To the Editor:
I read with interest the recently published discussion on the etiology and prevention of OHSS (1-2). While the reviews comprehensively covered their aims, there are some issues that should be highlighted.
Agonist and antagonist coast
Coasting, or the complete discontinuation of exogenous gonadotropin while continuing GnRH analogues administration, is a preventive measure that is completely related on serum E2 levels at gonadotropin discontinuation and on the drop in E2 levels on day of hCG administration (1). However, while “it is well established that high E2 levels are associated with a high incidence of OHSS” (1), OHSS may occur in patients who conceived spontaneously, and in those with low or high serum E2 levels on the day of hCG administration (details in ref. 3). These versatile observations actually suggest that the previously accepted risk factors to develop OHSS, especially high serum E2 levels, are unreliable for the prediction of severe OHSS (3).
Therefore, we were not surprised at the finding of the recently published Cochrane review (4), which reported no difference in the incidence of moderate or severe OHSS after coasting.
Preventing severe OHSS
At the end of this series of reviews, Meldrum has stated that “We do have all the tools at our disposal to prevent it (OHSS). Let’s make it a historical note” (2). This statement is actually a repetition of a Devroey et al opinion (5), entitled “An OHSS-Free Clinic,” which suggested that “The syndrome can be erased by applying ovarian stimulation using the combination of GnRH antagonist with GnRH agonist to trigger ovulation. In this case, the strategy is to freeze all of the oocytes or embryos for later use.”
It is noteworthy, that by a strict adherence to our previously published triage (6), that somehow went unnoticed, we have already been practicing an OHSS- Free clinic, for the last 6 years. In our practice, normal and high-responder patients undergoing their first IVF attempt are offered the COH with a GnRH antagonist. With this strategy we are able to substitute hCG with the GnRH agonist to trigger ovulation.
In patients in whom 40 years old, the COH protocol is individually tailored. In the latter groups, if the tailored COH protocols yield >20 oocytes, or >10 embryos develop, the patient is followed for 5 days after oocyte retrieval for signs of early OHSS (ultrasonographic signs of ascites, Hct levels for the degree of haemoconcentration). If early signs develop, embryo transfer is withheld and all resulting embryos cryopreserved. This approach limits early OHSS, if it appears, to a milder and shorter form. If it does not appear, we transfer one blastocyst, with the consequent decrease in the risk of multiple pregnancy to almost zero, thereby eliminating the risk of late OHSS.
The best means of prevention is individualization. We believe that by strict adherence to the aforementioned triage(6), combined with all the luteal support measures suggested (summarized at ref. 2), OHSS can be eliminated.
Professor Raoul Orvieto, M.D.
Infertility and IVF Unit, Barzilai Medical Center, Ashkelon, and
Faculty of Health Science, Ben Gurion University of the Negev, Beer Sheva, Israel
1. Aboulghar M. Agonist and antagonist coast. Fertil Steril 2012;97:523–6.
2. Meldrum DR. Preventing severe OHSS has many different facets. Fertil Steril 2012;97:536–8.
3. Orvieto R. Prediction of OHSS—challenging the estradiol mitos. Hum Reprod 2003;18:665–7.
4. D’Angelo A, Brown J, Amso NN. Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome. Cochrane Database Syst Rev 2011;15(6):CD002811.
5. Devroey P, Polyzos NP, Blockeel C. An OHSS-Free Clinic by segmentation of IVF treatment. Hum Reprod 2011;26:2593-7.
6. Orvieto R. Can we eliminate severe ovarian hyperstimulation syndrome? Hum Reprod 2005;20:320-2.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2012.03.019
The author responds:
I read with interest the letter by Dr. Orvieto commenting on the article “Agonist and antagonist coast” (1). We agree that a high estradiol (E2) level is not always associated with severe ovarian hyperstimulation syndrome (OHSS), however, a high E2 level has an important role in the prediction of OHSS (2) and lowering the E2 level helped to prevent OHSS (3). It was hypothesized that coasting diminishes the functional granulosa cell cohort, which may possibly result in the reduction of the chemicals that augment fluid extravascular accumulation (4).
A systematic review, which analyzed the evidence to justify the general acceptance of coasting, included 12 studies and 493 high-risk patients and showed pregnancy rates between 20% and 57% and a 2.5% hospitalization rate. This data suggest that triggering ovulation after a drop of E2 level below 3000 pg/ml will prevent OHSS in the majority of patients but will not abolish it completely (5).
