Can Ibuprofen Delay Ovulation in Natural Cycle-IVF?

Summary

During natural cycle in vitro fertilisation, no gonadotropin stimulation is used to stimulate oocyte production. Ovulation is induced with HCG (human chorionic gonadotropin) and the follicle is retrieved 36 hours later. In this study the patient in the intervention group will receive Ibuprofen as a study intervention beginning at the same time as the HCG injection. The treatment dose will either be 400mg every 8 to 12 hours or 800mg every 8 to 12 hours until the follicle retrieval, totalling 5 tablets. Instead of the usual time period of 36 hours, the follicular punction will occur after 42 hours. Should the oocyte still be accessible after this time period, then it is proven that Ibuprofen delays ovulation. In this case the patient will continue the regular NC-IVF treatment cycle. The study design is a admissible two-stage design. During stage 1, 8 cycles in 8 patients will be examined. Should it be the case that after these 8 patients have completed a cycle, 4 or more show a positive treatment effect from the Ibuprofen intake, then the study will continue to stage 2 with 17 more more patients, totalling 25. Should it be the case however, that after 8 patients, 3 or less show an effect of the Ibuprofen intake, then the study will be stopped prematurely for futility. The study intervention will be increased to 800mg of Ibuprofen and the study will recommence with 8 more patients. A control group will consist of women undergoing intrauterine insemination (IUI) or timed sexual intercourse (TSI). 42 hours after Beta-HCG injection, an ultrasound examination will be performed in order to determine the number of remaining follicles in the ovary. This examination is to verify and control the proposed time limit of 42 hours.

Timeline

Start

2016-01

Primary completion

2022-08-09

Completion

2022-08-09

Publications

• Background Espey LL. Current status of the hypothesis that mammalian ovulation is comparable to an inflammatory reaction. Biol Reprod. 1994 Feb;50(2):233-8. doi: 10.1095/biolreprod50.2.233.
• Background Tanaka N, Espey LL, Kawano T, Okamura H. Comparison of inhibitory actions of indomethacin and epostane on ovulation in rats. Am J Physiol. 1991 Feb;260(2 Pt 1):E170-4. doi: 10.1152/ajpendo.1991.260.2.E170.
• Background Diao HL, Zhu H, Ma H, Tan HN, Cong J, Su RW, Yang ZM. Rat ovulation, implantation and decidualization are severely compromised by COX-2 inhibitors. Front Biosci. 2007 May 1;12:3333-42. doi: 10.2741/2316.
• Background Gaytan M, Bellido C, Morales C, Sanchez-Criado JE, Gaytan F. Effects of selective inhibition of cyclooxygenase and lipooxygenase pathways in follicle rupture and ovulation in the rat. Reproduction. 2006 Oct;132(4):571-7. doi: 10.1530/rep.1.01236.
• Background Gaytan M, Morales C, Bellido C, Sanchez-Criado JE, Gaytan F. Non-steroidal anti-inflammatory drugs (NSAIDs) and ovulation: lessons from morphology. Histol Histopathol. 2006 May;21(5):541-56. doi: 10.14670/HH-21.541.
• Background Pall M, Friden BE, Brannstrom M. Induction of delayed follicular rupture in the human by the selective COX-2 inhibitor rofecoxib: a randomized double-blind study. Hum Reprod. 2001 Jul;16(7):1323-8. doi: 10.1093/humrep/16.7.1323.
• Background Edelman AB, Jensen JT, Doom C, Hennebold JD. Impact of the prostaglandin synthase-2 inhibitor celecoxib on ovulation and luteal events in women. Contraception. 2013 Mar;87(3):352-7. doi: 10.1016/j.contraception.2012.07.004. Epub 2012 Aug 16.
• Background Bata MS, Al-Ramahi M, Salhab AS, Gharaibeh MN, Schwartz J. Delay of ovulation by meloxicam in healthy cycling volunteers: A placebo-controlled, double-blind, crossover study. J Clin Pharmacol. 2006 Aug;46(8):925-32. doi: 10.1177/0091270006289483.
• Background Jesam C, Salvatierra AM, Schwartz JL, Croxatto HB. Suppression of follicular rupture with meloxicam, a cyclooxygenase-2 inhibitor: potential for emergency contraception. Hum Reprod. 2010 Feb;25(2):368-73. doi: 10.1093/humrep/dep392. Epub 2009 Nov 19.
• Background Kadoch IJ, Al-Khaduri M, Phillips SJ, Lapensee L, Couturier B, Hemmings R, Bissonnette F. Spontaneous ovulation rate before oocyte retrieval in modified natural cycle IVF with and without indomethacin. Reprod Biomed Online. 2008 Feb;16(2):245-9. doi: 10.1016/s1472-6483(10)60581-0.
• Background Kawachiya S, Matsumoto T, Bodri D, Kato K, Takehara Y, Kato O. Short-term, low-dose, non-steroidal anti-inflammatory drug application diminishes premature ovulation in natural-cycle IVF. Reprod Biomed Online. 2012 Mar;24(3):308-13. doi: 10.1016/j.rbmo.2011.12.002. Epub 2011 Dec 15.
• Background Rijken-Zijlstra TM, Haadsma ML, Hammer C, Burgerhof JG, Pelinck MJ, Simons AH, van Echten-Arends J, Arts JG, Land JA, Groen H, Hoek A. Effectiveness of indometacin to prevent ovulation in modified natural-cycle IVF: a randomized controlled trial. Reprod Biomed Online. 2013 Sep;27(3):297-304. doi: 10.1016/j.rbmo.2013.05.009. Epub 2013 May 22.

Drugs

Indications