This is not the most recent version of the article. View current version (30 AUG 2013)

Intervention Protocol

You have free access to this content

Natural cycle IVF for subfertile couples

  1. Thomas Allersma1,*,
  2. Cindy Farquhar2,
  3. Astrid EP Cantineau3

Editorial Group: Cochrane Menstrual Disorders and Subfertility Group

Published Online: 5 JUN 2013

DOI: 10.1002/14651858.CD010550


How to Cite

Allersma T, Farquhar C, Cantineau AEP. Natural cycle IVF for subfertile couples (Protocol). Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD010550. DOI: 10.1002/14651858.CD010550.

Author Information

  1. 1

    University Medical Centre Groningen, Groningen, Netherlands

  2. 2

    University of Auckland, Obstetrics and Gynaecology, Auckland, New Zealand

  3. 3

    University Medical Centre, Department of Obstetrics & Gynaecology, Groningen, Netherlands

*Thomas Allersma, University Medical Centre Groningen, Hanzeplein 1, Groningen, 9700 RB, Netherlands. t.b.allersma@student.rug.nl.

Publication History

  1. Publication Status: New
  2. Published Online: 5 JUN 2013

SEARCH

This is not the most recent version of the article. View current version (30 AUG 2013)

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Description of the condition

Subfertility is defined as the lack of achieving pregnancy after a period of 12 months of intercourse with the same partner without contraception. Subfertility affects 15% to 20% of couples trying to conceive (Evers 2002; Heineman 2011). Assisted reproduction techniques (ART) have been developed to improve the chance to achieve pregnancy. In vitro fertilisation (IVF) is one approach, where an oocyte and a spermatozoa are merged in a laboratory, before being implanted in the uterus. Although initially IVF was used mostly for women with tubal subfertility (Leeton 1982), the indications were soon expanded to include couples with menstrual cycle disorders, tubal abnormalities and male subfertility as well unexplained subfertility (Heineman 2011). For IVF, stimulating follicle growth and retrieval of the oocytes is necessary, for which several different methods are used. The first successful IVF treatment was performed in 1978 in an unstimulated, natural cycle. Although pregnancies did occur with early natural cycle IVF (NC-IVF),the success rates were low secondary to luteinising hormone (LH) surges which induce ovulation and result in cancellations (Rongieres-Bertrand 1999). The introduction of controlled ovarian hyperstimulation IVF (COH-IVF) became the standard ovarian stimulation method because of the improved success rates (Pelinck 2009).

Although COH-IVF increased pregnancy rates, it also meant an increase in costs and complications, mainly due to ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies. As up to 10 or more oocytes could be retrieved, however, the oocyte best suited for fertilisation based on morphology could be selected, which may have improved the success rate of the treatment (Rosen 2008; Wang 2011). Other technical improvements such as cryopreservation and vitrification (Geraedts 2012) have meant that oocytes could be preserved so that women do not have to repeat the full COH treatment when implantation of a fresh embryo fails. Initially IVF had live birth rates of less than 16% per transfer (Naaktgeboren 1985), but now most clinics are reporting live birth rates of 20% to 25% per started cycle for women under the age of 40 years (Heineman 2011).

With the development of gonadotrophin-releasing hormone (GnRH) antagonists, however, a new IVF treatment was developed, known as modified natural cycle IVF (MNC-IVF) with fewer complications and risks compared to COH protocols (Rongieres-Bertrand 1999). Because of this improvement in ovarian stimulation and also improved laboratory techniques such as culture media, NC-IVF has again been considered as an option. However, more MNC or NC treatments are likely to be necessary in order to obtain pregnancy rates comparable to COH-IVF (Pelinck 2009). Overall, the treatment costs might be lower in NC-IVF and MNC-IVF compared to COH-IVF, but it may cost the woman more effort to reach pregnancy because of the lower pregnancy rate per treatment and the need to repeat treatment cycles. On the other hand, the side effects of the hormone treatment and the emotional distress of stimulated IVF are often perceived as unacceptable and people seem to prefer the simplicity and short duration of a low stimulation treatment (Hojgaard 2001; Verberg 2008).

