PREDICTORS OF SUCCESSFUL INTRA UTERINE INSEMINATION
(IUI) TREATMENT FOR INFERTILE
COUPLES TREATED AT A MALAYSIAN CLINIC
DR. MASLINOR BINTI ISMAIL SENIOR LECTURER DU54
DEPARTMENT OF SOCIAL & PREVENTIVE MEDICINE FACULTY OF MEDICINE UNIVERSITY MALAYA
2
INTRODUCTION[1] • Infertility is defined as inability to
conceive within 2 years1 (WHO)
• 1O infertility • 2O infertility
• Prevalence of Infertility – WHO (2002) estimated;
• among countries; 3.5% to 30%2 • 186 million married women • 1 in 10 couples
– Malaysia (2006); 300,000 couples (age 20 to 403)
3
INTRODUCTION[2]
• The first human artificial insemination • 1700’s in England
• Worldwide • IUI success rate; 4% to 27%
4
INTRODUCTION[3]
• Infertility treatment modalities; • COH with oral medication; without IUI • COH with oral medication; with IUI • COH with oral medication & FSH/GnRHa; plus IUI • ART (Assisted Reproductive Technology)
COH = (Controlled Ovarian Hyperstimulation) ART = (Assisted Reproductive Technology) FSH = (Follicle Stimulating Hormone) GnRHa = (Gonadotrophin Releasing Hormone Agonist)
Literature Review on Prognostic factors of IUI success
Author/ Reference
Title/Location/Year Study design/Sample
Results Significant associated factors
Tomlinson MJ, et
al./Human Reproduction 1996
Prognostic indicators for intrauterine insemination (IUI): statistical model for IUI success/Royal Shrewsbury Hospital UK/1996
Retrospective Cohort/ 260IUI Cycles
Pregnancy rate=19.6% per cycle
4 significant IUI variables [follicle number (p < 0.005), endometrial thickness (p < 0.005), duration of infertility (p < 0.01) & progressive motility (p < 0.05)]
Nuojua-Huttunen S et
al/ Human Reproduction 1999
Intrauterine insemination (IUI) treatment in subfertility: an analysis of factors affecting outcome/ Dept. of O&G of Oulu University Hospital, Finland
Retrospective Cohort/ 811 IUI cycles from 1992-1996
Preg. rate (18%) was in the first cycle, no preg. in sixth cycles onwards, 97% preg. (99/102) occurred within the first 4 cycles
5 Predictive variables ie age women < 40(p=0.028, OR 3.24), Infertility duration (p=0.017, OR2.33), Infertility aetiology (unexplained) (p=0.045,OR 2.79), no. of treatment cycle(p=0.031)& no. of follicles (p=0.009)
Shibahara H et al./ Jichi Medical School,Japan 2004
Prediction of pregnancy by intrauterine insemination in patients with male factor infertility/University of Japan Reproductive & Andrology/2004
Retrospective cohort / 682 cycles
Pregnancy rate per cycle=7.2%(49/682) & per patient were 28.1% (45/160)
Male smoking decreases IUI success
Paul Y S Tay, et al / Medical Journal of Malaysia 2007; vol 62
Prognostic Factors influencing Pregnancy Rate After Stimulated Intrauterine Insemination / UMMC/ Jan 2002 - Dec 2005
Retrospective Cohort / 317 couples / 507 IUI cycles / Jan 2002-Dec 2005
Pregnancy rate per cycle=16.2% & per couple=25.9%
2 predictive variables ie age of women below 40 (p < 0.05) and TMSC (Total motile Sperm Count) (p < 0.01)
WEB OF CAUSATION: PREDICTORS OF IUI SUCCESS
IUI SUCCESS/PREGNANCY RATE
Medical history wife &
husband
Female Factor
• Total number of IUI cycles
Lifestyle
•Smoking status of husband
Socio-demographic•Duration of Infertility•Age of wife
Male Factor•Sperm count•Sperm motility
Biological•Thickness of Endometrium•Number of ovarian follicles
7
RATIONALE • Why should the problem be studied?
