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Ovulation triggers in anovulatory women undergoing ovulation induction

  1. Korula George1,*,
  2. Mohan S Kamath2,
  3. Raju Nair3,
  4. Prathap Tharyan4

Editorial Group: Cochrane Menstrual Disorders and Subfertility Group

Published Online: 31 JAN 2014

Assessed as up-to-date: 18 NOV 2013

DOI: 10.1002/14651858.CD006900.pub3


How to Cite

George K, Kamath MS, Nair R, Tharyan P. Ovulation triggers in anovulatory women undergoing ovulation induction. Cochrane Database of Systematic Reviews 2014, Issue 1. Art. No.: CD006900. DOI: 10.1002/14651858.CD006900.pub3.

Author Information

  1. 1

    Bangalore Baptist Hospital, Reproductive Medicine Unit, Bangalore, Karnataka State, India

  2. 2

    Christian Medical College and Hospital, Reproductive Medicine Unit, Vellore, Tamil Nadu, India

  3. 3

    Matha Assisted Reproductive Centre(m.arc), Reproductive Medicine Unit, Kottayam, kerala, India

  4. 4

    Christian Medical College, South Asian Cochrane Network & Centre, Prof. BV Moses Centre for Evidence-Informed Health Care and Health Policy, Vellore, Tamil Nadu, India

*Korula George, Reproductive Medicine Unit, Bangalore Baptist Hospital, Bellary Road, Hebbal, Bangalore, Karnataka State, 560024, India. gkorula@gmail.com.

Publication History

  1. Publication Status: Stable (no update expected for reasons given in 'What's new')
  2. Published Online: 31 JAN 2014

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Characteristics of included studies [ordered by study ID]
George 2007

MethodsMethod: randomised, single-centre, parallel-group, open-label, controlled trial

Trial duration: one year


ParticipantsNumber randomly assigned: 180

Inclusion criteria

  • Anovulatory women planned for ovulation induction with clomiphene citrate
  • Anovulation diagnosed by irregular cycles of longer than 35 days or by serum progesterone > 10 ng/mL carried out on the 21st day of the cycle in women with regular 28-day cycles


Baseline characteristics included age, BMI, dose of drugs used, number and size of dominant follicle, ovulation monitored by ultrasound and serum progesterone


InterventionsIntervention

hCG 5000 IU intramuscularly in the morning between 9 AM and 10 AM; couples were advised to have intercourse the following night, about 36 hours later (n = 90)
Control

No hCG trigger; participants were advised to have intercourse frequently over the next few days (n = 90)

In both arms, clomiphene citrate was started from day two at a starting dose of 100 mg daily, monitored by transvaginal ultrasound on day 13 and afterwards, depending upon follicular size and growth
Follicle judged to be mature when measuring 18 mm or larger
Randomisation to respective groups was carried out after follicular development

Ovulation was assessed by ultrasound after four days and by serum progesterone after seven days


OutcomesOutcomes included in review

  • Ovulation by ultrasound/serum progesterone
  • Clinical pregnancy rates
  • Miscarriage rates
  • Live birth rate


Additional outcome in the trial not included in the review

  • Biochemical pregnancy rate


Additional outcomes provided by the author and included in the review but not reported in the trial publication

  • Multiple pregnancy rate
  • Preterm delivery rate


NotesSetting: Reproductive Medicine Unit, Department of Obstetrics and Gynaecology, Christian Medical College & Hospital, Vellore, Tamil Nadu, India

Funding: intramural research funds of the Christian Medical College, Vellore

Comments

  • Sample size calculated as 90 women in each arm, based on anticipated ovulation rate
  • Randomisation was done once the dominant follicle was observed on ultrasound


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote from report: "random numbers were generated using randomisation tables"

Allocation concealment (selection bias)Low riskQuote from report: by "opening consecutively numbered sealed opaque envelopes"

Blinding of participants and personnel (performance bias)
All outcomes
Low riskOpen-label trial. Even though participants and the investigator were not blinded, risk of performance bias was considered unlikely

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOpen-label trial. However, all outcomes were objective; possibility of detection bias unlikely