 

Description of the intervention

In both NC-IVF and MNC-IVF, the treatment cycles of women with a normal menstrual function are monitored in order to measure the follicle structure and endometrial morphology. When the follicle reaches an estimated size of 15 to 20 mm, human chorionic gonadotrophin (hCG) is administered intramuscularly and ovulation is thereby induced (Nargund 2001). The oocyte is then retrieved by aspirating the follicle under vaginal ultrasound guidance.

The potential advantages of both NC-IVF and MNC-IVF are the following:

  • the almost complete absence of multiple pregnancies
  • the very low risk of ovarian hyperstimulation syndrome
  • the reduced length of stimulation
  • the reduction in both physical and emotional stress as ovarian stimulation is not used or only used as a very low-dose protocol
  • the reduced costs
  • No resting cycle following a failed cycle is needed (Pelinck 2002)

Cryopreservation after MNC-IVF and NC-IVF is generally not possible, so there are no embryos available for freezing. Therefore NC-IVF and MNC-IVF may be preferable for couples who object to embryo freezing for cultural or religious reasons.

The potential disadvantages of NC-IVF include:

  • a higher cancellation rate (due to premature LH surges)
  • the lowered chances of a live birth per started cycle
  • the lowered chances of embryo transfer after a thawed cycle

The treatment is physically less demanding than the COH treatment, and usually no resting cycle is necessary after a failed treatment. The treatment can therefore be repeated in the following cycle. However, because only one oocyte is retrieved, and therefore only one embryo is implanted, the pregnancy rates per woman per cycle are low at 6% to 7% (Pelinck 2002; Zayed 1997).

 

How the intervention might work

In COH-IVF, follicle stimulating hormone (FSH) is administered to stimulate the growth of 5 to 15 follicles. To prevent early oocyte maturation caused by premature LH production, a GnRH agonist is used for suppressing the pituitary release of both LH and FSH. Down-regulation by continuous administration first causes a LH and FSH hypersecretion, followed by depletion of the pituitary store and desensitisation after approximately 10 days.

  • In the 'long protocol' down-regulation begins in the cycle prior to the treatment cycle
  • In the 'short' or 'flare-up protocol' the GnRH agonist is administered from day one of the treatment cycle
  • In the 'ultrashort protocol' only three doses of the agonist are used (Elder 2011)

As an alternative to the GnRH agonist, a GnRH antagonist can be used to prevent a LH surge in COH. The antagonist binds to and immediately blocks receptors on the pituitary, rapidly inhibiting the release of gonadotrophins. Different protocols for GnRH antagonist administration using different doses are used, varying from multiple-dose fixed (0.25 mg daily from day six to seven of stimulation) to single-dose (single administration of 3 mg on day seven to eight of stimulation) (Al-Inany 2011).

When two or more follicles reach a size of 18 to 20 mm (Heineman 2011), hCG is administered for the final maturation. Finally, 34 to 36 hours after hCG administration, the oocyte retrieval procedure is performed. This is done transvaginally under vaginal ultrasound guidance and usually mild sedation.

There are two types of natural cycle IVF:

1. Natural Cycle-IVF

  • In natural cycle IVF (NC-IVF) no drugs are administered
  • When the follicle is approaching maturity (follicle size 10 mm approximately), then oocyte retrieval is planned
  • Ovulation triggering with hCG administration is given when the follicle size is 15 to 20 mm, or when the serum estradiol rises
  • In the case of a LH surge, either cancellation or advancement of oocyte retrieval occurs (Pelinck 2009; Zayed 1997)

2. Modified Natural Cycle-IVF

  • In MNC-IVF gonadotrophin protocols are used to stimulate follicular growth. Different protocols start administering FSH at different stages in the cycle but all protocols use a similar short stimulation period of two to four days
  • After six days of ovarian stimulation or when the largest follicle measures 14 mm, then GnRH antagonists (for a variable number of days according to differing protocols) are administered to suppress LH secretion in order to prevent premature ovulation
  • When the leading follicle reaches a size of at least 16 to 18 mm, ovulation is triggered in the same manner as in COH-IVF, but only one oocyte is fully grown and retrieved.