The commonest treatment, the cheapest compared to other methods.
To calculate IUI success rate at LPPKN.
To identify whether socio-demographic
characteristics, lifestyle, female & male characteristics are predictors.
8
STUDY OBJECTIVES
GENERAL
• To determine association of prognostic factors with success rate of IUI treatment for infertile couples
treated at LPPKN
9
STUDY OBJECTIVES: SPECIFIC
• To described socio-demographic characteristics of couples involved in the IUI treatment
• To determine association of socio-
demographic factors with success rate of IUI treatment
10
STUDY OBJECTIVES: SPECIFIC
• To determine association of lifestyle factors, biological factors, male factors, female factors, medical history wife & medical history husband with success rate of IUI treatment
• To determine the success rate of IUI treatment for
LPPKN
• To determine the number of treatment cycle needed for successful IUI
11
STUDY OVERVIEW • Location of study
• Infertility Clinic at 6th Floor of LPPKN Head Office
– Jalan Raja Laut, Kuala Lumpur
• Methods of data collection – No counter check information with wife/husband
• Sampling Procedure: Universal Sampling
• Time frame:1st Jan. 2000 till 31st Dec. 2006
RESEARCH METHOD: RETROSPECTIVE COHORT
THE PAST THE PRESENT
n = 2007
•282 defaulted 1st f/up •63 sperm count < (1 x 106 /ml) •77 had abnormal tubal function
STUDY POPULATION = 1585
INCLUSION CRITERIA 1) Malaysian with 1O or
2O infertility 2) Completed basic
infertility evaluation 3) Treatment method
only IUI
EXCLUSION CRITERIA 1) Abnormal tubal function 2) Defaulted 1st f/up 3) Sperm count less than 1 X 106
13
SAMPLE SIZE ESTIMATION
• With α of 0.05 & a power of 80%, a sample size of 1324 will be able to detect a 10% difference in the prevalence of smoking among men.
• This assumes that the prevalence of smoking
in men is 37% among infertile & 47% among non infertile (HR of 1.3)5.
14
LISTS OF 29 VARIABLES IN THIS STUDY
• Socio-demographic variables Types & Duration of infertility Age of women Race of wife Past Medical History Wife & Husband Job (wife & husband) Total Family Income BMI Smoking status
• Male variables Sperm count Sperm motility
• Female variables Menarche Duration of period
Frequency of SI Interval of period Dysmenorrhea Contraception
Intermenstrual bleed Postcoital bleed Discharge Dyspareunia
Galactorrhea Parity History of Post Appendicectomy Total number of IUI cycle
Thickness of Endometrium Number of Ovarian Follicles
15
DATA ANALYSIS – Software SPSS 15.0
1. Descriptive analysis
2. Inferential analysis • p value = 0.05, Crude Hazard ratio, 95% CI via Chi-
square, Kaplan-Meier Estimates, Log Rank & Nelson Aelen Estimates
3. Multivariate analysis • Control for confounding via Cox-Regression (censored
cases) • Test for Interaction (First Order Interaction) • Developed a final model for independent predictors
(Adjusted Hazard Rate Ratio)
SOCIO-DEMOGRAPHIC CHARACTERISTICS N = 1585
Characteristics Mean/median Age of female
37.5 years (Range 29; 25 to 54)
Total family income
RM 3100 (1st =2200,2nd =3100 & 3rd =4344.8)
Infertility duration
11 years (1st =8,2nd =11 & 3rd =13)
BMI of wife
23.1 (Range 30.7; 13.4 to 44.1)
Total cigarettes per day
2 sticks (1st =2,2nd =2 & 3rd =3)
17
SOCIO-DEMOGRAPHIC VARIABLES Characteristics n %
Duration of Infertility (years)
< 9.9 10 till 19.9 > 20
591 941 53
37.3 59.4 3.4
Age of wife (years)
< 40 > 40
1174 411
74 26
Job (wife)
Not working Prof & Technical Admin & Managerial Clerical
229 453 290 394
14.4 28.6 18.3 24.9
Total family income
Sales, service & Prod.
