A randomized clinical trial to determine optimal infertility treatment in older couples The forty and over treatment trial

In older infertile women, treatment initiated with two cycles of CC/IUI or FSH/IUI compared with immediate IVF demonstrated superior pregnancy rates with fewer treatment cycles in the immediate IVF group.

Marlene Goldman, Sc.D., Kim L. Thornton, M.D., David Ryley, M.D., Michael M. Alper, M.D., June L. Fung, Ph.D., Mark D. Hornstein, M.D., Richard H. Reindollar, M.D.

Volume 101, Issue 6, Pages 1574–1581.e2


To determine the optimal infertility therapy for women at the end of their reproductive potential.

Randomized clinical trial.

Academic medical centers and private infertility center in a state with mandated insurance coverage.

Couples with ≥6 months of unexplained infertility; female partner aged 38–42 years.

Randomized to treatment with two cycles of clomiphene citrate (CC) and intrauterine insemination (IUI), follicle stimulating hormone (FSH)/IUI, or immediate IVF, followed by IVF if not pregnant.

Main Outcome Measure(s):
Proportion with a clinically recognized pregnancy, number of treatment cycles, and time to conception after two treatment cycles and at the end of treatment.

We randomized 154 couples to receive CC/IUI (N = 51), FSH/IUI (N = 52), or immediate IVF (N = 51); 140 (90.9%) couples initiated treatment. The cumulative clinical pregnancy rates per couple after the first two cycles of CC/IUI, FSH/IUI, or immediate IVF were 21.6%, 17.3%, and 49.0%, respectively. After all treatments, 110 (71.4%) of 154 couples had conceived a clinically recognized pregnancy, and 46.1% had delivered at least one live-born baby; 84.2% of all live-born infants resulting from treatment were achieved via IVF. There were 36% fewer treatment cycles in the IVF arm compared with either COH/IUI arm, and the couples conceived a pregnancy leading to a live birth after fewer treatment cycles.

A randomized controlled trial in older women with unexplained infertility to compare treatment initiated with two cycles of controlled ovarian hyperstimulation/IUI versus immediate IVF demonstrated superior pregnancy rates with fewer treatment cycles in the immediate IVF group.

Clinical Trial Registration Number:

  • Jason Kovac

    Also looking at it from the male perspective… what role does the partner’s semen analysis play in outcomes? Is partner age relevant? Are they able to follow these couples and determine outcomes with respect to things like congenital anomalies and autism?

  • Micah Hill

    Thank you for the nice article. I anticipate the data being very helpful in counseling and managing patients with unexplained infertility, even as the FAST trial was. I have a couple of quesitons.
    1. Im having a hard time understanding the Kaplan Meier graphs. Why do the COH-IUI graphs not increase after 3 months? I understand they get converted to IVF at this point, but shouldnt those pregnancies still be counted in the group they were assigned to, similar to the Kaplan Meier graphs from the proir FAST trial?
    2. I was hoping to see data on cost analysis, similar again to the FAST trial, which I found very helpful in patient counseling. A rough look at the data in this trial seems to suggest that the clomid-IUI group followed by IVF may actually be more cost effective in this age group than just straight IVF? I realize the discussion said the decision was made to focus on efficacy as opposed to cost effectiveness. I think the later data would be helpful!

  • Juan Garcia-Velasco, MD

    Extremely attractive study, specially in western world were time is really crucial as couples and women have babies at a later stage every year. This RCT suggests not to lose valuable time with techniques that yield low PR beyond 38. Would these data be applicable to single women who may be fertile but have no partner and doubt between donor IUI vs donor IVF?

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