Abstract
Introduction
About 17% of couples in industrialised countries seek help for infertility, which may be caused by ovulatory failure, tubal damage or endometriosis, or a low sperm count. In resource-rich countries, 80-90% of couples attempting to conceive are successful after 1 year and 95% after 2 years.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for infertility caused by ovulation disorders? What are the effects of treatments for tubal infertility? What are the effects of treatments for infertility associated with endometriosis? We searched: Medline, Embase, The Cochrane Library and other important databases up to April 2004 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 56 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: clomifene; cyclofenil; drug-induced ovarian suppression; gonadotrophin priming of oocytes before in vitro maturation; gonadotrophins; gonadotrophin-releasing hormone agonists plus gonadotrophins; gonadotrophin-releasing hormone antagonists; in vitro fertilisation; intrauterine insemination plus controlled ovarian stimulation; intrauterine insemination plus gonadotrophins; laparoscopic ablation of endometrial deposits; laparoscopic ovarian drilling; metformin; ovarian wedge biopsy; pulsatile gonadotrophin-releasing hormone; selective salpingography plus tubal catheterisation; tamoxifen; tubal flushing with oil-soluble media or with water-soluble media; tubal surgery before in vitro fertilisation.
Key Points
About 17% of couples in industrialised countries seek help for infertility, which may be caused by ovulatory failure, tubal damage or endometriosis or a low sperm count.
In women with infertility, in vitro fertilisation may be as likely to lead to pregnancy as intracytoplasmic sperm injection, but increases the risks of multiple pregnancy.
Gonadotrophin releasing hormone agonists also increase pregnancy rates, but gonadotrophin releasing hormone antagonists may be less effective.
Intrauterine insemination plus controlled ovarian stimulation is considered to be beneficial in women with unexplained infertility or cervical hostility.
In women with ovulatory disorders, clomifene and tamoxifen increase ovulation and pregnancy rates, and metformin increases ovulation rates.
Gonadotrophins may increase pregnancy rates but may increase the risk of ovarian cancer, ovarian hyperstimulation syndrome and multiple pregnancy.
Laparoscopic ovarian drilling may be as effective as gonadotrophins.
We don't know whether cyclofenil, pulsed gonadotrophin releasing hormone, gonadotrophin priming of oocytes before in vitro maturation, or ovarian wedge biopsy increase pregnancy rates compared with no treatment.
In women with tubal infertility, tubal flushing increases pregnancy rates, with oil soluble media possibly more effective than water soluble media.
Tubal surgery before in vitro fertilisation may increase pregnancy rates compared with no treatment in women with hydrosalpinges, but we don't know whether selective salpingography plus tubal catheterisation is beneficial.
In women with endometriosis, adding gonadotrophins to intrauterine insemination increases live birth rates compared with intrauterine insemination alone.
Laparoscopic ablation of endometrial deposits may increase live birth rates compared with diagnostic laparoscopy.
Drugs to induce ovarian suppression may not increase pregnancy rates.
About this condition
Definition
This review focuses on infertility related to factors associated with the woman rather than the man. Normal fertility has been defined as achieving a pregnancy within 2 years by regular unprotected sexual intercourse. However, many define infertility as the failure to conceive after 1 year of unprotected intercourse. Infertility can be primary, in women who have never conceived, or secondary, in women who have previously conceived. This review will deal with infertility owing to endometriosis, ovulation disorders, and tubal infertility. Endometriosis is a progressive disease which occurs when the endometrial tissue lining the uterus grows outside the uterus and attaches to the ovaries, fallopian tubes, or other organs in the abdominal cavity (See endometriosis). Ovulation disorders are defined by the failure of an ovum to be expelled because of a malfunction in the ovary, and are a major cause of infertility. Tubal infertility is the inability to conceive owing to a blockage in one or both fallopian tubes, and is a common cause of infertility.