Regardless of the immediate pituitary recovery after stopping the GnRH antagonist, luteal phase support improves pregnancy rates for MNC-IVF (Chavez-Badiola 2011).

Both MNC-IVF and NC-IVF have oocyte retrieval performed in the same manner as COH-IVF, that is, with vaginal ultrasound and usually mild sedation.

 

Why it is important to do this review

When choosing between different IVF protocols, couples need to balance the benefits and harms. As described, standard protocol IVF is associated with higher birth rates than the natural cycle treatments, whereas complications such as OHSS and multiple pregnancies are reduced in the natural cycle treatments. Although studies have shown that natural cycle IVF is a low-risk, low-cost (to the patient) and patient-friendly procedure, results have often been based on small study populations. Furthermore, studies comparing NC-IVF, MNC-IVF and COH-IVF report different outcomes. This review will evaluate the evidence from randomised controlled trials on NC-IVF, MNC-IVF and COH-IVF and report the pregnancy outcomes and the harms of treatment.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

To compare the effectiveness and safety of natural cycle IVF (NC-IVF and MNC-IVF) with COH-IVF in subfertile couples.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Criteria for considering studies for this review

 

Types of studies

In this review we will include only truly randomised controlled trials (RCTs).

 

Types of participants

Inclusion criteria:

  • No age restriction
  • Subfertile couples undertaking an IVF treatment
  • Both male and female factor subfertility
  • Both nulliparous and multiparous women
  • With or without a previous IVF treatment

Exclusion criteria:

  • None

 

Types of interventions

1. All trials comparing either NC-IVF or MNC-IVF with COH-IVF will be eligible for inclusion.

2. All trials comparing different protocols of MNC-IVF will also be eligible for inclusion.

 

Types of outcome measures

 

Primary outcomes

Effectiveness:

Live birth rate per woman, defined as the delivery of one or more living fetuses after 20 completed weeks of gestation.

Adverse effect:

Ovarian hyperstimulation syndrome (OHSS) per woman.

 

Secondary outcomes

Effectiveness:

  • Pregnancy rates per woman, defined as the successful implantation of a fetus, confirmed by the visualisation of a gestational sac
  • Ongoing pregnancies per woman, defined as the confirmed presence of a gestational sac and a fetal heart beat after 12 weeks gestation
  • Number of oocytes retrieved per woman
  • Time from start of treatment to live birth
  • Number of cycles required to conceive
  • Cumulative pregnancy or live birth rate

Adverse effects:

  • Multiple pregnancies per treatment
  • Lack of embryos for cryopreservation
  • Cycle cancellation rates per woman
  • Gestational abnormalities (ectopic pregnancy, fetal growth disorders, preterm births and miscarriages) per woman
  • Cancellation of the treatment, due to patient motivation or adverse effects
  • Cost effectiveness, evaluating the total costs to reach pregnancy in the different IVF treatments

 

Search methods for identification of studies

We will search for all published and unpublished randomised controlled trials studying either NC-IVF and MNC-IVF versus COH-IVF. We will use the following search strategies, in consultation with the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Trials Search Co-ordinator. We will apply no language restrictions.

 

Electronic searches

We will search the following databases:

  • Menstrual Disorders and Subfertility Group Specialised Register (MDSG) (Appendix 1)
  • The Cochrane Central Register of Controlled Trials (CENTRAL) (Ovid) (Appendix 2)
  • MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) (Ovid) (Appendix 3)
  • EMBASE (Ovid) (Appendix 4)
  • PsycINFO (Ovid) (Appendix 5)
  • CINAHL (Ebsco) Appendix 6)

Other electronic sources of trials will include the following:

  • Trial registers for ongoing and registered trials: 'ClinicalTrials.gov' a service of the US National Institutes of Health (http://clinicaltrials.gov/ct2/home) and The World Health Organization International Trials Registry Platform search portal (http://www.who.int/trialsearch/Default.aspx). (Appendix 7)
  • Conference abstracts in the ISI Web of Knowledge (http://isiwebofknowledge.com/). (Appendix 8)
  • LILACS database, as a source of trials from the Portuguese- and Spanish-speaking world (htpp://regional.bvsalud.org/php/index.php?lang=en) (choose ’LILACS’ in ’all sources’ drop-down box).
  • PubMed (http://www.ncbi.nlm.nih.gov/pubmed/). (Appendix 9)
  • OpenSIGLE database for grey literature from Europe (http://opensigle.inist.fr/).

The MEDLINE random controlled filter will be the Cochrane highly sensitive search strategy for identifying randomised controlled trials, which is found in the Cochrane Handbook of Systematic Reviews of Interventions (Cochrane Handbook), whereas the EMBASE filter has been developed by the Scottish Intercollegiate Guidelines Network (SIGN).

 

Searching other resources

In order to obtain additional relevant data, we will examine reference lists of eligible articles and will contact the study authors where necessary. Professor Cindy Farquhar and Dr Astrid Cantineau will act as experts on different IVF treatments, and we will request additional information about unpublished trials from the authors. We will handsearch non-indexed journals in collaboration with the Cochrane Menstrual Disorders and Subfertility Group Trials Search Co-ordinator.

 

Data collection and analysis

 

Selection of studies

Thomas Allersma and Astrid Cantineau will independently scan the titles and abstracts of the articles retrieved by the search. Those judged to be irrelevant will be removed, while the full texts of potentially eligible articles will be retrieved and also independently examined by the two authors. They will assess the full-text articles according to the inclusion criteria, and will select those eligible for inclusion in the review. Any doubts or disagreements regarding the inclusion of an article will be discussed with a third author, in order to reach an acceptable compromise.

 

Data extraction and management

The authors will design and pilot test a data extraction form. We will include the following characteristics of included studies in the extraction form: methods, participants, interventions and outcomes. Both authors will train with the extraction form using a representative sample of the studies to be reviewed, and in case of disagreement, will achieve a consensus in consultation with a third author. Where necessary, we will modify the extraction form. If studies are reported in more than one publication, we will extract data from the different reports directly into a single data extraction form so that no data will be missed.

 

Assessment of risk of bias in included studies

The Cochrane Collaboration’s recommended tool for assessing risk of bias is a domain-based evaluation (Cochrane Handbook). Assessments are made for the following domains:

  • Selection bias (Random sequence generation and Allocation concealment);
  • Performance bias (Blinding of participants and personnel);
  • Detection bias (Blinding of outcome assessment);
  • Attrition bias (Incomplete outcome data);
  • Reporting bias (Selective reporting);
  • Other bias.

These assessments will be:

  • high risk of bias;
  • unclear risk of bias;
  • low risk of bias.

See Appendix 10 for details.

 

Measures of treatment effect

For dichotomous data (e.g. live birth rate, pregnancy rate, ongoing pregnancy rate, failure to freeze embryos, cycle cancellation, cancellation of treatment, OHSS, multiple pregnancies, number of cycles required to conceive, gestational abnormalities or cumulative pregnancy or live birth rate), we will use the numbers of events in the control and intervention groups of each study to calculate Mantel-Haenszel odds ratios (ORs). For continuous data (e.g. number of oocytes retrieved per woman or time from start of treatment to live birth), if all studies report exactly the same outcomes we will calculate mean differences (MDs) between treatment groups. If similar outcomes are reported on different scales (e.g. cost effectiveness) we will calculate the standardised mean difference (SMD). We will reverse the direction of effect of individual studies, if required, to ensure consistency across trials. We will present 95% confidence intervals for all outcomes. Where data to calculate ORs or MDs are not available, we will utilise the most detailed numerical data available that may facilitate similar analyses of included studies (e.g. test statistics, P values). We will compare the magnitude and direction of effect reported by studies with how they are presented in the review, taking account of legitimate differences.

