BALTIMORE — Couples who bypassed intrauterine insemination (IUI) and went straight to in vitro fertilization (IVF) achieved a live birth faster, a multicenter randomized controlled trial in New Zealand showed.
At 7 months, 31% of those in the IUI group achieved a live birth, compared with 55% of those in the IVF group (adjusted risk difference [aRD] -24 percentage points, 95% CI -31 to -16), reported Lucy Prentice, MBChB, of the University of Auckland in New Zealand, and colleagues at the American Society for Reproductive Medicine (ASRM) annual meeting and simultaneously in the New England Journal of Medicine.
That gap closed by 20 months, after those in the IUI group were offered IVF in the second stage of the trial (70% and 71%, respectively), they reported.
“Our finding that IUI with ovarian stimulation was not noninferior to IVF in stage 1 calls into question current international guideline recommendations,” the researchers wrote.
Even though the cumulative live birth rate was similar in the two groups, the time to live birth appeared to favor IVF, they noted.
However, the “choice of first-line treatment should be guided not only by effectiveness but also by cost-effectiveness at stage 1, access to care, patient preferences, treatment burden, and safety,” they wrote.
“This is the largest trial that has directly compared IUI with IVF in couples with unexplained infertility and we believe the only trial that has assessed the pre-treatment strategy,” Prentice told MedPage Today. “We think it has the potential to offer widespread clinical impact.”
The results suggest that couples can go directly to IVF, the most effective treatment, or start with the less-invasive IUI and be assured that it won’t reduce their overall chance of having a baby if they need to progress to IVF, she said.
Rachel Weinerman, MD, an ob/gyn and reproductive endocrinologist at Case Western Reserve University in Cleveland who wasn’t involved in the study, said it “confirms that IVF is more effective than multiple IUIs for patients with unexplained infertility.”
“However, current recommendations, which generally include IUI followed by IVF, are reasonable and in fact result in similar cumulative live birth rates if failed IUIs are followed by one cycle of IVF,” Weinerman added.
She said she will still recommend three cycles of IUI followed by IVF for most patients because they’ll get pregnant with a cheaper and easier medication than if they went straight to IVF.
“Since IVF is a more expensive treatment option and not always covered by insurance, this study demonstrates that IUI followed by IVF if not successful is still a reasonable approach despite the overall higher success rates with IVF,” Weinerman said. Conversely, for patients whose insurance prefers IVF, going straight to IVF is also reasonable.
The Fertility and IVF and IUI Trial for Unexplained Infertility (FIIX) took place across 6 fertility clinics in New Zealand from August 2019 to March 2024. A total of 737 couples were randomized; 288 couples in the IUI group and 297 in the IVF group were included in the final analysis. Mean maternal age was 34.3 and most characteristics between groups were similar at baseline, though the IVF group had more common history of previous live birth.
Those randomized to the IUI group could have up to 4 cycles of IUI with oral ovarian stimulation and then after 7 months, couples without live birth could proceed to two cycles of IVF if needed. Those in the IVF group had one cycle of IVF including the transfer of all embryos, and then proceeded to a second round of IVF after 7 months if needed.
The primary endpoint was the 7-month mark when the authors conducted a non-inferiority analysis of the cumulative live birth rate. At this point, there were 89 births in the IUI group and 165 in the IVF group. The secondary endpoint was at 20 months and a superiority analysis was performed using logistic regression. Here, there were 257 live births in the IUI pretreatment group and 265 in the direct IVF group.
There were 6 serious adverse events in the IUI group and 14 in the IVF group, most of which were related to oocyte retrieval or hyperstimulation, the researchers reported.
As for limitations, Prentice and team noted that they used a broad definition of unexplained fertility and that the findings may not be generalizable to couples with unexpected fertility of shorter duration. The pandemic posed challenges, but the researchers altered protocol and analyses, excluding all couples in stage 1 during lockdown, and increased the sample size. It’s also possible that women with undiagnosed endometriosis were included. Lastly, due to the nature of the interventions, blinding was not possible.
Still, they concluded that while international guidelines recommend IUI as first-line treatment before IVF, the “evidence supporting these recommendations is limited, and the guidelines are based largely on trials that showed a benefit of IUI with ovarian stimulation over expectant management.” Thus, they could be reconsidered in light of these new findings.