Incidence/ Prevalence
Although there is no evidence of a major change in the prevalence of female infertility, many more couples are seeking help than previously. Currently, about 1/6 (17%) couples in industrialised countries will seek medical advice for infertility. Rates of primary infertility vary widely between countries, ranging from < 6% in China, Malawi, Tanzania, and Zambia; 9% in the Philippines; > 10% in Finland, Sweden, and Canada; and 18% in Switzerland. Reported rates of secondary infertility are less reliable.
Aetiology/ Risk factors
In the UK, about 10-20% of infertility cases are unexplained. The rest are caused by ovulatory failure (27%), tubal damage (14%), endometriosis (5%), low sperm count or quality (19%), and other causes (5%).
Prognosis
In developed countries, 80-90% of couples attempting to conceive are successful after 1 year and 95% after 2 years. The chances of becoming pregnant vary with the cause and duration of infertility, the woman's age, the woman's previous pregnancy history, and the availability of different treatment options. For the first 2-3 years of unexplained infertility, cumulative conception rates remain high (27-46%) but decrease with increasing age of the woman and duration of infertility. The background rates of spontaneous pregnancy in infertile couples can be calculated from longitudinal studies of infertile couples who have been observed without treatment.
Aims of intervention
To achieve the delivery of one healthy baby; to reduce the distress associated with infertility, with minimal adverse effects.
Outcomes
Live births, miscarriages, multiple pregnancies, incidence of ovarian hyperstimulation syndrome, satisfaction with services and treatments, acceptance of childlessness if treatment is unsuccessful. Pregnancy and ovulation rates are important intermediate outcomes. Spontaneous pregnancies can occur without treatment in couples who are considered infertile. Effectiveness of treatments for infertility should be assessed on the basis of pregnancy rates over and above the spontaneous pregnancy rates otherwise the impacts of treatments may be overestimated.
Methods
Clinical Evidence search and appraisal April 2004. Crossover design: For infertility, RCTs with a crossover design may overestimate the treatment effect because pregnancies occurring in the first half of the trial will remove couples from the second half. Crossover trials were included in some systematic reviews where no or few RCTs using a parallel group design were available. Ideally, only data from the first half of the trial, before crossover, should be used. However, post-crossover results are reported in the absence of pre-crossover results. However, a study that used a computer model to compare the results of crossover and parallel designed trials suggests that any overestimation may be clinically irrelevant.We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).
Table.
GRADE evaluation of interventions for female infertility
| Important outcomes | Pregnancy rates, live birth rates, adverse effects | ||||||||
| Number of studies (participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of treatments for infertility caused by ovulation disorders? | |||||||||
| 2 (192) | Pregnancy rate | Clomifene v placebo | 4 | –1 | 0 | 0 | +1 | High | Quality point deducted for sparse data. Effect size point added for RR greater than 2 |
| 2 (152) | Pregnancy rate | Clomifene v tamoxifen | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 3 (173) | Pregnancy rate | Clomifene v clomifene plus metformin | 4 | 0 | 0 | –1 | +1 | High | Directness point deducted for narrow inclusion criteria. Effect size point added for OR greater than 2 |
| 1 (28) [ | Pregnancy rate | Clomifene v pulsatile gonadotrophin releasing hormone plus GnRH agonist | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for narrow inclusion criteria |
| 5 (at least 33,537) | Ovarian cancer | Clomifene v no clomifene | 2 | 0 | –1 | 0 | 0 | Very low | Consistency point deducted for conflicting results |
| 2 (50) | Live birth rate | Metformin v placebo | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for narrow inclusion criteria |