The letter to the editor refers to a recent Cochrane review (6). The Cochrane review included four randomized studies, two of which compared coasting with early follicular aspiration, a procedure which never gained acceptance in clinical practice. The third study compared coasting with GnRH antagonist and there were no OHSS cases in both arms. The fourth and only study that compared coasting versus no coasting, showed a significant reduction in OHSS in the coasting arm. We assume that this Cochrane review lacks the evidence that coasting is not effective in prevention of OHSS.
Dr. Orvieto suggests a protocol of embryo transfer of one blastocyst on day 5 if no signs of early OHSS develop, otherwise they cryopreserved all embryos for further transfer. This protocol requires good freezing protocol and is an optional preventive measure for OHSS. In GnRH antagonist cycles, another option is supplementing luteal phase with one bolus of 1500 IU hCG on the day of ovum pickup in addition to the standard luteal phase support (LPS) with progesterone and E2 (7). The delivery rate increased remarkably to rates comparable to hCG triggering. However, a 9.6% difference in delivery rate still exists in favor of hCG triggering (8).
It seems that, currently, coasting and cycle cancellation are the only options in cycles treated with the long GnRHa protocol. In GnRH antagonist cycles, triggering ovulation of a bolus of GnRHa with modified luteal phase support is a valid option for preventing OHSS.
Mohamed Aboulghar, M.D.
The Egyptian IVF Center, Maadi, Cairo; and Department of Obstetrics and Gynecology, Cairo University, Cairo, Egypt
1. Aboulghar M. Agonist and antagonist coast. Fertil Steril 2012;97:523-6.
2. Aboulghar M. Prediction of ovarian hyperstimulation syndrome (OHSS). Estradiol level has an important role in the prediction of OHSS. Hum Reprod. 2003 Jun;18:1140-1.
3. Aboulghar M. Symposium: Update on prediction and management of OHSS. Prevention of OHSS. Reprod Biomed Online 2009;19:33-42.
4. Tortoteillo DV, McGovern PG, Colon JM, Skurnick JH, Lipetz K, Santoro N. Coasting does not adversely affect cycle outcome in a subset of highly responsive in vitro fertilization patients. Fertil Steril 1998;69:454-60.
5. Delvigne A, Rozenberg S. A qualitative systematic review of coasting, a procedure to avoid ovarian hyperstimulation syndrome in IVF patients. Hum Reprod Update. 2002 May-Jun;8:291-6.
6. D’Angelo A, Brown J, Amso NN. Coasting (withholding gonadotrophins) for preventing ovarian hyperstimualtion syndrome. Cochrane Database Syst Rev 2011;15:CD002811.
7. Humaidan P, Quartarolo J, Papanikolaou EG. Preventing ovarian hyperstimulation syndrome: guidance for the clinician. Fertil Steril. 2010;94:389-400.
8. Humaidan P, Kol S, Papanilolaou EG. GnRH agonist for triggering of final oocyte maturation: time for a change of practice? Hum Reprod Update 2011;17:10-24.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2012.03.022
The author responds:
I appreciate the letter by Orvieto, which allows reemphasis of some of the points we made, and, more importantly, raises two preventive strategies that were not included in any of our reviews.
First, I agree that coasting does not entirely eliminate OHSS. However, Dr. Aboulghar commented on the reasons why the recent Cochrane review concluded that coasting was not an effective strategy. I support his view that coasting reduces the risk of OHSS, and the marked decrease of VEGF by small follicles provides a logical mechanism of that effect.
We did not mention two important points made by Dr. Orvieto. First, the occurrence of any early signs of OHSS prior to embryo transfer should prompt consideration of cryopreservation of all embryos. Fortunately, in these high responders day 5 transfer will usually be planned, which allows for a longer period of observation. It is this particular clinical situation that prompted me to exhort SART to allow any such cycle to be recorded as a “freeze-all” cycle. Treating such a cycle as a failed fresh ET will inevitably influence practitioners in their decision because of competition among programs for higher reported results, in turn influencing the number of patients choosing their clinic. We also did not mention that transfer of a single embryo in high-risk patients will markedly reduce the risk of severe late OHSS, which is most often associated with multiple pregnancies.
All of this discussion further emphasizes that prevention of OHSS has many different facets and requires the clinician to exercise optimum judgment at multiple points in the patient’s treatment, from initial choice of COH regimen through decision on the number of embryos (one) that is optimal in high-risk patients.
As Dr. Orvieto further emphasizes, individualization is key to an effective strategy. Not every clinic may have a fully optimized cryopreservation program, and while an antagonist regimen with agonist trigger appears to be associated with good success following fresh embryo transfer, much more experience will be required to give complete assurance that results are fully equivalent to other more “tried-and-true” protocols.
David R. Meldrum, M.D.
Reproductive Partners Medical Group, Redondo Beach, California
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2012.03.020