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Assisted Reproduction · Outcomes and Effectiveness

Higher Pregnancy Success Rates in Patients with Diminished Ovarian Reserve < 40 Years When Initially Treated by Intrauterine Insemination with Mild Ovarian Stimulation Compared to In Vitro Fertilization Alone: A Pilot Study

Deneer JJM, Le Cessie S, van Santbrink EJP, van der Westerlaken LAJ, Lashley EELO

Published June 2025 Reproductive Sciences, 32(6), 2010-2018
DOI 10.1007/s43032-025-01830-w PMC PMC12187811

RRM Academy Synopsis

Clinical pregnancy was higher with IUI first in low reserve under 40

Clinical pregnancy was more common at the Dutch hospital that mostly began with IUI than at the one that mostly began with IVF. The retrospective cohort followed 135 women under 40 with diminished ovarian reserve for 24 months. About 6 out of 10 women had a clinical pregnancy at the first, against about 4 out of 10 at the second.

Key Findings

  • At Center 1, 45/73 (61.6%) women had a clinical pregnancy within 24 months, against 26/62 (41.9%) at Center 2 (difference 19.7%, 95% CI 3.1%-36.3%, p = 0.02).
  • Protocol A (IUI with ovarian stimulation, then IVF) covered 53 women (72.6%) at Center 1 and 19 (30.6%) at Center 2. Protocol B (IVF alone) covered 20 (27.4%) and 43 (69.4%).
  • The instrumental variable estimate was 46.9% (10.2%−70.6%) more women with a clinical pregnancy under protocol A than under IVF alone.
  • Ongoing pregnancy occurred in 37/73 (50.7%) versus 25/62 (40.3%) women (difference 10.4%, 95% CI −6.4%, 27.1%). Live birth occurred in 37/73 (50.7%) versus 22/62 (35.5%) (difference 15.2%, 95% CI −1.3%, 31.7%).
  • Early miscarriage occurred in 11/46 (23.9%) women with a biochemical pregnancy at Center 1 and 14/31 (45.2%) at Center 2.

Interpretation

The study is a pilot retrospective cohort of 135 women at two Dutch hospitals. The authors state that referral followed postal code, which they describe as random allocation. They used an instrumental variable analysis with the center standing in for allocation. The authors note that this method rests on three assumptions and that unknown differences between the centers could explain the result. The centers also used different drug protocols for IVF stimulation. Among the pregnancy rates, only clinical pregnancy differed significantly. The cohort includes only women under 40. Sixteen women conceived spontaneously and were counted in the outcomes.

RRM Context

The cohort had low reserve by test cut-offs and no known cause. IVF bypasses the reproductive system without resolving why conception fails. IUI with ovarian stimulation proceeds without that diagnosis. Restorative reproductive medicine treats such a result as the start of a cause-based evaluation of both partners.

Our editorial summary of this paper, not the article's abstract.

Abstract

For women with idiopathic diminished ovarian reserve (DOR), direct start with IVF has been suggested to potentially shorten the time to pregnancy. Others however prefer intra-uterine insemination with ovarian stimulation (IUI + OS) due to the expected low response in IVF. In this pilot study, we determined the effect of these two strategies in women with DOR < 40 years. From a retrospective cohort, we included 135 women that met the diagnostic criteria of DOR. Patients were randomly referred to two different outpatient clinics in the Netherlands between 2012-2018 because of subfertility. Primary outcome was clinical pregnancy; secondary outcomes included ongoing pregnancies, live births, time to pregnancy and pregnancy-related complications. An instrumental variable analysis was used to assess the average effect of treatment with IUI + OS followed by IVF (protocol A) compared to IVF alone (protocol B) and correct for (unknown) confounders. Treatment protocol A was performed in 72.6% patients in Centre 1 and 30.6% in Centre 2. In Centre 1 61.6% (45/73) women had a clinical pregnancy compared to 41.9% (26/62) in Centre 2 (difference 19.7% (95% CI 3.1%-36.3%), p = 0.02). Early miscarriage occurred in 24% of the women in Centre 1 in comparison to 45% of the women in Centre 2. There were no significant differences in pregnancy-related complications. This pilot study suggests that women < 40 with DOR, if treated with IUI + OS followed by IVF, have higher estimated cumulative clinical pregnancy success, with a trend towards higher ongoing pregnancies and live births, in comparison to women treated with IVF alone.

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Related research

Assisted Reproduction › Outcomes and Effectiveness › Outcomes by Diagnosis
Julia J. M. Deneer, Saskia Le Cessie, Evert J. P. van Santbrink, Lucette A. J. van der Westerlaken, Eileen E. L. O. Lashley
J Deneer, S Cessie, E Santbrink, L Westerlaken, E Lashley
DOI 10.1007/s43032-025-01830-w 10.1007/s43032-025-01830-w Deneer et al. 2025, Deneer 2025

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