Cochrane Clinical Answers - Fulltext - How does natural cycle in vitro fertilization compare with controlled ovarian hyperstimulation in subfertile couples?

Question:How does natural cycle in vitro fertilization compare with controlled ovarian hyperstimulation in subfertile couples?

Clinical Answer:

Both natural cycle IVF and controlled ovarian hyperstimulation (“standard”) IVF yield similar rates of conception and live births in subfertile couples undergoing in vitro fertilization, with the caveat that studies to date are not sufficiently robust to demonstrate a clinically meaningful difference between approaches. Adverse effects such as ovarian hyperstimulation, multiple gestations, ectopic pregnancy and fetal growth disorders were also comparable, but again the trials were underpowered to show clinically important differences between groups. Subfertile couples seeking the “best” treatment approach to infertility need to be given detailed information about the two procedures, and allowed to choose based on personal preference.

When comparing natural cycle IVF with controlled ovarian hyperstimulation, moderate-quality evidence found similar rates of live births (434 vs. 530 per 1000 women had a live birth) and ongoing pregnancies (on average 416 vs. 494 per 1000 women respectively). Low-quality evidence demonstrated similar rates of clinical pregnancy (on overage 119 per 1000 with natural cycle vs. 207 per 1000 with standard IVF). As might be expected, ovarian hyperstimulation syndrome was noted more often in women receiving standard IVF (67 per 1000 vs. 13 per 1000 for natural cycle IVF), but the evidence was deemed very low quality as studies were not sufficiently powered to show a difference. Likewise very low-quality evidence revealed no disparity in multiple pregnancy rates among the two procedures (on average 20 per 1000 with natural cycle vs. 26 per 1000 with standard IVF). Only one trial with 18 women reported the incidence of gestational abnormalities, which were similar for the two procedures (111 per 1000 with natural cycle vs. 222 per 1000 with standard IVF).

Full outcome data is detailed below:

1.Natural cycle IVF versus standard IVF with controlled ovarian hyperstimulation

  • Population, Intervention, Comparator

    Population:

    Subfertile women and couples undertaking an IVF treatment for different indications (unexplained or mild male subfertility, tubal pathology or indication not reported). One trial (140 women) only included women who were poor responders in previous IVF cycles

    Intervention:

    Natural cycle IVG: no treatment (4 trials); human menopausal gonadotropin (HMG) 150 IU/day given intramuscularly (1 trial) or a GnRH antagonist used and FSH continued up to the day of ovulation triggering (1 trial)

    Comparator:

    Controlled ovarian hyperstimulation: clomiphene citrate (2 trials); luteal phase initiated GnRH suppression followed by HMG administration (1 trial); GnRH agonist (0.05 mg buserelin) from the first day of the menstrual cycle in combination with 600 IU FSH from the third day of the menstrual cycle (1 trial); GnRH agonist (triptorelin 0.1 mg/day subcutaneously) used in combination with recombinant FSH 150 to 300 IU/day or 150 IU FSH (1 trial) FSH 150 IU, continued until at least 2 follicles greater than 18mm had developed (treatment initiation and duration not reported) (1 trial)

  • OUTCOME 1.1: Live births

    Quality of the evidence:

    The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was moderate quality. See Summary of findings from Cochrane review

    Narrative result:

    Two RCTs with 425 participants found no statistically significant difference between groups but would have been underpowered to detect a clinically meaningful difference.

    Relative effect or mean difference:

    There was no statistically significant difference between groups (OR 0.68, 95% CI 0.46 to 1.01).

    Forest plot from Cochrane Review

    Absolute effect:

    434 per 1000 women (95% CI 342 to 532) with natural cycle compared with 530 per 1000 women with standard IVF.

    Reference:
    Allersma T, Farquhar C, Cantineau AEP. Natural cycle in vitro fertilisation (IVF) for subfertile couples. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD010550. DOI: 10.1002/14651858.CD010550.pub2. [Review search date: July 2013]
    • OUTCOME 1.2: Clinical pregnancy

      Quality of the evidence:

      The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was low quality. See Summary of findings from Cochrane review

      Narrative result:

      Four RCTs with 351 participants found no statistically significant difference between groups but would have been underpowered to detect a clinically meaningful difference. Subgroup analysis by number of cycles (single or up to 3) and by treatment type also were too underpowered to provide relevant results.

      Relative effect or mean difference:

      There was no statistically significant difference between groups (OR 0.52, 95% CI 0.17 to 1.61).

      Forest plot from Cochrane Review

      Absolute effect:

      119 per 1000 women (95% CI 42 to 295) with natural cycle compared with 207per 1000 women with standard IVF.

      Reference:
      Allersma T, Farquhar C, Cantineau AEP. Natural cycle in vitro fertilisation (IVF) for subfertile couples. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD010550. DOI: 10.1002/14651858.CD010550.pub2. [Review search date: July 2013]
      • OUTCOME 1.3: Ongoing pregnancy (defined as the presence of a gestational sac and fetal heart beat after 12 weeks gestation)

        Quality of the evidence:

        The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was moderate quality. See Summary of findings from Cochrane review

        Narrative result:

        Three RCTs with 485 participants found no statistically significant difference between groups but would have been underpowered to detect a clinically meaningful difference.