< RM 2000 RM 2000 – RM 3999.9 RM 4000 – 5999.9 > RM 6000
219
358 751 328 148
13.8
22.6 47.4 20.7 9.3
18
LIFESTYLE VARIABLES Characteristics N %
BMI of wife
Underweight Normal weight Overweight Obesity
149 884 376 176
9.4 55.8 23.7 11.1
Smoking Status (husband)
Non smoker Smoker
1062 523
67 33
Total Number of Cigarettes (husband)
0 sticks < 10 sticks 10 till 19 sticks > 20 sticks
1062 129 246 148
67 8.2 15.5 9.3
19
MALE VARIABLES Characteristics N %
Past medical history of husband
Nil HT & DM Asthma Mumps Others
1331 116 43 21 74
84 7.3 2.7 1.3 4.7
Sperm Count (X 106)
< 10 10.1 – 19.9 > 20
175 45
1359
11.1 2.8 86.1
Sperm motility (%)
< 10 10.1 – 25 25.1 – 40 > 40
68 77
257 1175
4.3 4.9 16.3 74.5
20
FEMALE VARIABLES Characteristics N %
Interval of mensus (days)
< 30 30 till 59 > 20
483 982 120
30.4 62 7.6
Dysmenorrhea
Nil Mild Severe
648 763 174
40.9 48.1 11
Total number of IUI cycles
1 to 2 3 to 4 > 5
1111 379 92
70 24 6
History of post appendicectomy
No Yes
1539
46
97.1 2.9
21
SUCCESS RATE OR PREGNANCY RATE OF IUI
AT LPPKN
• Pregnancy rate per cycle = 3.6% • Pregnancy rate per couple = 7.4%
HAZARD CURVE (PREGNANCY RATE) & NELSON AELEN ESTIMATES
13.8%
19.1%
25.9%
23
VARIABLES WITH SIGNIFICANT ASSOCIATION USING KAPLAN-MEIER &
LOG RANK (p-value) • p-value < 0.05
1. Duration of marriage
(years) 2. Age of Women (years) 3. Job (wife) 4. Smoking status 5. Sperm count 6. Sperm motility 7. Interval between
mensus 8. Total number of IUI
cycle
• 0.05 ≤ p-value ≤ 0.25
1. BMI wife 2. Total family Income 3. Past medical history
(male) 4. Total number of
cigarrettes 5. Dysmenorrhea 6. History of post
appendicectomy
24
KAPLAN-MEIER & LOG RANK FOR PREDICTORS Characteristics 6 MONTHS 2 YEARS
P-value CM/% PREG CM/%PREG Duration of Infertility (years)
< 9.9 10 till 19.9 > 20
<0.0005 0.84 / 16% 0.92 / 8% 0.97 / 3%
0.65 / 35% 0.86 / 14%
- Age of wife (years)
< 40 > 40
<0.001
0.87 / 13% 0.97 / 3%
0.75 / 25% 0.93 / 7%
Sperm count (X 106)
< 10 10.1 till 19.9 > 20
<0.01
0.98 / 2% 0.93 / 7% 0.89 / 11%
0.95 / 5% 0.93 / 7% 0.77 / 23%
Total number of IUI cycle
1 to 2 3 to 4
> 5
<0.0005
CM = CUM.