Incomplete outcome data (attrition bias)
All outcomes
Low riskVery low attrition rate (< 2%). Quote from report arm: "One woman in group A (hCG) and 2 women in group B (no hCG) were lost to follow-up after randomisation and were not evaluated in the trial"

Selective reporting (reporting bias)Low riskEven though the trial protocol was not available, all prestated outcomes were reported

Other biasLow riskNo other bias detected

Yilmaz 2006

MethodsMethod: Randomised, two-centre, parallel-group, single-blinded, controlled trial

Trial duration: two years (from May 2002 to April 2004)


ParticipantsNumber randomly assigned: 133

Inclusion criteria

  • Primary infertility
  • Normoprolactinemic and normogonadotropic (WHO class 2 ovarian dysfunction)
  • Age 20 to 40 years
  • Duration of primary infertility: two years
  • No history of ovulation induction treatment and thyroid disease
  • Normal results on hysterosalpingogram
  • Normal semen analysis


Anovulation diagnosed by oligomenorrhoea (35 days to six months)/amenorrhoea longer than six months

Baseline characteristics include age, BMI, duration of infertility, type of infertility, semen analysis report, dose of drugs used, number and size of dominant follicles, ovulation by ultrasound and serum progesterone


InterventionsIntervention
hCG 10,000 units (Pregnyl 10,000 IU IM) was administered when one or more follicles reached 18 mm diameter by ultrasound. Intercourse was advised accordingly (n = 60)

Control
No hCG; natural intercourse advised five days after last dose of clomiphene citrate (n = 65)

In both arms, clomiphene citrate 50 mg was given from day five to day nine
Ovulation was assessed by ultrasound and by serum progesterone level


OutcomesOutcomes included in review

  • Ovulation rate
  • Pregnancy rate
  • Clinical pregnancy rate
  • Multiple pregnancy rate
  • Preterm delivery rate


Outcomes reported in the trial and not included in the review

  • Fertilisation rate
  • Implantation rate
  • Abortion rate
  • Assessment of luteal phase by mid-luteal serum progesterone
  • Luteal phase length.


Outcome provided by the author and included in the review but not reported in the trial publication

  • Live birth rate
  • Preterm delivery rate
  • Miscarriage rate


NotesSetting: Department of Reproductive Endocrinology, Zekai Tahir Burak Women’s Health Education and Research Hospital, Ankara; and Department of Reproductive Endocrinology, Suleymaniye Maternity Hospital, Istanbul, Turkey

Funding: not mentioned

Comments

  • Sample size calculated was 117 in each arm, based on anticipated ovulation rate. Of 133 women (unclear whether eligible or randomised), eight were lost to follow-up, and results were reported for 125 randomly assigned women. Reason for not achieving calculated sample size not mentioned
  • Randomisation done before the start of therapy. Twenty-three women did not respond to ovulation induction
  • Definition of abortion: detected chemically but not by ultrasound scan at seven weeks' gestation
  • Analysis was by intention-to-treat


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote from the report: "determined by a random number table"

Allocation concealment (selection bias)Low riskQuote from the report: "opaque envelope technique"

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe sonographer was blinded. Even though participants and other investigators were not blinded, the risk of performance bias is highly unlikely

Blinding of outcome assessment (detection bias)
All outcomes
Low riskAll outcomes were objective; possibility of detection bias unlikely

Incomplete outcome data (attrition bias)
All outcomes
Low riskEight participants among the 133 women dropped out of the study, and their allocated intervention was unclear. All other randomly assigned participants completed the study. The numbers completing the trial in both arms were roughly similar and would not alter the results significantly

Selective reporting (reporting bias)Low riskEven though the trial protocol was not available, all prestated outcomes were reported

Other biasUnclear riskThe number of women recruited did not reach the calculated sample size (117 in each arm). Reason for not achieving calculated sample size not mentioned.