 

Unit of analysis issues

The unit of primary analysis will be per woman randomised to the intervention or control groups. Data collected from different studies will have to be comparable; if a study measures multiple cycles per woman, only data from the first cycle will be used (collected from authors where necessary). For the primary analysis, we will count multiple live births as one live birth event. If we include a cross-over study, we will only use the data up to the cross-over point.

 

Dealing with missing data

If relevant data are missing from one of the included studies, we will contact the original investigator to request the missing data. If the missing data are unobtainable, the authors will determine whether the data are missing at random or not and will adjust accordingly (Cochrane Handbook). The potential impact will be reported in the Discussion section. If live birth is mentioned as an outcome measure but not reported in the results section, we will assume an (ongoing) pregnancy did not occur. For the secondary outcomes, we will only analyse the available data. When assumptions are made, we will perform sensitivity analyses to assess how sensitive results are to reasonable changes.

 

Assessment of heterogeneity

We will assess clinical and methodological heterogeneity, and when study participants, interventions and outcomes are judged to be sufficiently similar, we will conduct a meta-analysis to provide a meaningful summary. We will assess statistical heterogeneity by visually inspecting the plot and using the I² statistic. We will interpret the results of the I² statistic according to the Cochrane Handbook:

  • 0% to 35%: might not be important;
  • 36% to 55%: may represent moderate heterogeneity;
  • 56% to 80%: may represent substantial heterogeneity;
  • 81% to 100%: considerable heterogeneity.

 

Assessment of reporting biases

In order to minimise the impact of reporting biases, we will construct an extensive search for eligible articles and we will carefully inspect the included articles for reporting biases, such as publication bias, duplication bias or outcome reporting bias. We will compare outcomes reported in final published studies with preplanned outcomes reported in published protocols, and contact the original investigator where necessary. Where possible we will include unpublished data by searching for it or by contacting the original investigator. When 10 or more studies of varying size are analysed, we will use Review Manager 5 to construct a funnel plot in order to investigate possible reporting biases.

 

Data synthesis

We will use a fixed-effect model to compare the estimates of the intervention effect. If moderate to considerable heterogeneity is identified, we will use a random-effects model to combine the data from the included studies in a sensitivity analysis, using the following comparison:

NC-IVF (NC-IVF and MNC-IVF) versus COH-IVF.

 

Subgroup analysis and investigation of heterogeneity

Where possible, we will conduct subgroup analyses in order to investigate heterogeneous results, in the following subgroups:

  • Cause of subfertility; grouped by unexplained subfertility, male factor subfertility, tubal disease and ovulation disorder
  • Age; < 38 years or > 38 years
  • Prior treatment; has the patient had an IVF treatment before
  • Intervention; grouped by NC- or MNC-IVF

 

Sensitivity analysis

We will conduct sensitivity analyses to examine whether the conclusions are affected by different assumptions, and therefore decisions, regarding the eligibility and analysis of the studies. We will analyse results to test for differences if:

  • Another analysis method (risk ratio) was used
  • Studies with high risk of bias were excluded
  • Studies with a large sample size were excluded
  • The early studies of IVF (pre-1990) were excluded, as ovulation stimulation protocols were still being developed and natural cycle IVF success rates may be lower than current natural cycles

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

We would like to thank the Cochrane Menstrual Disorders and Subfertility Group; in particular Marian Showell (Trials Search Co-ordinator) for writing and running the search, and Vanessa Jordan (NZ Cochrane Fellow) for answering questions.

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Appendix 1. MDSG search strategy

<inception - present>

Keywords CONTAINS "natural cycle" or "natural cycles" or "modified ICSI" or "modified natural cycle" or "unstimulated ovaries" or Title CONTAINS "natural cycle" or "natural cycles" or "modified ICSI" or "modified natural cycle" or "unstimulated ovaries"

 

Appendix 2. CENTRAL search strategy

EBM Reviews - Cochrane Central Register of Controlled Trials <1977 - present>

1     exp embryo transfer/ or exp fertilization in vitro/ or exp sperm injections, intracytoplasmic/

2     vitro fertili?ation.tw.