0.83 / 17% 0.95 / 5% 0.99 / 1% PROPORTION
0.66 / 34% 0.84 / 16% 0.90 /10%
25
KAPLAN-MEIER & LOG RANK FOR PREDICTORS Characteristics 6 MONTHS 2 YEARS
P-value CM/% PREG CM/%PREG BMI of wife
Underweight Normal weight Overweight Obesity
<0.25
0.92 / 8% 0.90 / 10% 0.88 / 12% 0.90 / 10%
0.92 / 8% 0.80 / 20% 0.79 / 21% 0.60 / 40%
Smoking status
Non smoker Smoker
<0.05
0.91 / 9% 0.86 /14%
0.82 / 18% 0.73 / 27%
Total Number of cigarettes
< 10 sticks 10 till 19 sticks > 20 sticks
<0.25
0.83 / 17% 0.86 / 14%
0.90 / 10%
0.77 / 23% 0.70 / 30%
0.78 / 22%
26
PREDICTORS OF IUI SUCCESS RATE • Multivariate analysis using Cox-Regression due
to censored data
• Selection of variables for the final predictive model from 14 variables was done manually by removing each variables backwardly using the ‘Enter’ method in the Cox-Regression
• Variables in the final model – Duration of infertility (years) – Age of wife (years) – Sperm Count (X 106 ) – Total number of IUI cycle
• No Interaction between variables in the final model.(First order interaction)
27
PROGNOSTIC MODEL OF IUI PREDICTORS Characteristics Crude Adjusted
HRR 95% CI HRR 95% CI Duration of Infertility (years)
< 9.9 10 till 19.9 > 20
Ref 0.4 0.2
0.3 , 0.6 0.03 , 1.3
Ref 0.5 0.4
0.3 , 0.7 0.1 , 2.9
Age of wife (years)
< 40 > 40
Ref 0.3
0.2 ,0.6
Ref 0.5
0.2 ,0.9
Sperm count (X 106)
< 10 10.1 till 19.9 > 20
Ref 1.2 4.4
0.1 , 11.7 1.4 , 14.0
Ref 1.4 4.3
0.1 , 13.0 1.4 , 13.7
Total number of IUI cycle
1 to 2 3 to 4
> 5
Ref 0.2 0.1
0.2 , 0.4 0.01 , 0.2
Ref 0.3 0.1
0.2, 0.4 0.02 , 0.3
28
DISCUSSION [1] • Pregnancy/Success Rate;
– Per Cycle is 3.6%
Low compared to other studies; 1. Tomlinson MJ, et al./Human Reproduction
1996 = 19.6% per cycle
2. Nuojua-Huttunen S et al/ Human Reproduction 1999 = 18% per cycle
3. Shibahara H et al./ Jichi Medical School,Japan 2004 = 7.2% per cycle
4. Paul Y S Tay, et al / Medical Journal of Malaysia 2007 = 16.1% per cycle & 25.9% per couple
29
DISCUSSION [2] • Duration of Infertility
Findings: Significantly affect outcome of IUI were supported by;
1. Mathieu et al 1995 2. Tomlinson et al 1996 3. Nuojua-Huttunen S et al / (Human Reproduction 1999)
Findings: Did not significantly affect outcome of IUI; 1. Deaton et al 1990 2. Paul Y S Tay, et al / (Medical Journal of Malaysia 2007)
Findings: >4 years duration of infertility; the likelihood of a life birth decrease is shown by;
1. Collins et al 1995 2. Snick et al 1997
30
DISCUSSION [3] • Age of women
Findings: Significantly affect outcome of IUI were supported by;
Tomlinson et al (1996) Agarwal & Buyalos (1997) Brzechffa et al (1998) Nuojua-Huttunen S et al / (Human Reproduction 1999) Paul Y S Tay, et al / (Medical Journal of Malaysia 2007)
Findings: Did not significantly affect outcome of IUI were shown by;
1. Mathieu et al (1995)
Findings: Studies that shown decrease in female reproductive capacity with advancing age
1. Collins et al (1995) 2. Scott et al (1995)
31
DISCUSSION [4]
• Sperm count Findings: Significantly affect outcome of
IUI were supported by; 1. Paul Y S Tay, et al / (Medical Journal of
Malaysia 2007)
Findings: Did not significantly affect outcome of IUI was shown by; 1. Sinikka Nuojua-Huttunen et al (1999)
32
DISCUSSION [5]
• Total number of IUI cycle
Findings: Significantly affect outcome of IUI were supported by;
