Key messages
- ‘Fertility medicines’ are the range of hormones and medicines used to help women get pregnant. This review shows that, in a comparison of two widely-used fertility medicines – gonadotropins and anti-oestrogens – gonadotropins probably increase the number of live births.
- We have little to no confidence in the evidence comparing the effectiveness of other fertility medicines, both for live birth and multiple pregnancy (expecting more than one baby) rates.
- To improve the evidence, future studies of intrauterine insemination (where sperm is placed directly in the womb) should compare fertility medicines with a placebo (dummy drug). More studies comparing anti-oestrogens with aromatase inhibitors (another widely-used fertility drug) are also needed.
What is infertility?
Infertility is when a woman is unable to get pregnant after 1 year (or longer) of regular, unprotected sex. Sometimes, doctors distinguish between older and younger women, since natural fertility declines with age. Some providers treat women aged 35 years or older for infertility after 6 months of unprotected sex.
How is infertility treated?
Treatment for infertility depends on what may be causing it. Our review focused on intrauterine insemination combined with various fertility medicines. Fertility medicines work by causing the release of hormones that prompt ovulation – that is, the release of an egg from the ovary. Intrauterine insemination is where sperm is placed directly into the uterus (womb) using a thin, flexible plastic tube inserted through the vagina and cervix.
There are many different fertility medicines. The ones most commonly prescribed include:
- gonadotropins (injectable hormones started early in the menstrual cycle to cause multiple eggs to grow to a mature size);
- anti-oestrogens and aromatase inhibitors (oral medicines used to trigger ovulation);
- gonadotropin-releasing hormone (GnRH) agonists and antagonists (medicines used to regulate egg development and ovulation).
What did we want to find out?
We wanted to find out which fertility medicines, combined with intrauterine insemination, are most effective, for women who release an egg during menstruation (ovulatory women).
We were interested in the effects of fertility medicines on:
- live births;
- multiple pregnancies;
- ‘clinical pregnancy’ (defined as evidence of a gestational sac, the fluid-filled structure around a foetus, with a positive heartbeat);
- miscarriages (defined as loss of pregnancy during the first 12 weeks);
- ovarian hyperstimulation syndrome (OHSS, a condition where excess hormones can overstimulate the ovaries, leading to various complications); and
- ectopic pregnancy, defined as a pregnancy outside the womb.
What did we do?
We searched for studies that compared different fertility medicines for ovulatory women having intrauterine insemination.
We compared and summarised their results, and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We found 82 studies, involving 12,614 women. The women ranged from 18 to 44 years old. Slightly more than two-thirds (57) of the studies included women or couples with unexplained infertility (the lack of an obvious cause of infertility), male infertility, endometriosis (a painful condition when tissue similar to the lining of the uterus grows outside the uterus), or more than one of these factors.
The studies were conducted in 17 countries around the world, with more than half conducted in India, Iran, Italy, Spain and the USA.
There were more than 20 different comparisons between the various fertility medicines.
Only around one-fifth (17) of studies reported information about live birth rates.
Main results
Gonadotropins compared to anti-oestrogens (13 studies): probably increase the chance of live birth. If the chance of a live birth following anti-oestrogens is assumed to be 22.8%, the chance following gonadotropins would be between 23.7% and 34.6%.
We don’t know if gonadotropins make any difference to multiple pregnancy rate.
Aromatase inhibitors versus anti-oestrogens (8 studies)
We don’t know if aromatise inhibitors make any difference to:
· live birth rate; or
· multiple pregnancy rate.
Gonadotropins plus GnRH antagonists versus gonadotropins alone (14 studies)
We don’t know if gonadotropins plus GnRH antagonists make any difference to:
· live birth rate; or
· multiple pregnancy rate.
Aromatase inhibitors versus gonadotropins (6 studies): may decrease the chance of a live birth. If the chance of a live birth following gonadotropins is assumed to be 31.9%, the chance following aromatase inhibitors would be between 13.7% and 25%.
We don’t know if aromatase inhibitors make any difference to multiple pregnancy rate.
Aromatase inhibitors plus gonadotropins versus anti-oestrogens plus gonadotropins (8 studies):
We don’t know if aromatase inhibitors plus gonadotropins make any difference to:
· live birth rate; or
· multiple pregnancy rate.
What are the limitations of the evidence?
Our confidence in the evidence ranged from very low to moderate. More than three-quarters of the studies had weaknesses in their methods that could affect the reliability of their results, and many of the studies were small.
How up to date is this evidence?
The evidence is up to date to November 2020.
Based on the available results, gonadotropins probably improve cumulative live birth rate compared with anti-oestrogens (moderate-certainty evidence). Gonadotropins may also improve cumulative live birth rate when compared with aromatase inhibitors (low-certainty evidence). From the available data, there is no convincing evidence that aromatase inhibitors lead to higher live birth rates compared to anti-oestrogens. None of the agents compared lead to significantly higher multiple pregnancy rates. Based on low-certainty evidence, there does not seem to be a role for different combined therapies, nor for adding GnRH agonists or GnRH antagonists in IUI programs.
Intrauterine insemination (IUI), combined with ovarian stimulation (OS), has been demonstrated to be an effective treatment for infertile couples. Several agents for ovarian stimulation, combined with IUI, have been proposed, but it is still not clear which agents for stimulation are the most effective. This is an update of the review, first published in 2007.