3     ivf-et.tw.

4     ivf.tw.

5     icsi.tw.

6     intracytoplasmic sperm injection$.tw.

7     assisted reproduct$.tw.

8     ovulation induc$.tw.

9     (ovari$ adj2 stimulat$).tw.

10     superovulat$.tw.

11     ovarian hyperstimulation.tw.

12     COH.tw.

13     infertil$.tw.

14     subfertil$.tw.

15     (ovari$ adj2 induction).tw.

16     (stimulat$ adj3 cycle$).tw.

17     (embryo$ or blastocyst$).tw.

18     or/1-17

19     natural.tw.

20     (modified adj5 cycle$).tw.

21     MNC IVF.tw.

22     NCIVF.tw.

23     NC-IVF.tw.

24     unstimulated.tw.

25     or/19-24

26     18 and 25

 

Appendix 3. MEDLINE search strategy

Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) <1946 - present>

1     exp embryo transfer/ or exp fertilization in vitro/ or exp sperm injections, intracytoplasmic/

2     vitro fertili?ation.tw.

3     ivf-et.tw.

4     ivf.tw.

5     icsi.tw.

6     intracytoplasmic sperm injection$.tw.

7     assisted reproduct$.tw.

8     ovulation induc$.tw.

9     (ovari$ adj2 stimulat$).tw.

10     superovulat$.tw.

11     ovarian hyperstimulation.tw.

12     COH.tw.

13     infertil$.tw.

14     subfertil$.tw.

15     (ovari$ adj2 induction).tw.

16     (stimulat$ adj3 cycle$).tw.

17     (embryo$ or blastocyst$).tw.

18     or/1-17

19     natural.tw.

20     (modified adj5 cycle$).tw.

21     MNC IVF.tw.

22     NCIVF.tw.

23     NC-IVF.tw.

24     unstimulated.tw.

25     'not stimulated'.tw.

26     no stimulation.tw.

27     or/19-26

28     18 and 27

29     randomized controlled trial.pt.

30     controlled clinical trial.pt.

31     randomized.ab.

32     randomised.ab.

33     placebo.tw.

34     clinical trials as topic.sh.

35     randomly.ab.

36     trial.ti.

37     (crossover or cross-over or cross over).tw.

38     or/29-37

39     exp animals/ not humans.sh.

40     38 not 39

41     28 and 40

 

Appendix 4. EMBASE search strategy

Embase <1980 - present>

1     exp embryo transfer/ or exp fertilization in vitro/ or exp intracytoplasmic sperm injection/

2     in vitro fertili?ation.tw.

3     icsi.tw.

4     intracytoplasmic sperm injection$.tw.

5     ivf.tw.

6     assisted reproduct$.tw.

7     intrauterine insemination$.tw.

8     ovulation induc$.tw.

9     (ovari$ adj2 stimulat$).tw.

10     superovulat$.tw.

11     ovarian hyperstimulation.tw.

12     COH.tw.

13     infertil$.tw.

14     subfertil$.tw.

15     (ovari$ adj2 induction).tw.

16     embryo$.tw.

17     blastocyst$.tw.

18     (stimulat$ adj3 cycle$).tw.

19     or/1-18

20     natural$.tw.

21     (modified adj5 cycle$).tw.

22     NCIVF.tw.

23     NC-IVF.tw.

24     MNC-IVF.tw.

25     unstimulated.tw.

26     simple protocol.tw.

27     no stimulation.tw.

28     'not stimulated'.tw.

29     or/20-28

30     19 and 29

31     Clinical Trial/

32     Randomized Controlled Trial/

33     exp randomization/

34     Single Blind Procedure/

35     Double Blind Procedure/

36     Crossover Procedure/

37     Placebo/

38     Randomi?ed controlled trial$.tw.

39     Rct.tw.

40     random allocation.tw.

41     randomly allocated.tw.

42     allocated randomly.tw.

43     (allocated adj2 random).tw.