1. Tomlinson et al 1989 2. Burr et al 1996 3. Sinikka Nuojua-Huttunen et al 1999 4. Paul Y S Tay et al 2007
33
STRENGTH OF THE STUDY
1. First study which attempts to collect data of IUI patients treated at LPPKN.
2. Relatively inexpensive. 3. No risk to the couples. 4. Not many missing of relevant data
well organized medical records at LPPKN twice clerking of every patient during first visit
5. Power of study more than 0.8 (0.87).
34
LIMITATIONS OF THE STUDY [1]
1. Some important information may be missing or unavailable.
• beyond the capability & control of the researcher
2. Follicular development monitoring by vaginal ultrasound is operator dependent.
• beyond the capability & control of the researcher
3. Due to large proportion of participants are lost to follow-up, the internal validity of the study is threatened.
• Conducted study via Universal Sampling to get more samples (Kenneth J.Rothman 2002)
35
LIMITATIONS OF THE STUDY [2]
4. Confounders need to be considered. • a measure to control is by applying
multivariate analysis during statistical analysis
5. Patient’s understanding of the definition of ‘smoker in male’ may cause differential misclassification bias.
• beyond the capability & control of the researcher
36
CONCLUSIONS 1. Pregnancy rate per cycle is 3.6%
while Pregnancy rate per couple is 7.4%
2. This study showed that duration of infertility age of wife sperm count total number of IUI cycle
PREDICTORS OF IUI SUCCESS
37
RECOMMENDATIONS 1. A women should maintain BMI at normal weight
in order to increase chance of increasing IUI success.
2. Since declination of IUI success rate is only obvious in heavy smoker (20 sticks & above), the husband must be advocated to stop smoking.
3. IUI should not be an option to couple with more than 10 years of infertility.
4. IUI treatment should only be an option for women whom are below the age of 40 years old
5. Patients whom fails the 5th cycle of IUI should be referred for ART.
38
REFERENCES 1. Jaffe SB, Jewelewicz R. The basic infertility evaluation. Fertil Steril,
1991; 56”599-612. 2. ESHRE Capri Workshop. Guidelines to the Prevalence, Diagnosis,
Treatment and Management of Infertility, 1996. Excerpts Hum Reprod, 1996, 4:1-33.
3. Schmidt L, Munster K. Infertility, involuntary infecundity, and the seeking of medical advice in industrialized countries 1970-1992: a review of concepts, measurements and results. Hum Reprod, 1995; 10: 1407-18.
4. Sundby J, Schei B. Infertility and subfertility in Norwegian women aged 40-42. Prevalence and risk factors. Acta Obstet Gynecol Scand, 1996; 75: 832-7.
5. Chanda A, Stephen EH. Impaired fecundity in the United States : 1982-1995. Fam Plann Perspect, 199; 30: 34-42.
6. Buckett W, Bentik B. The epidemiology of infertility in a rural population. Acta Obstet Gynecol Scand, 1997; 76: 233-7.
7. Wulff M, Hogberg U, Stenlund H. Infertility in an industrial setting – a population based study from Northern Sweden. Acta Gynecol, 1997; 76: 673-9.