To assess the effects of agents for ovarian stimulation for intrauterine insemination in infertile ovulatory women.
We searched the Cochrane Gynaecology and Fertility Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two trial registers from their inception to November 2020. We performed reference checking and contacted study authors and experts in the field to identify additional studies.
We included truly randomised controlled trials (RCTs) that compared different agents for ovarian stimulation combined with IUI for infertile ovulatory women concerning couples with unexplained infertility. mild male factor infertility and minimal to mild endometriosis.
We used standard methodological procedures recommended by Cochrane.
In this updated review, we have included a total of 82 studies, involving 12,614 women. Due to the multitude of comparisons between different agents for ovarian stimulation, we highlight the seven most often reported here.
Gonadotropins versus anti-oestrogens (13 studies)
For live birth, the results of five studies were pooled and showed a probable improvement in the cumulative live birth rate for gonadotropins compared to anti-oestrogens (odds ratio (OR) 1.37, 95% confidence interval (CI) 1.05 to 1.79; I2 = 30%; 5 studies, 1924 participants; moderate-certainty evidence). This suggests that if the chance of live birth following anti-oestrogens is assumed to be 22.8%, the chance following gonadotropins would be between 23.7% and 34.6%. The pooled effect of seven studies revealed that we are uncertain whether gonadotropins lead to a higher multiple pregnancy rate compared with anti-oestrogens (OR 1.58, 95% CI 0.60 to 4.17; I2 = 58%; 7 studies, 2139 participants; low-certainty evidence).
Aromatase inhibitors versus anti-oestrogens (8 studies)
One study reported live birth rates for this comparison. We are uncertain whether aromatase inhibitors improve live birth rate compared with anti-oestrogens (OR 0.75, CI 95% 0.51 to 1.11; 1 study, 599 participants; low-certainty evidence). This suggests that if the chance of live birth following anti-oestrogens is 23.4%, the chance following aromatase inhibitors would be between 13.5% and 25.3%. The results of pooling four studies revealed that we are uncertain whether aromatase inhibitors compared with anti-oestrogens lead to a higher multiple pregnancy rate (OR 1.28, CI 95% 0.61 to 2.68; I2 = 0%; 4 studies, 1000 participants; low-certainty evidence).
Gonadotropins with GnRH (gonadotropin-releasing hormone) agonist versus gonadotropins alone (4 studies)
No data were available for live birth. The pooled effect of two studies revealed that we are uncertain whether gonadotropins with GnRH agonist lead to a higher multiple pregnancy rate compared to gonadotropins alone (OR 2.53, 95% CI 0.82 to 7.86; I2 = 0; 2 studies, 264 participants; very low-certainty evidence).
Gonadotropins with GnRH antagonist versus gonadotropins alone (14 studies)
Three studies reported live birth rate per couple, and we are uncertain whether gonadotropins with GnRH antagonist improve live birth rate compared to gonadotropins (OR 1.5, 95% CI 0.52 to 4.39; I2 = 81%; 3 studies, 419 participants; very low-certainty evidence). This suggests that if the chance of a live birth following gonadotropins alone is 25.7%, the chance following gonadotropins combined with GnRH antagonist would be between 15.2% and 60.3%. We are also uncertain whether gonadotropins combined with GnRH antagonist lead to a higher multiple pregnancy rate compared with gonadotropins alone (OR 1.30, 95% CI 0.74 to 2.28; I2 = 0%; 10 studies, 2095 participants; moderate-certainty evidence).
Gonadotropins with anti-oestrogens versus gonadotropins alone (2 studies)
Neither of the studies reported data for live birth rate. We are uncertain whether gonadotropins combined with anti-oestrogens lead to a higher multiple pregnancy rate compared with gonadotropins alone, based on one study (OR 3.03, 95% CI 0.12 to 75.1; 1 study, 230 participants; low-certainty evidence).
Aromatase inhibitors versus gonadotropins (6 studies)
Two studies revealed that aromatase inhibitors may decrease live birth rate compared with gonadotropins (OR 0.49, 95% CI 0.34 to 0.71; I2=0%; 2 studies, 651 participants; low-certainty evidence). This suggests that if the chance of a live birth following gonadotropins alone is 31.9%, the chance of live birth following aromatase inhibitors would be between 13.7% and 25%. We are uncertain whether aromatase inhibitors compared with gonadotropins lead to a higher multiple pregnancy rate (OR 0.69, 95% CI 0.06 to 8.17; I2=77%; 3 studies, 731 participants; very low-certainty evidence).
Aromatase inhibitors with gonadotropins versus anti-oestrogens with gonadotropins (8 studies)
We are uncertain whether aromatase inhibitors combined with gonadotropins improve live birth rate compared with anti-oestrogens plus gonadotropins (OR 0.99, 95% CI 0.3 8 to 2.54; I2 = 69%; 3 studies, 708 participants; very low-certainty evidence). This suggests that if the chance of a live birth following anti-oestrogens plus gonadotropins is 13.8%, the chance following aromatase inhibitors plus gonadotropins would be between 5.7% and 28.9%. We are uncertain of the effect of aromatase inhibitors combined with gonadotropins compared to anti-oestrogens combined with gonadotropins on multiple pregnancy rate (OR 1.31, 95% CI 0.39 to 4.37; I2 = 0%; 5 studies, 901 participants; low-certainty evidence).