44     Single blind$.tw.

45     Double blind$.tw.

46     ((treble or triple) adj blind$).tw.

47     placebo$.tw.

48     prospective study/

49     or/31-48

50     case study/

51     case report.tw.

52     abstract report/ or letter/

53     or/50-52

54     49 not 53

55     30 and 54

56     (2010$ or 2011$ or 2012$ or 2013$).em.

57     55 and 56

 

Appendix 5. PsycINFO search strategy

PsycINFO <1806 - present>

1     random.tw.

2     control.tw.

3     double-blind.tw.

4     clinical trials/

5     placebo/

6     exp Treatment/

7     or/1-6

8     natural cycle$.tw.

9     7 and 8

 

Appendix 6. CINAHL search strategy

<inception - present>

1 (MH "Fertilization in Vitro") OR "ivf"

2 TX intracytoplasmic sperm injection

3 TX icsi

4 S1 OR S2 OR S3

5 TX natural cycle

6 TX modified cycle

7 TX unstimulated cycles

8 S5 OR S6 OR S7

9 S4 AND S8

 

Appendix 7. clinicaltrials.gov and WHO portal for ongoing trials search strategy

<inception - present>

Keywords included:

Natural cycle

Modified cycle

Unstimulated cycle

 

Appendix 8. ISI Web of Knowledge search strategy

<inception - present>

Natural cycle AND IVF or ICSI

Modified cycle AND IVF or ICSI

 

Appendix 9. PubMed search strategy

<inception - present>

((((((((("Fertilization in Vitro"[Mesh]) AND "Sperm Injections, Intracytoplasmic"[Mesh]) AND "Ovulation Induction"[Mesh]) OR ivf[tw]) OR Fertilization in Vitro[tw]) OR icsi[tw]) OR (stimulated cycle[tw] OR stimulated cycles[tw])) AND (natural cycle[tw] OR natural cycle/mild[tw] OR natural cyclers[tw] OR natural cycles[tw])) OR (modified cycle[tw] OR modified cycles[tw])) OR (unstimulated cycle[tw] OR unstimulated cycles[tw]) AND Randomized Controlled Trial[ptyp]

 

Appendix 10. Risk of bias assessments

Random sequence generation (selection bias)

  • Adequate: randomisation by a computer or a list of random numbers, each number linked to a different participant.
  • Inadequate: randomisation according to date of birth, case record number or date of presentation.
  • Unclear: insufficient information about randomisation process.

Allocation concealment (selection bias)

  • Adequate: participants are ordered alphabetically or sequentially numbered, opaque, sealed envelopes are used.
  • Inadequate: use of unsealed or non-opaque envelopes, inadequate sequence allocation (date of birth, case record number or date of presentation), or an adequate sequence allocation is inadequately concealed.
  • Unclear: insufficient information about allocation concealment.

Blinding of participants and personnel (performance bias)

  • Adequate: blinding of participants, researchers and all care providers, or incomplete or no blinding in case the outcomes were unlikely to be influenced.
  • Inadequate: incomplete or no blinding of participants, researchers and all care providers in case the outcomes were likely to be influenced.
  • Unclear: insufficient information about blinding of participants and personnel.

Blinding of outcome assessment (detection bias)

  • Adequate: blinding of researchers, or incomplete or no blinding in case the outcomes were unlikely to be influenced.
  • Inadequate: incomplete or no blinding of researchers in case the outcomes were likely to be influenced.
  • Unclear: insufficient information about blinding of the outcome assessor.

Incomplete outcome data (attrition bias)

  • Adequate: there are no missing outcome data, or missing data has no influence on the outcomes.
  • Inadequate: missing data are likely to influence the outcomes.
  • Unclear: insufficient information about the completeness of the outcome data.

Selective reporting (reporting bias)

  • Adequate: all outcomes in the protocol have been published or all outcomes listed in the methods section are reported in the results.
  • Inadequate: not all outcomes in the protocol or in the methods section are reported in the results.
  • Unclear: insufficient information about outcome reporting.

