7,8).
Classification of OHSS
OHSS may be mild, moderate, or severe; early or late in onset; spontaneous or iatrogenic in etiology.
Early OHSS presents 3 to 7 days after the trigger to induce ovulation whereas late OHSS presents 12 to 17 days after ovulation. Early OHSS relates to “excessive” pre-ovulatory response to stimulation whereas late OHSS depends on the occurrence of pregnancy, is more likely to be severe, and is only poorly related to pre-ovulatory events.
There has been no unanimity in classifying OHSS, and divergent classifications have made comparisons between studies difficult. In 1999, Rizk and Aboulghar introduced a classification dividing the syndrome into moderate (group B) and severe (group C) with the purpose of categorizing patients into more defined clinical groups, which correlate with the prognosis of the syndrome. The new classification can be correlated with the treatment protocol and prognosis (9). The mild degree (group A) of OHSS, used by most previous authors was omitted from the new classification as this degree occurs in the majority of cases of ovarian stimulation and does not require special treatment. The great majority of cases of OHSS with ovulation induction present with symptoms belonging to category of mild OHSS. During clomiphene citrate ovulation induction cycles, the incidence of mild OHSS might be seen in up to 13% of cycles (10). ESHRE and the ASRM also support this classification categorizing OHSS into mild, moderate, and severe forms.
Classification of Severity of OHSS (RCOG Guideline No. 5)
Grade | Symptoms |
Mild OHSS | Abdominal bloating Mild abdominal pain Ovarian size usually less than 8 cm |
Moderate OHSS | Moderate abdominal pain Nausea with or without vomiting Ultrasound evidence of ascites Ovarian size usually 8–12 cm |
Severe OHSS | Clinical ascites (occasionally hydrothorax) Oliguria Hemoconcentration with a hematocrit >45% Hypoproteinemia Ovarian size usually more than 12 cm |
Critical OHSS | Tense ascites or large hydrothorax Hematocrit >55% White cell count >25,000/ml Oliguria or anuria Thromboembolism Acute respiratory syndrome |
The Royal College of Obstetricians and Gynaecologists (RCOG), through its Guideline and Audit Committee and Professional Standards Committee, produces Clinical Governance guidance documents for gynecologists practicing in the United Kingdom. This provides us with a classification and advice on appropriate treatment. With the reflection on mild and moderate OHSS classification, modified as suggested by Mathur in 2005 (11). Table 24.3 is the used classification of severity of OHSS in the United Kingdom with the footnote that ovarian size may not correlate with severity of OHSS in cases of assisted reproduction because of the effect of follicular aspiration.
Prediction of OHSS
Prediction of OHSS is the cornerstone of prevention. Prediction is based on identifying the characteristics of the patients who would be high responders for primary prevention as well as identifying the patient at risk during stimulation.
Patient characteristics of women at risk for OHSS mentioned in literature are previous OHSS, youth, low BMI, PCO(S), high AMH, and single nucleotide polymorphism for FSH-R, LH-R, E2-R, and AMH-R (12).
For secondary prevention ultrasonography and estradiol assessment during stimulation can be used. A rapid rise of estradiol or a high serum level (4000 pg/ml) are associated with over-response (13,14).
Ultrasound is widely used for monitoring follicular development in assisted conception (see also Chapter 21). The number, size, and pattern of distribution of the follicles are important in the prediction of OHSS (9). The diagnosis of polycystic ovaries at ultrasound examination (the necklace sign) improved the prediction of OHSS to 79% (15). Also, it was stated that a decrease in the fraction of mature follicles and an increase in the fraction of very small follicles correlated with an augmented risk for the development of severe OHSS (16). Additionally, there was a significant correlation between the baseline ovarian volume and the subsequent occurrence of OHSS 13.2+/15 ml versus 8.9+/-3.7 ml (P = 0.035), suggesting that volumetry of the ovaries could help to detect patients at risk of developing OHSS in case of stimulation for IVF (17). Keeping in mind that all these studies were about ovarian stimulation for IVF, the actual predictive value of these tests are difficult to extrapolate to ovulation induction. One can, however, hypothesize that predicting the patients at risk for OHSS is comparable to the ones doing so during ovulation induction.
Checa et al. concluded, in a small prospective study, that an antral follicle count of 16 is predictive (sensitivity of 100%, specificity of 93%) for exacerbated response leading to cycle cancellation not commenting on OHSS (18).
In the majority of studies regarding ovulation induction, the under- or over-response is examined and not OHSS. The link between clomiphene citrate over-response or clomiphene citrate resistance and the response to gonadotropins needs to be explored. Our own unpublished experience with PCOS patients showed clomiphene citrate resistance is associated with over-response using standard ovarian stimulation for IVF.
Patients who hyper-responded on clomiphene citrate are likely to over-respond to ovarian stimulation and would therefore be classified as being at risk for OHSS. The response to clomiphene citrate depends on metabolism; therefore, the response to exogenous FSH cannot directly be correlated.
Prevention of Ovarian Hyperstimulation Syndrome
Laparoscopic Ovarian Drilling in PCOS Patients (See Also Chapter 16)
As previously mentioned, women suffering from PCOS are a challenging group. The threshold beyond which women over-respond to stimulation is difficult to determine. In reviews looking at ovarian drilling for ovulation induction and the efficacy, there is no difference in live birth rate (19). There is, however, no data on OHSS.
Laparoscopic ovarian drilling has been used successfully for prevention of OHSS in patients with polycystic ovaries undergoing IVF (20).
As ovarian drilling can make clomiphene citrate–resistant ovaries more susceptible for stimulation; needing less aggressive stimulation will reduce the risk of developing OHSS in theory (LOE 4).
Metformin
Short-term co-treatment with metformin for patients with PCOS undergoing IVF/ICSI cycles does not improve the response to stimulation but significantly improves the pregnancy outcome and reduces the risk of OHSS (21). No data is available for ovulation induction with metformin and a potential reduction of OHSS.
Cancel Cycle/Withhold hCG
As identifying the few patients who will develop OHSS with ovulation induction is so difficult, we can only focus on secondary prevention. This is when we diagnose over-response.
In order to prevent the angiogenesis of the follicles leading to the syndrome, ovulation should be avoided. Administration of hCG as an ovulation trigger is likely to have a negative effect and should be avoided in hyper-response. The couples should be advised to refrain from intercourse as the development of a pregnancy, especially a multiple pregnancy, will further stimulate the ovaries. Two to ten percent of IUI cycles get cancelled due to mild OHSS (10
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