        Relative effect or mean difference:

        There was no statistically significant difference between groups (OR 0.72, 95% CI 0.50 to 1.05).

        Forest plot from Cochrane Review

        Absolute effect:

        416 per 1000 women (95% CI 328 to 508) with natural cycle compared with 494per 1000 women with standard IVF.

        Reference:
        Allersma T, Farquhar C, Cantineau AEP. Natural cycle in vitro fertilisation (IVF) for subfertile couples. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD010550. DOI: 10.1002/14651858.CD010550.pub2. [Review search date: July 2013]
        • OUTCOME 1.4: Adverse effects

          Narrative result:

          Similar rates of adverse effects were reported in both groups, but the analyses would have been underpowered to detect a clinically meaningful difference.

          Reference:
          Allersma T, Farquhar C, Cantineau AEP. Natural cycle in vitro fertilisation (IVF) for subfertile couples. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD010550. DOI: 10.1002/14651858.CD010550.pub2. [Review search date: July 2013]
          • Subgroup analysis 1.4.1: Adverse effects - Ovarian hyperstimulation syndrome (OHSS)
            Quality of the evidence:

            The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was very low quality. See Summary of findings from Cochrane review

            Narrative result:

            One RCT with 60 participants found no statistically significant difference between groups but would have been underpowered to detect a clinically meaningful difference.

            Relative effect or mean difference:

            There was no statistically significant difference between groups (OR 0.19, 95% CI 0.01 to 4.06).

            Forest plot from Cochrane Review

            Absolute effect:

            13 per 1000 women (95% CI 1 to 225) with natural cycle compared with 67 per 1000 women with standard IVF.

            Reference:
            Allersma T, Farquhar C, Cantineau AEP. Natural cycle in vitro fertilisation (IVF) for subfertile couples. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD010550. DOI: 10.1002/14651858.CD010550.pub2. [Review search date: July 2013]
          • Subgroup analysis 1.4.2: Adverse effects - Multiple pregnancies
            Quality of the evidence:

            The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was very low quality. See Summary of findings from Cochrane review

            Narrative result:

            Two RCTs with 527 participants found no statistically significant difference between groups but would have been underpowered to detect a clinically meaningful difference.

            Relative effect or mean difference:

            There was no statistically significant difference between groups (OR 0.76, 95% CI 0.25 to 2.31).

            Forest plot from Cochrane Review

            Absolute effect:

            20 per 1000 women (95% CI 7 to 58) with natural cycle compared with 26 per 1000 women with standard IVF.

            Reference:
            Allersma T, Farquhar C, Cantineau AEP. Natural cycle in vitro fertilisation (IVF) for subfertile couples. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD010550. DOI: 10.1002/14651858.CD010550.pub2. [Review search date: July 2013]
          • Subgroup analysis 1.4.3: Adverse effects - Gestational abnormalities (defined as ectopic pregnancy, fetal growth disorders, preterm births and miscarriages)
            Risk of bias of studies:

            The reviewers did not perform a GRADE assessment of the quality of the evidence. The study failed to report adequate allocation concealment, but reported adequate blinding of participants/carers/outcome assessors and had low numbers of withdrawals.

            Narrative result:

            One RCT with 18 participants found no statistically significant difference between groups but would have been underpowered to detect a clinically meaningful difference.

            Relative effect or mean difference:

            There was no statistically significant difference between groups (OR 0.44, 95% CI 0.03 to 5.93).

            Forest plot from Cochrane Review

            Absolute effect:

            111 per 1000 women (95% CI 9 to 629) with natural cycle compared with 222 per 1000 women with standard IVF.

            Reference:
            Allersma T, Farquhar C, Cantineau AEP. Natural cycle in vitro fertilisation (IVF) for subfertile couples. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD010550. DOI: 10.1002/14651858.CD010550.pub2. [Review search date: July 2013]
        • OUTCOME 1.5: Cost effectiveness

          Narrative result:

          The reviewers found insufficient data in the trials to perform a cost-effectiveness assessment.

          Reference:
          Allersma T, Farquhar C, Cantineau AEP. Natural cycle in vitro fertilisation (IVF) for subfertile couples. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD010550. DOI: 10.1002/14651858.CD010550.pub2. [Review search date: July 2013]

          Additional Information:

          DOI

          10.1002/cca.1179

          Publication Dates

          1. Published Online: 7 MAR 2016

          CCA derived from

          Allersma T, Farquhar C, Cantineau AEP. Natural cycle in vitro fertilisation (IVF) for subfertile couples. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD010550. DOI: 10.1002/14651858.CD010550.pub2. [Review search date: July 2013]

          How to Cite

          How does natural cycle in vitro fertilization compare with controlled ovarian hyperstimulation in subfertile couples? E. Chris Vincent (MD) (on behalf of Cochrane Clinical Answers Editors). Cochrane Clinical Answers 2016. DOI: 10.1002/cca.1179.

          Further Information

          • CCA Associate editor: E. Chris Vincent (MD), Associate Clinical Professor, Family Medicine, University of Washington School of Medicine, Washington/King, USA.
          • CCA Editor: Karen Pettersen. Correspondence to kpettersen@wiley.com.