| 5 (172) ] | Pregnancy rate | Metformin v placebo | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for narrow inclusion criteria |
| 1 (161) | Pregnancy rates | Metformin v ovarian drilling | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for narrow inclusion criteria |
| 1 (213) | Pregnancy rate | Cyclofenil v placebo | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for broad inclusion criteria |
| 4 (396) [ | Pregnancy rate | Human menopausal gonadotrophin v urinary follicle-stimulating hormone | 4 | 0 | 0 | –2 | 0 | Low | Directness points deducted for narrow inclusion criteria and interventions |
| 4 (1214) | Pregnancy or live births | Human menopausal gonadotrophins v recombinant follicle-stimulating hormone | 4 | 0 | 0 | –2 | 0 | Low | Directness point deducted for narrow inclusion criteria and interventions |
| 3 (457) | Pregnancy rates | Recombinant follicle-stimulating hormone v urinary follicle stimulating hormone | 4 | 0 | 0 | –2 | 0 | Low | Directness point deducted for narrow inclusion criteria and interventions |
| 6 (371) | Pregnancy rate | Gonadotrophins v laparoscopic ovarian drilling | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for narrow inclusion criteria |
| 1 (200) | Ovarian cancer | Human menopausal gonadotrophins v control | 2 | –1 | 0 | 0 | +1 | Low | Quality point deducted for methodological flaws. Effect size point added for RR greater than 2 |
| 10 RCTs [ | Pregnancy rate | Gonadotrophin-releasing hormone agonists plus gonadotrophins v gonadotrophins alone | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for broad inclusion criteria |
| 6 (552) | Pregnancy rate | Depot gonadotrophin-releasing hormone agonist v daily gonadotrophin-releasing hormone agonist | 4 | 0 | 0 | 0 | 0 | High | |
| 26 RCTs | Pregnancy rates | Long v short gonadotrophin-releasing hormone agonist protocol | 4 | 0 | 0 | 0 | 0 | High | |
| 9 (1014) | Pregnancy rate | Intranasal gonadotrophin-releasing hormone agonists v other routes | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for uncertain clinical relevance of outcome measure |
| 5 (1796) | Pregnancy rates | Gonadotrophin-releasing hormone antagonist v gonadotrophin-releasing hormone agonists | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for broad inclusion criteria |
| 1 (399) [ | Pregnancy /live birth rate | Immediate v delayed in vitro fertilisation | 4 | 0 | 0 | –1 | +1 | High | Directness point deducted for different duration of treatment between groups. Effect size point added for RR greater than 2 |
| 1 (423) | Pregnancy rate | In vitro fertilisation v intracytoplasmic sperm injection | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for broad inclusion criteria |
| 3 (105) | Pregnancy rates | Priming with gonadotrophins v no priming | 4 | –2 | –1 | 0 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Consistency point deducted for conflicting results |
| What are the effects of treatments for tubal infertility? | |||||||||
| 10 (615) | Pregnancy rate | Selective salpingography plus tubal catheterisation v hysteroscopy | 2 | 0 | 0 | 0 | +1 | Moderate | Effect size point added for RR greater than 2 |
| 3 (382) | Pregnancy rate | Tubal flushing with oil-soluble media v no treatment | 4 | –1 | 0 | –1 | +1 | Moderate | Quality point deducted for statistical heterogeneity. Directness point deducted for broad inclusion criteria. Effect size point added for OR greater than 2 |
| 1 (158) | Birth rate | Tubal flushing with oil soluble media v no treatment | 4 | –1 | 0 | –1 | +1 | Moderate | Quality point deducted for sparse data. Directness point deducted for broad inclusion criteria. Effect size point added for OR greater than 2 |
| 6 (1483) | Pregnancy rate | Tubal flushing with oil-based media v water-based | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for broad inclusion criteria |
| 2 (931) ] | Live birth rate | Tubal flushing with oil-based media v water-based | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for broad inclusion criteria |
| 3 (295) | Pregnancy rate | Tubal surgery v no treatment/medical treatment | 4 | 0 | 0 | -2 | 0 | Low | Directness points deducted for narrow inclusion criteria and use of different comparators |
