Table 1.
GRADE evaluation of interventions for female infertility
| Important outcomes | Live birth rates, pregnancy rates, ovulation 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? | |||||||||
| 3 (133) | Pregnancy rate | Clomifene v placebo | 4 | –2 | 0 | 0 | +2 | High | Quality points deducted for sparse data and results post-crossover. Effect size points added for OR >5 |
| 3 (133) | Ovulation rate | Clomifene v placebo | 4 | –2 | 0 | 0 | +2 | High | Quality points deducted for sparse data and results post-crossover. Effects size point added for OR >5 |
| 1 (95) | Live birth rate | Clomifene v tamoxifen | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 3 (256) | Pregnancy rate | Clomifene v tamoxifen | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (95) | Ovulation rate | Clomifene v tamoxifen | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (72) | Live birth rate | Clomifene v laparoscopic ovarian drilling | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for additional treatments |
| 1 (72) | Pregnancy rate | Clomifene v laparoscopic ovarian drilling | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for additional treatments |
| 1 (72) | Ovulation rate | Clomifene v laparoscopic ovarian drilling | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 2 (50) | Live birth rate | Metformin v placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and low event rate leading to wide confidence intervals |
| 6 (479) | Pregnancy rate | Metformin v placebo | 4 | 0 | 0 | 0 | 0 | High | |
| 13 (875) | Ovulation rate | Metformin v placebo | 4 | 0 | 0 | 0 | 0 | High | |
| 3 (600) | Live birth rate | Metformin v clomifene | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for significant statistical heterogeneity in analysis |
| 3 (600) | Pregnancy rate | Metformin v clomifene | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for significant statistical heterogeneity in analysis. Consistency point deducted for conflicting results |
| 3 (594 women, 2470 cycles) | Ovulation rate | Metformin v clomifene | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for significant statistical heterogeneity in analysis. Consistency point deducted for conflicting results |
| 4 (752) | Live birth rate | Metformin plus clomifene v clomifene alone | 4 | 0 | 0 | 0 | 0 | High | |
| 8 (976) | Pregnancy rate | Metformin plus clomifene v clomifene alone | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for significant statistical heterogeneity. Consistency point deducted for different results between analyses |
| 12 (2700) | Ovulation rate | Metformin plus clomifene v clomifene alone | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for significant statistical heterogeneity. Consistency point deducted for different results between analyses |
| 7 (627) | Pregnancy rate | Urinary follicle-stimulating hormone v hMG | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for methodological weaknesses in included studies (blinding and method of randomisation not reported) |
| 7 (627) | Ovulation rate | Urinary follicle-stimulating hormone v hMG | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for methodological weaknesses in included studies (blinding and method of randomisation not reported) |
| 3 (122) | Live birth rate | Gonadotrophins plus metformin v gonadotrophins alone | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| at least 4 (at least 154) | Pregnancy rate | Gonadotrophins plus metformin v gonadotrophins alone | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and inclusion of post-crossover results from one RCT |
| 2 (305) | Live birth rate | Urinary hCG plus clomifene citrate v clomifene citrate alone | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for methodological weakness in included RCTs (underpowered and no blinding) |
| 2 (305) | Pregnancy rate | Urinary hCG plus clomifene citrate v clomifene citrate alone | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for methodological weakness in one RCT (underpowered and no blinding) |
| 2 (305) | Ovulation rate | Urinary hCG plus clomifene citrate v clomifene citrate alone | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for methodological weakness in one RCT (underpowered and no blinding) |
| 3 (211) | Pregnancy rate | Gonadotrophin-releasing hormone agonists plus gonadotrophins v gonadotrophins alone | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for methodological weaknesses in included RCTs (not stating method of randomisation and lack of blinding) |
| 3 (187) | Ovulation rate | Gonadotrophin-releasing hormone agonists plus gonadotrophins v gonadotrophins alone | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data and methodological weaknesses in included RCTs (not stating method of randomisation and lack of blinding) |
| 2 (204) | Live birth rate | Gonadotrophin-releasing hormone antagonists v gonadotrophin-releasing hormone agonists in an IVF cycle | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting |
| 4 (305) | Pregnancy rate | Gonadotrophin-releasing hormone antagonists v gonadotrophin-releasing hormone agonists in an IVF cycle | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for inclusion of unpublished data and methodological flaws in 2 RCTs (not stating method of randomisation) |
| 1 (28) | Pregnancy rate | Pulsatile gonadotrophin-releasing hormone v clomifene | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and methodological weaknesses |
| 1 (28) | Ovulation rate | Pulsatile gonadotrophin-releasing hormone v clomifene | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and methodological weaknesses |
| 2 (218) | Live birth rate | Laparoscopic ovarian drilling v gonadotrophins | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for inclusion of additional treatments in one RCT. |
