Dopamine agonists to prevent ovarian hyperstimulation syndrome in women undergoing assisted reproduction technology

Review question

Are dopamine agonists effective and safe for preventing ovarian hyperstimulation syndrome (OHSS) in women at high risk of OHSS (e.g. women with polycystic ovaries or a high oocyte yield following stimulation)? How effective are they compared to other active treatments (e.g. human albumin)?

Background

OHSS occurs because of overstimulation of the ovaries (female reproductive organs that produce eggs and sex hormones) in fertility treatment (called assisted reproductive technology). It is characterised by enlarged ovaries and movement of fluid from the blood vessels to other body cavities, resulting in abdominal (stomach) bloating, increased risk of blood clots and a reduction in the blood supply to important organs. In most cases, the condition is mild and resolves itself without treatment, but some women develop a moderate or severe form of OHSS, which requires hospitalisation. There is no cure for OHSS other than waiting for it to settle down and reducing symptoms while in hospital. Medicines called dopamine agonists have been introduced to try and prevent OHSS.

Study characteristics

This review included 16 randomised controlled trials involving 2091 women at high risk of OHSS, which evaluated three different dopamine agonists (cabergoline, bromocriptine and quinagolide). The main outcome measures were the number of new cases (incidence) of moderate or severe OHSS and live birth rate. The evidence is current to August 2016.

Key results

Dopamine agonists appear to reduce the incidence of moderate or severe OHSS in women at high risk of OHSS (moderate quality evidence) compared with placebo or no treatment. This suggests that if 29% of women taking placebo or no treatment have moderate or severe OHSS, between 7% and 14% of women taking dopamine agonists will have moderate or severe OHSS. For women who had a fresh embryo transferred as part of their treatment cycle, there was no evidence that dopamine agonists influenced pregnancy outcomes, but they might increase the risk of side effects, such as stomach upsets. There was no evidence of a difference between a dopamine agonist plus another active treatment versus another active treatment on incidence of moderate or severe OHSS and live birth rate.

There was no evidence of a difference in OHSS rates between cabergoline and placebo treatments (e.g. hydroxyethyl starch, prednisolone or 'coasting' (withholding any more ovarian stimulation for a few days)). Cabergoline was associated with an increased clinical pregnancy rate compared with coasting.

Quality of evidence

The quality of the evidence ranged from very low to moderate. Limitations included poor reporting of study methods and imprecision (too few events) for some comparisons.

Authors' conclusions: 

Dopamine agonists appear to reduce the incidence of moderate or severe OHSS in women at high risk of OHSS (moderate quality evidence). If a fresh embryo transfer is performed, the use of dopamine agonists does not affect the pregnancy outcome (live birth rate, clinical pregnancy rate and miscarriage rate) (very low to moderate quality evidence). However, dopamine agonists might increase the risk of adverse events, such as gastrointestinal symptoms. Further research should focus on dose-finding, comparisons with other effective treatments and consideration of combination treatments. Therefore, large, well-designed and well-executed RCTs that involve more clinical endpoints (e.g., live birth rate) are necessary to further evaluate the role of dopamine agonists in OHSS prevention.

Read the full abstract...
Background: 

Ovarian hyperstimulation syndrome (OHSS) is a potentially serious complication of ovarian stimulation in assisted reproduction technology (ART). It is characterised by enlarged ovaries and an acute fluid shift from the intravascular space to the third space, resulting in bloating, increased risk of venous thromboembolism and decreased organ perfusion. Most cases are mild, but forms of moderate or severe OHSS appear in 3% to 8% of in vitro fertilisation (IVF) cycles. The dopamine agonist cabergoline was introduced as a secondary prevention intervention for OHSS in women at high risk of OHSS undergoing ART treatment. As cabergoline seemed to be effective in preventing OHSS, other types of dopamine agonists, such as quinagolide and bromocriptine, have since been studied in ART to prevent OHSS.

Objectives: 

To assess the effectiveness and safety of dopamine agonists in preventing OHSS in high-risk women undergoing ART treatment.

Search strategy: 

We searched several databases from inception to August 2016 (Cochrane Gynaecology and Fertility Specialised Register of trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, PsycINFO, Clinicaltrials.gov and the World Health Organization International Trials Registry Platform (ICTRP)) for randomised controlled trials (RCTs) assessing the effect of dopamine agonist in preventing OHSS. We handsearched the reference lists of relevant studies.

Selection criteria: 

We considered RCTs which compared dopamine agonists with placebo/no intervention or another intervention for preventing OHSS in high-risk women for inclusion. Primary outcome measures were incidence of moderate or severe OHSS and live birth rate. Secondary endpoints were clinical pregnancy rate, multiple pregnancy rate, miscarriage rate and any other adverse effects of the treatment.

Data collection and analysis: 

Two authors independently screened titles, abstracts and full texts of publications, selected studies, extracted data and assessed risk of bias. We resolved any disagreements by consensus. We reported pooled results as odds ratios (OR) and 95% confidence interval (95% CI) by the Mantel-Haenszel method. In addition, we graded the overall quality of the evidence using GRADE criteria.

Main results: 

The search identified 14 new RCTs since the last published version of this review, resulting in 16 included RCTs involving 2091 high-risk women for this updated review. They evaluated three types of dopamine agonists: cabergoline, quinagolide and bromocriptine.

When compared with placebo or no intervention, dopamine agonists seemed effective in the prevention of moderate or severe OHSS (OR 0.27, 95% CI 0.19 to 0.39; 1022 participants; 8 studies; I2 = 0%; moderate quality evidence). This suggests that if 29% of women undergoing ART experience moderate or severe OHSS, the use of dopamine agonists will lower this to 7% to 14% of women. There was no evidence of a difference in live birth rate, clinical pregnancy rate, multiple pregnancy rate or miscarriage rate (very low to moderate quality evidence). However, taking dopamine agonists (especially quinagolide) may increase the incidence of adverse events such as gastrointestinal adverse effects (OR 4.54, 95% CI 1.49 to 13.84; 264 participants; 2 studies; I2 = 49%, very low quality evidence).

When we compared dopamine agonist plus co-intervention with co-intervention, there was no evidence of a difference in the outcomes of moderate or severe OHSS, live birth rate, clinical pregnancy rate, miscarriage rate or adverse events. The co-interventions were hydroxyethyl starch (two RCTs) and albumin (one RCT).

Cabergoline was associated with a lower risk of moderate or severe OHSS compared with human albumin (OR 0.21, 95% CI 0.12 to 0.38; 296 participants; 3 studies; I2 = 72%). However, there was no evidence of a difference between cabergoline and hydroxyethyl starch, coasting (withholding any more ovarian stimulation for a few days) or prednisolone. There was an increased clinical pregnancy rate in the cabergoline group when cabergoline was compared with coasting (OR 2.65, 95% CI 1.13 to 6.21; 120 participants; 2 studies; I2 = 0%). In other respects, there was no evidence of a difference in clinical pregnancy rate, multiple pregnancy rate or miscarriage rate between cabergoline and other active interventions.

The quality of the evidence between dopamine agonist and placebo or no intervention ranged from very low to moderate, mainly due to poor reporting of study methods (mostly a lack of details on randomisation or blinding) and serious imprecision for some comparisons.

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