|Year : 2017 | Volume
| Issue : 1 | Page : 1-2
Managing ovarian hyperstimulation syndrome:Prevention is better
Department of Obstetrics and Gynaecology, Sheffield Teaching Hospitals NHS Foundation Trust, University of Sheffield, Sheffield, UK
|Date of Web Publication||10-Sep-2018|
Sheffield Teaching Hospitals NHS Foundation Trust, University of Sheffield, Sheffield
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Ola B. Managing ovarian hyperstimulation syndrome:Prevention is better. Afr J Infertil Assist Concept 2017;2:1-2
It is almost 40 years since Steptoe and Edwards reported the birth of a baby girl conceived through in vitro fertilization (IVF) and embryo transfer. Twenty years later almost to the day, a strong case was made against new reproductive technologies for developing countries, which was published in a 1996 editorial of the British Journal of Obstetrics and Gynaecology. Fortunately, not everyone headed that call and today, assisted conception treatments are widely available in many developing countries not only for reproductive failure but increasingly also for newer indications. Thanks to assisted reproductive technologies (ARTs), it is now possible to use preimplantation genetic screening or diagnosis to screen/diagnose embryos for heritable genetic or chromosomal abnormalities for couples with significant family history or for sex selection to prevent a gender-linked heritable disease. ART has also facilitated conception of human leukocyte antigen-compatible “savior siblings” when another child has an incurable disease and allows fertility preservation (by sperm, eggs, ovarian tissue, or embryo cryopreservation) for people suffering cancer that may require surgery, chemotherapy, or radiotherapy. Furthermore, ART has made it possible for doctors to use egg, sperm, or embryo donations to treat women with ovarian failure and surrogacy for women with damaged uteri or those with congenital mullerian agenesis or dysgenesis. For all its benefits, IVF is not without complications; and perhaps, the most serious is ovarian hyperstimulation syndrome (OHSS).
Mild OHSS is very common, occurring in 20%–33% of IVFs, moderate disease occurs in 2%–6%, and the severe OHSS occurs in 0.5%–2%. It is characterized by painful ovarian enlargement due to multiple ovarian follicles and increased production of vasoactive substances resulting in generalized capillary permeability, hemoconcentration, and fluid shifts into the third space. Although generally considered an iatrogenic condition, on rare occasions, it has been described complicating multiple and molar, even singleton pregnancies. When OHSS complicates fertility treatments, this has been associated more with the use of follicle-stimulating hormone (FSH) than antioestrogens such as clomifene or tamoxifen. OHSS is not a condition to be underestimated regarding the devastation it can cause or the rapidity with which it can progress over a short period. Typically, symptoms and signs start with use of human chorionic gonadotropin (HCG) as trigger. Two types are recognized based on time of presentation: early OHSS, which occurs within 10 days and is usually mild or moderate in severity, and later presentation, usually associated with pregnancy and frequently severe with a protracted course, sometimes needing critical care management. Mortality from OHSS has been estimated at 1:30,000 women in the UK.
Over the years, a lot has already been written about the various treatments of mild, moderate, severe, and critical OHSS. These well-trodden steps are not the subject of this commentary.
It is not possible to completely eliminate OHSS; however, the incidence of moderate-severe disease can be significantly reduced by high indices of suspicion, early detection of risk factors, and careful management choices. Those at increased risk are usually young and of slim physique, or women with polycystic ovary syndrome (PCOS), or those with a history of overresponse. In addition, one should be cautious in women with antral follicle counts >12 in each ovary, or high serum levels of antimullerian hormone (>20 pmol/L or >2.8 ng/mL) associated with established PCOS. Other indices include high estradiol levels (E2) >15,000 pmol/L (>4000 pg/mL) or a rapid increase (≥75%) in 24 h, associated with many developing follicles, or more than 20 follicles of large and medium sizes, or where more than 15 eggs collected when HCG has been used as trigger.
When seeing patients with polycystic ovarian syndrome who are planning IVF or intracytoplasmic sperm injection (ICSI), a GnRH antagonist cycle is preferable. If, however, they are undergoing a GnRH agonist downregulation cycle, the addition of metformin at a dose ≥1000 mg for at least 3 weeks before egg collection has been shown to reduce the incidence of OHSS in one systematic review that pooled the results of five randomized controlled trials (RCTs). The same systematic review also found, in one of the RCTs, that miscarriage rates were reduced and live birth rate significantly increased. Recent evidence shows that a similar short course of metformin does not reduce moderate-severe OHSS in GnRH antagonist cycles.