| 3 (295) | Live birth rate | Tubal surgery v no treatment/medical treatment | 4 | 0 | 0 | –2 | +1 | Low | Directness points deducted for narrow inclusion criteria and use of different comparators. Effect size point added for RR greater than 2 |
| 1 (63) | Pregnancy rate | CO2 laser adhesiolysis v diathermy adhesiolysis | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (63) | Birth rate | CO2 laser adhesiolysis v diathermy adhesiolysis | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 10 (1674) | Pregnancy rate | Postoperative treatments plus surgery v tubal surgery alone | 4 | –1 | 0 | –1 | 0 | Low | Quality points deducted for methodological flaws. Directness point deducted for wide range of interventions |
| What are the effects of treatments for infertility associated with endometriosis? | |||||||||
| 7 (402) | Pregnancy rate | Ovulation suppression v placebo | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for wide range of interventions |
| 10 (843) | Pregnancy rate | Ovulation suppression v danazol | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for wide range of interventions |
| 21 (3879) | Pregnancy rate | Medical ovulation suppression v laparoscopic ablation of endometrial deposits | 2 | –1 | 0 | –1 | 0 | Very low | Quality point deducted for incomplete reporting of results. Directness point deducted for wide range of interventions |
| 1 (103 couples) | Birth rate | Intrauterine insemination plus gonadotrophins v no treatment | 4 | –1 | 0 | –1 | +2 | High | Quality point deducted for sparse data. Directness point deducted for narrow inclusion criteria. Effect size points added for OR greater than 5 |
| 1 1 (57 couples) | Pregnancy rate | Intrauterine insemination plus gonadotrophins v intrauterine insemination alone | 4 | –1 | 0 | 0 | +2 | High | Quality point deducted for sparse data. Effect size points added for OR greater than 5 |
| 2 (437) | Live birth or pregnancy rate | Laparoscopic surgery v diagnostic laparoscopy | 4 | 0 | 0 | 0 | 0 | High |
Type of evidence: 4 = RCT; 2 = Observational; 1 = Non-analytical/expert opinion.Consistency: similarity of results across studies. Directness: generalisability of population or outcomes.Effect size: based on relative risk or odds ratio.
Glossary
- Adhesiolysis
Division of adhesions, which are bands of scar tissue that form after infection or surgery.
- Anovulation
is the failure to ovulate (expel a mature oocyte) owing to dysfunction of the ovary or suppression by drug treatment. Anovulation is a common cause of female infertility. Most often, women who do not ovulate also do not menstruate (amenorrhea).
- Delayed in vitro fertilisation
In vitro fertilisation treatment after 6 months of being assessed in an infertility clinic after at least 12 months of infertility.
- Endometriosis
is a progressive disease which occurs when the endometrial tissue lining the uterus grows outside the uterus and attaches to the ovaries, fallopian tubes or other organs in the abdominal cavity. Symptoms include painful menstrual periods, abnormal menstrual bleeding, and pain during or after sexual intercourse.
- Gonadotrophin priming of oocytes
This is the in vitro maturation of oocytes using gonadotrophins (hormones stimulate and control reproductive activity) from the germinal vesicle (early) stage of development to the metaphase II (mature) stage.
- High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
- Hydrosalpinges
is the abnormal distension of one or both fallopian tubes owing to fluid build up, usually because of inflammation.
- Hydrotubation
Flushing of the fallopian tubes through the cervix and uterine cavity to remove surgical debris and reduce the incidence of tubal reocclusion.
- Immediate in vitro fertilisation
In vitro fertilisation treatment within 6 months of being assessed in an infertility clinic after at least 12 months of infertility.
- In vitro fertilisation
(IVF) is a technique where female oocytes (eggs) are fertilised with sperm from a male partner outside the body in a fluid medium in the laboratory. Embryos are transferred later to the uterus using a special catheter.