Other sources of bias

  • Adequate: no further biases were found.
  • Inadequate: other biases were found.
  • Unclear: insufficient information about other biases.

 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

Thomas Allersma and Astrid Cantineau will extract data. Thomas Allersma will enter the data and write the review. Cindy Farquhar will help drafting the review, act as a clinical expert and comment on the review. Astrid Cantineau will act as a clinical expert and comment on the review.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

No declaration of interests.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Internal sources

  • None, Not specified.

 

External sources

  • None, Not specified.

References

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Acknowledgements
  7. Appendices
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support
  11. Additional references
Al-Inany 2011
Chavez-Badiola 2011
  • Chavez-Badiola AE, Allahbadla GN. Minimal Stimulation IVF: Milder, Mildest Or Back to Nature. Jaypee Brothers Medical Publisher (P) Ltd, 2011.
Cochrane Handbook
  • Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Wiley-Blackwell.
Elder 2011
  • Elder K, Dale B. In vitro fertilization. Cambridge University Press, 2011.
Evers 2002
Geraedts 2012
  • Geraedts JP, Gianaroli L. Embryo selection and IVF. Human Reproduction 2012; Vol. 27, issue 9:2876-7. [PUBMED: 22763374]
Heineman 2011
  • Heineman J, Evers JLH, Massuger LFAG, Steegers EAP. Obstetrie en Gynaecology De voortplanting van de mens. Elsevier Gezondheidszorg, 2011.
Hojgaard 2001
Leeton 1982
  • Leeton J. The management of infertility: where to stop. Clinical Reproduction and Fertility 1982;1(4):249-59. [PUBMED: 6821241]
Naaktgeboren 1985
  • Naaktgeboren N, Devroey P, Traey E, Wisanto A, Van Steirteghem AC. Success of in vitro fertilization and embryo transfer in relation to the causes of infertility. Acta Europaea Fertilitatis 1985;16(4):281-7. [PUBMED: 2933915]
Nargund 2001
  • Nargund G, Waterstone J, Bland J, Philips Z, Parsons J, Campbell S. Cumulative conception and live birth rates in natural (unstimulated) IVF cycles. Human Reproduction 2001;16(2):259-62. [PUBMED: 11157816]
Pelinck 2002
Pelinck 2009
  • Pelinck MJ. Modified natural cycle IVF: feasibility and results. http://dissertations.ub.rug.nl/faculties/medicine/2009/m.j.pelinck/?pLanguage=en&pFullItemRecord=ON (accessed 26th April 2013). Unpublished, 2009.
Rongieres-Bertrand 1999
  • Rongieres-Bertrand C, Olivennes F, Righini C, Fanchin R, Taieb J, Hamamah S, et al. Revival of the natural cycles in in-vitro fertilization with the use of a new gonadotrophin-releasing hormone antagonist (Cetrorelix): a pilot study with minimal stimulation. Human Reproduction 1999;14(3):683-8. [PUBMED: 10221695]
Rosen 2008
  • Rosen MP, Shen S, Dobson AT, Rinaudo PF, McCulloch CE, Cedars MI. A quantitative assessment of follicle size on oocyte developmental competence. Fertility and Sterility 2008;90(3):684-90. [PUBMED: 18249377]
Verberg 2008
  • Verberg MF, Eijkemans MJ, Heijnen EM, Broekmans FJ, De Klerk C, Fauser BC, et al. Why do couples drop-out from IVF treatment? A prospective cohort study. Human Reproduction 2008;23(9):2050-5. [PUBMED: 18544578]
Wang 2011
  • Wang SX. The past, present, and future of embryo selection in in vitro fertilization: Frontiers in Reproduction Conference. The Yale Journal of Biology and Medicine 2011;84(4):487-90. [PUBMED: 22180687]
Zayed 1997
  • Zayed F, Lenton EA, Cooke ID. Natural cycle in-vitro fertilization in couples with unexplained infertility: impact of various factors on outcome. Human Reproduction 1997;12(11):2402-7. [PUBMED: 9436673]