When the increased risk of OHSS is identified after IVF/ICSI has already started, there is still a lot that can be done to prevent moderate and severe OHSS. These include adopting the use of GnRH antagonist instead of GnRH agonist for downregulation, which reduces the risk of severe OHSS by 40%, without adversely affecting clinical pregnancy outcomes. Furthermore, a high risk can be significantly reduced using a GnRH agonist as a substitute for HCG to trigger final oocyte maturation. It should, however, be pointed out that, if a fresh embryo transfer is planned in this group, the clinical pregnancy rates will be adversely affected unless the luteal phase is rescued with small-dose injections of HCG after GnRH agonist trigger. Although there is no general agreement, one effective luteal phase rescue regime is HCG 1500 i.u., given at the time of egg collection followed 500 i.u., on day 5, in addition to routine administration of progesterone luteal support. The alternative is to freeze all embryos on day 2–3 and plan a frozen embryo replacement transfer in a future natural or HRT cycles.
Coasting before egg collection is no longer popular because of adverse effects on pregnancy outcomes. Coasting involves stopping gonadotropin for a few days while continuing with GnRHa and delaying the administration of a reduced dose of HCG until estradiol level has fallen significantly. Although proven to reduce incidence of all OHSS from 26.5% to 5.8% in one study, coasting for more than 3 days is associated with reduction in egg yield by an average of four oocytes, a reduction in clinical pregnancy rates, and a halving of live birth rate.
If worsening symptoms and signs become evident just before HCG trigger, a few options are available to prevent moderate OHSS. If it is not warranted or desirable to withhold HCG and cancel the cycle, then one could consider prophylactic cabergoline (a dopamine agonist). This drug acts by inactivating the vasoactivity of vascular endothelial growth factor. One regime is 0.5 mg/day from day of HCG administration for 8–10 days, which reduces the risk of moderate OHSS by 60%, without adverse outcomes on CPR. However, it does not appear to significantly reduce the rate of severe OHSS.
Frequently, it is after egg collection that one is able to intervene to reduce the incidence and severity of OHSS. In many centers with good cryopreservation protocols and facilities, the treatment cycle can be cancelled after egg collection with all embryos frozen on day 2 or 3. This measure is proven to prevent late-onset OHSS. The patient must also be prohibited from using nonsteroidal anti-inflammatory drugs for pain control as these prostaglandin synthetase inhibitors may worsen renal function. Where a patient insists on fresh transfer, elective single embryo transfer and the use of progesterone instead of HCG for luteal support must be advised.
The role of albumin needs to be clarified. It binds vasoactive substances, increases intravascular oncotic pressure, and is useful in the management of established severe or critical OHSS. However, there is no evidence that prophylactic infusion of albumin or its alternative, hydroxyl ethyl starch at the time of egg retrieval prevents OHSS. The risk of viral and prion transmission during albumin infusion is another concern that restricts the use of albumin infusions in OHSS.
It is crucially important to follow-up patients considered to be at high risk of OHSS or venous thromboembolism, for early detection of those prone to developing the late-onset severe forms.
Not infrequently, our first contact is when a patient previously treated or identified as high risk of recurrent OHSS attends or returns to our clinic. In these cases, one should ideally consider changing from an agonist to an antagonist downregulation protocol. Alternatively, if patient must remain on an agonist protocol for medical reasons, the FSH stimulation dose should be reduced significantly. For patients with PCOS, metformin pretreatment should be considered, as this is proven to reduce OHSS and miscarriage rates. In vitro oocyte maturation for PCOS is still experimental and not yet widely available.
In conclusion, there are now over 5 million births from IVF/ICSI, and the number is steadily increasing. It will be near impossible to determine how many of these babies were conceived in Africa. What is sure, though, is that the needs for IVF/ICSI are now much wider than infertility indications. Hence, the challenge to minimize the risk of OHSS has never been greater. The adage “prevention is better than cure” is very apt for OHSS. It costs very little to prevent OHSS in most cases; yet on the contrary, one study published in 2011 estimated that the tangible costs of treating severe OHSS range between £850 and £1200. These estimates do not include intangible financial costs, loss of earnings, human suffering, disabilities, and deaths following severe or critical OHSS.