Effectiveness of indometacin to prevent ovulation in modified natural-cycle IVF: A randomized controlled trial

Abstract

Modified natural-cycle IVF has a lower pregnancy rate per started cycle as compared with IVF with ovarian stimulation due to, for example, premature ovulation. Indometacin administered before ovulation prevents follicle rupture. Therefore, addition of indometacin may improve the effectiveness of modified natural-cycle IVF. This double-blind, randomized, placebo-controlled trial with indometacin or placebo in 120 women aged 27–36 years compared the number of patients without premature ovulation as compared with the number of patients with one or more ovulations in a maximum of six cycles. Indometacin had no significant influence on the probability of a premature ovulation in patients during the six cycles (OR 2.38, 95% CI 0.94–6.04). A subgroup analysis showed a significant influence of indometacin in decreasing the probability of a premature ovulation in cycles without LH surge at the day of human chorionic gonadotrophin administration (OR 8.29, 95% CI 1.63–42.3, P = 0.009). Although this study could not detect a significantly lower ovulation rate in the indometacin group versus the placebo group, the data suggest that a subgroup of patients without LH surge prior to oocyte retrieval might benefit from indometacin in modified natural-cycle IVF.

Modified natural-cycle IVF is a mild form of IVF, with a lower pregnancy rate per started cycle as compared with IVF with ovarian stimulation because of several unfavourable cycle events, such as ovulation before oocyte retrieval. Indometacin is a cheap drug, commonly used to reduce fever, pain and swelling caused by inflammation. It has been shown that indometacin administered before ovulation prevents this from happening. Therefore, it has been suggested that indometacin may improve the effectiveness of modified natural-cycle IVF. In this study, we assigned 120 women aged 27–36 years randomly to an indometacin group (60 women) and a group of women who used placebo (also 60 women). We evaluated whether indometacin could indeed prevent ovulation during a maximum of six modified natural-cycle IVF cycles. When we compared the two groups of women, indometacin did not seem to prevent ovulation compared with women who used placebo. Within these groups, however, the patients with a low level of LH (a hormone involved in ovulation) on the day that administration indometacin or placebo was started, indometacin did decrease the chance of an untimely ovulation. So although we could not detect a lower ovulation rate in the indometacin group versus the placebo group, our data suggest that a subgroup of patients with low LH concentrations prior to oocyte retrieval might benefit from indometacin in modified natural-cycle IVF.

Introduction

There is an increasing interest in mild stimulation protocols in IVF, of which modified natural-cycle IVF is an example (Aanesen et al., 2010, Nargund and Frydman, 2007). Compared with IVF with ovarian stimulation, modified natural-cycle IVF is considered to minimize serious treatment complications such as multiple pregnancies and ovarian hyperstimulation syndrome. Furthermore, costs of medication are lower, treatment cycles can be performed at short intervals in consecutive cycles, oocyte retrieval can be performed without analgesia and since only one embryo is available for transfer, embryo surplus is avoided (Pelinck et al., 2005).

In modified natural-cycle IVF, the one follicle that spontaneously develops to dominance is used. A gonadotrophin-releasing hormone (GnRH) antagonist is applied in the late follicular phase to prevent ovulation and FSH is given concomitantly to warrant follicle growth and to maintain oestradiol concentrations. Ovulation is triggered with human chorionic gonadotrophin (HCG), after which the oocyte retrieval is scheduled. Luteal support is considered mandatory (Nargund et al., 2007, Vlaisavljevic, 2007). In this study centre, the reported ongoing pregnancy rate per started cycle is 8% (95% confidence interval (CI) 6.4–10.2%) and the cumulative ongoing pregnancy rate for up to three cycles is 21% (95% CI 16.4–25.3%) and for up to nine cycles is 44.4% (95% CI 38.3–50.5%) (Nargund et al., 2007, Pelinck et al., 2005, Pelinck et al., 2006, Pelinck et al., 2007).

The lower pregnancy rate per started cycle in modified natural-cycle IVF compared with IVF–ovarian stimulation is a logical consequence, since only one follicle is available in modified natural-cycle IVF. Approximately six modified natural-cycle IVF cycles are needed to achieve pregnancy rates comparable to those for one IVF–ovarian stimulation cycle (Pelinck et al., 2008). Possible unfavourable cycle events have great impact on the outcome. These unfavourable cycle events are inadequate growth of the dominant follicle or premature surge in LH observed in 10% of started cycles, spontaneous ovulation before oocyte retrieval occurring in 9% of started cycles, failure to collect an oocyte in 25% of oocyte retrievals and fertilization failure or no transferable embryo in 30% of cycles in which an oocyte is obtained (Pelinck et al., 2007).

A possible way to optimize the pregnancy rate per modified natural-cycle IVF cycle started is to reduce the number of premature ovulations. Adding indometacin, a nonsteroidal anti-inflammatory drug (NSAID) to the treatment protocol might prevent ovulation (Nargund et al., 2001, Okuda et al., 1983). Indometacin inhibits the production of prostaglandins, which are essential for follicle rupture and ovulation. It has been shown that indometacin, administered before ovulation, prevents follicle rupture without apparent effects on menstrual cycle length or FSH, LH, oestradiol and progesterone concentrations (Athanasiou et al., 1996, Hester et al., 2010). Three retrospective studies have suggested that indometacin may be effective in preventing or delaying ovulation (Kadoch et al., 2008, Kawachiya et al., 2012, Nargund and Wei, 1996).

The present study investigated the effectiveness of indometacin in preventing premature ovulation in modified natural-cycle IVF in a double-blind, randomized, placebo-controlled trial.