Twenty-three women did not respond (did not develop a follicle) after randomisation. However, the numbers completing the trial were roughly equal in the two arms

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Harrison 1983RCT; women with unexplained infertility were studied

Sutaria 1980RCT: cross-over design

 
Comparison 1. Human chorionic gonadotrophin versus no treatment (in clomiphene-induced cycles)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Live birth rate per woman randomly assigned2305Odds Ratio (M-H, Fixed, 95% CI)0.97 [0.52, 1.83]

 2 Ovulation rate per woman randomly assigned2305Odds Ratio (M-H, Random, 95% CI)0.99 [0.36, 2.77]

 3 Clinical pregnancy rate per woman randomly assigned2305Odds Ratio (M-H, Fixed, 95% CI)1.02 [0.56, 1.89]

 4 Multiple pregnancy rate per woman randomly assigned2305Odds Ratio (M-H, Fixed, 95% CI)0.45 [0.04, 5.13]

 5 Miscarriage rate per clinical pregnancy254Odds Ratio (M-H, Fixed, 95% CI)1.19 [0.17, 8.23]

 6 Preterm delivery rate per woman randomly assigned2305Odds Ratio (M-H, Fixed, 95% CI)0.30 [0.01, 7.58]

 
Summary of findings for the main comparison. Human chorionic gonadotrophin versus no ovulation trigger in clomiphene-induced cycles

What are the effects of human chorionic gonadotrophin versus no ovulation trigger in clomiphene-induced cycles in women with anovulatory infertility?

Patient or population: women with anovulatory infertility undergoing ovulation induction with clomiphene citrate
Settings: infertility clinics in university hospitals
Intervention: human chorionic gonadotrophin (urinary hCG) versus no ovulation trigger in clomiphene-induced cycles

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

No ovulation triggerHuman chorionic gonadotrophin

Live birth rate

Live fetus delivered beyond 20 completed weeks' gestation
194 per 1000189 per 1000
(111 to 306)
OR 0.97
(0.52 to 1.83)
305
(two studies)
⊕⊕⊝⊝
low1,2,3,4,5

(because of very serious imprecision)

Ovulation rate

Ultrasound evidence of collapsed follicle or mid-luteal serum progesterone < 10 ng/mL
861 per 1000860 per 1000
(690 to 945)
OR 0.99
(0.36 to 2.77)
305
(two studies)
⊕⊕⊝⊝

low1,3,4,5,6

(because of very serious imprecision)

Clinical pregnancy rate

Ultrasound evidence of pregnancy
200 per 1000203 per 1000
(123 to 321)
OR 1.02
(0.56 to 1.89)
305
(two studies)
⊕⊕⊝⊝
low1,3,4,5,7

(because of very serious imprecision)

Miscarriage rate per clinical pregnancy

Spontaneous pregnancy loss before 20 weeks' gestation
108 per 1000126 per 1000
(20 to 499)
OR 1.19
(0.17 to 8.23)
54
(two studies)
⊕⊕⊝⊝
low1,3,4,5,8

(because of very serious imprecision)

*The basis for the assumed risk is the median control group risk in the two studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: 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.
Very low quality: We are very uncertain about the estimate.

 1No study limitations: Both trials were free of the risk of bias that could seriously undermine confidence in their results. Not downgraded.
2No serious Inconsistency: The trials differed in the direction of effect of the point estimates, but the confidence intervals overlapped, and I2 was 16%. Not downgraded.
3No serious indirectness: Participants and interventions were representative of usual clinical practice. Not downgraded.
4Very serious imprecision: Upper and lower limits of the 95% CI indicated appreciable benefit for hCG and for no hCG, with no statistically significant difference; the total sample size in the two trials was much smaller than the optimal information size. Downgraded by two levels.
5Publication bias: It is unlikely that any study was missed.
6No serious inconsistency: Trials differed in direction of effect of point estimates, but confidence intervals overlapped, the Chi2 test did not rule out chance (P value 0.14) and I2 was 55%. Not downgraded.
7No serious inconsistency: Trials differed in direction of effect of point estimates, but confidence intervals overlapped, and I2 was 35%. Not downgraded.
8No serious inconsistency: Trials differed in direction of effect of point estimates, but confidence intervals overlapped, and I2 was 0%. Not downgraded.