- Laparoscopic ovarian drilling (ovarian diathermy)
Ovarian drilling can be performed laparoscopically by either cautery or laser vapourisation (using CO2 , argon, or Nd:YAG lasers), which are used to create multiple perforations (about 10 holes per ovary) of the ovarian surface and stroma (inner area of the ovary). This is thought to cause ovulation by restoring the intra-ovarian hormonal environment to normal, which in turn beneficially affects the hypothalamic–pituitary–ovarian axis.
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Macrosurgery
Surgery without dedicated optical magnification.
- Microsurgery
Surgery involving optical magnification to allow the use of much finer instruments and suture material in addition to a non-touch technique, with the aim of minimising tissue handling and damage.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Ovarian hyperstimulation syndrome (OHSS)
can occur in mild, moderate, and severe forms. Mild ovarian hyperstimulation syndrome is characterised by fluid accumulation, as shown by weight gain, abdominal distension, and discomfort. Moderate ovarian hyperstimulation syndrome is associated with nausea and vomiting, ovarian enlargement, abdominal distension, discomfort, and dyspnoea. Severe ovarian hyperstimulation syndrome is a life threatening condition, in which there is contraction of the intravascular volume, tense ascites, pleural and pericardial effusions, severe haemoconcentration, and the development of hepatorenal failure. Deaths have occurred, caused usually by cerebrovascular thrombosis, renal failure, or cardiac tamponade.
- Ovulation disorders
are defined by the failure of an ovum to be expelled owing to a malfunction in the ovary. Ovulation disorders are a major cause of infertility and can often be corrected with medication. Ovulation disorders often result in infrequent menstruation (oligomenorrhea).
- Pituitary downregulation (long protocol)
This is the process by which the release of gonadotrophins from the pituitary gland is stopped after repeated administration of gonadotrophin releasing hormone (GnRH) analogues, this in turn controls reproductive function.
- Polycystic ovary syndrome (PCOS)
results from an accumulation of incompletely developed follicles in the ovaries owing to chronic anovulation. PCOS is characterised by irregular or absent menstrual cycles, multiple small cysts on the ovaries (polycystic ovaries), mild hirsutism, and infertility. Many women also have increased insulin resistance.
- Pulsatile gonadotrophin releasing hormone
is a hormone produced and released by the hypothalamus at intervals (pulses). Pulsatile gonadotrophin releasing hormone controls the production and release of gonadotrophins from the pituitary gland, which in turn controls reproductive function.
- Salpingography
is a technique used to diagnose blockages in the fallopian tubes. It involves the radiographic imaging of the fallopian tubes after the injection of radio-opaque contrast medium (dye) through the cervix to the uterine cavity. If the fallopian tubes are open the dye flows into the tubes and then spills out to the abdominal cavity. This is documented in a series of x-ray images during the procedure. If tubes are blocked from the proximal end, a very narrow catheter is introduced under radiographic imaging (selective salpingography and tubal catheterisation) to remove the obstruction if possible.
- Second look laparoscopy
Laparoscopy performed some time after tubal surgery (either open or laparoscopic) with the aim of dividing adhesions relating to the initial procedure.
- Tubal flushing
involves injecting an oil or water soluble contrast medium into the fallopian tubes to flush out any blockages in the tubes. Flushing out any tubal “plugs” which may be causing proximal tubal occlusion using oil or water soluble media may have a fertility enhancing effect.
- Tubal infertility
is the inability to conceive owing to a blockage in one or both fallopian tubes and is a common cause of infertility. The tubal blockages are usually caused either by pelvic infection, such as pelvic inflammatory disease (PID) or endometriosis. Blockages may also be caused by scar tissue that forms after pelvic surgery.
- Tubal surgery
techniques are used to restore the patency of the fallopian tubes in women with tubal infertility as an alternative to in vitro fertilisation. Surgery may either be open microsurgery or laparoscopic microsurgery.
- Very low-quality evidence
Any estimate of effect is very uncertain.
See erectile dysfunction
See fibroids
See pelvic inflammatory disease
See varicocele
See endometriosis
See polycystic ovary syndrome
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