| at least 3 (at least 254) | Pregnancy rate | Laparoscopic ovarian drilling v gonadotrophins | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for inclusion of additional treatments |
| 1 (50) | Ovulation rate | Laparoscopic ovarian drilling v gonadotrophins | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (109) | Live birth rate | Laparoscopic ovarian drilling v metformin | 4 | –1 | 0 | 0 | 0 | Moderate | Quality points deducted for sparse data |
| 2 (270) | Pregnancy rate | Laparoscopic ovarian drilling v metformin | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting. Directness point deducted for inclusion of other treatments in one RCT |
| 1 (161) | Ovulation rate | Laparoscopic ovarian drilling v metformin | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for incomplete reporting and sparse data. Directness point deducted for inclusion of other treatments in one RCT |
| 1 (42) | Live birth rate | Laparoscopic ovarian drilling v laparoscopic ovarian drilling plus metformin | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and methodological weaknesses |
| 1 (42) | Pregnancy rate | Laparoscopic ovarian drilling v laparoscopic ovarian drilling plus metformin | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and methodological weaknesses |
| 3 (272) | Live birth rate | Metformin plus IVF v IVF alone | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for inclusion of ICSI in some studies |
| 5 (426) | Pregnancy rate | Metformin plus IVF v IVF alone | 4 | 0 | 0 | –2 | 0 | Low | Directness points deducted for inclusion of ICSI in some studies and different result in subgroup analysis |
| 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? | |||||||||
| 1 (31) | Pregnancy rate | Tubal flushing with oil-based media v water-based | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and subgroup analysis |
| 3 (295) | Live birth rate | Tubal surgery v no treatment/medical treatment | 4 | 0 | 0 | –2 | +1 | Moderate | Directness points deducted for narrow inclusion criteria and use of different comparators. Effect size point added for RR >2 |
| 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 |
| 1 (63) | Pregnancy rate | CO2 laser adhesiolysis v diathermy adhesiolysis | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| What are the effects of treatments for infertility associated with endometriosis? | |||||||||
| 11 (557) | Pregnancy rate | Ovulation suppression v placebo | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for wide range of interventions |
| 1 (103) | Live 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 >5 |
| 1 (57) | 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 >5 |
| 1 (51) | Pregnancy rate | Intrauterine insemination plus clomifene v no treatment/expectant management | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for no pre-crossover statistical assessment between groups |
| 1 (62) | Live birth rate | Tubal flushing with oil soluble contrast media v no treatment/expectant management | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and subgroup analysis |
| 1 (62) | Pregnancy rate | Tubal flushing with oil soluble contrast media v no treatment/expectant management | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and subgroup analysis |
| 2 (437) | Pregnancy rate | Laparoscopic surgery v no surgery | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for composite outcome |
| What are the effects of treatments for unexplained fertility? | |||||||||
| 1 (387) | Live birth rate | Clomifene v placebo/expectant management | 4 | 0 | 0 | 0 | 0 | High | |
| 2 (460) | Pregnancy rate | Clomifene v placebo/expectant management | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for inclusion of one study published in abstract form |
| 1 (384) | Live birth rate | Unstimulated IUI v expectant management | 4 | 0 | 0 | 0 | 0 | High | |
| 1 (384) | Pregnancy rate | Unstimulated IUI v expectant management | 4 | 0 | 0 | 0 | 0 | High | |
| 1 (113) | Live birth rate | Unstimulated IUI v IVF | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (51) | Pregnancy rate | Stimulated IUI v expectant management | 4 | –2 | 0 | –1 | +1 | Low | Quality points deducted for sparse data and poor follow-up. Directness point deducted for inclusion of women with endometriosis. Effect size point added for effect size >2 |
| 1 (40) | Pregnancy rate | Stimulated IUI v clomifene | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and subgroup analysis |
| 4 (396) | Live birth rate | Stimulated IUI v unstimulated IUI | 4 | 0 | 0 | 0 | +1 | High | Effect size point added for effect size >2 |
| 4 (396) | Pregnancy rate | Stimulated IUI v unstimulated IUI | 4 | 0 | 0 | 0 | +1 | High | Effect size point added for effect size >2 |
| 1 (118) | Live birth rate | Stimulated IUI v IVF | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (51) | Live birth rate | IVF v expectant management | 4 | –2 | 0 | –1 | +2 | Moderate | Quality points deducted for sparse data and unequal follow-up between groups. Directness point deducted for uncertainty about significance of result. Effect size points added for effect size >5 |
| 2 (86) | Pregnancy rate | IVF v expectant management | 4 | –2 | 0 | 0 | +1 | Moderate | Quality points deducted for sparse data and unequal follow-up between groups. Effect size point added for effect size >2 |
Type of evidence: 4 = RCT. Consistency: similarity of results across studies. Directness: generalisability of population or outcomes. Effect size: based on relative risk or odds ratio.hCG, human chorionic gonadotrophin; hMG, human menopausal gonadotrophin; ICSI, intracytoplasmic sperm injection; IUI, intrauterine insemination; IVF, in vitro fertilisation.