39
THANK YOU FOR YOUR
ATTENTION
CONTACT ME AT:
• [email protected] • 012-3301400 • 03-79674761
JOURNAL ARTICLE
General characteristics n %
Types of infertility
Duration of infertility
(years)
Age of female
(years)
Primary/Secondary
< 5
5 – 9.9
10 - 14.9
15 – 19.9
> 20
<30
30 -39
40 – 49
>49
1215/370
88
503
731
210
49
53
1008
512
12
76.7/23.3
5.6
31.7
46.1
13.2
3.1
3.3
63.6
32.3
0.8
Ethnicity of female
Religion of female
Malay
Chinese
Indian
Sabah & Sarawak
Others
Islam
Buddha
Hindu
Others
1022
317
240
2
4
1023
316
238
8
64.5
20.0
15.1
0.1
0.3
64.5
19.9
15.0
0.5
Employment status
Occupational group of
female
Male/Female
Professional & Technical
Administrative & Managerial
Clerical
Sales
Services
Production
Agricultural
1572/1357
453
290
394
37
88
94
0
99.2/85.6
28.6
18.3
24.9
2.3
5.6
5.9
0
Household income
BMI of female
Smoking status of
husband
Number of cigarettes
per day
< RM 2000
RM 2000 – RM3999
RM 4000 – RM5999
RM 6000 – RM7999
RM8000 – RM9999
>RM9999
Underweight
Normal weight
Overweight
Obese
Yes/No
< 10
10 – 19
>19
358
751
328
96
25
27
149
884
376
176
523/1062
222
499
313
22.6
47.4
20.7
6.0
1.6
1.7
9.4
55.8
23.7
11.1
33 /67
21.5
48.2
30.3
Table I: Baseline characteristics of the cohort (N= 1585)
APPENDIX
SEARCH STRATEGY • Literature r/v identified by searching:
– The bibliographic database – Pub Med, Science Direct, OVID & MEDLINE – Internet search engine – Google search, Yahoo search – Hand searches – books & non-indexed journal
• Search term combination used – ‘Intra Uterine Insemination”, “IUI and infertility”, “IUI and prognostic factors
of success rate”, “IUI and predictors of pregnancy rate”
• Search included: – published articles from 1950 till 2007 – published reports of cohort, case control & randomized control trial – studies related to predictors/prognostic factors of IUI – outcome of study was pregnancy – Full text article only – English only – Critical appraisal using CASP for cohort
49
50
INTRODUCTION[3] • Infertility treatment modalities;
• COH with oral medication; without IUI • COH with oral medication; with IUI • COH with oral medication +/- FSH/GnRHa; plus IUI • ART (Assisted Reproductive Technology)
– DIPI (Direct Intra Peritoneal Insemination) – ZIFT (Zygote Intra Fallopian Transfer) – GIFT (Gamete Intra Fallopian Transfer) – IVF (In Vitro Fertilization) – ICSI (Intra Cytoplasmic Sperm Injection)
COH = (Controlled Ovarian Hyperstimulation) ART = (Assisted Reproductive Technology) FSH = (Follicle Stimulating Hormone) GnRHa = (Gonadotrophin Releasing Hormone Agonist)
SAMPLE SIZE MATRIX Sample size
matrix Hazard ratio, ψ
1.2 1.25 1.3 1.5 1.8 2.0 2.5 3.0
pº
0.20 2801 1805 1324 535 244 172 94 64
0.30 2174 1442 1036 425 198 141 79 55
0.40 1938 1290 931 387 184 132 76 54
0.50 1895 1267 918 387 187 136 80 58
0.60 2010 1349 981 420 207 152 92 67
0.70 2339 1576 1151 500 250 186 114 85
Ψ : Hazard ratio of smoking in infertile group relative to non infertile group
pº : Probability of smoking in non infertile group
52
SAMPLE CALCULATION:
1. Hazard ratio of smoking HR= 1.42 CI= [1.27, 1.58] (Augood et al. 1998)
2. Smoking posed the greatest risk with an adjusted Hazard ratio of 2.96 (Chia, S.E. et al.2000 )
3. Male smoking prevalence among infertile
population (Erik Tielemans. et al.2000 )
4. Prevalence of smoking among men taken as 46.4% (Source from National Health & Morbidity Survey III, 2006)
**Based on the above data, calculation of sample size done using PS Programme Version 2.0 Software
Alpha 0.05 Power of Study = 80 Exposed:Unexposed as 1:1
WEB OF CAUSATION: PREDICTORS OF IUI SUCCESS
IUI SUCCESS/PREGNANCY RATE
Medical history wife &
husband•H/O of DM/HT•H/O of Asthma•H/O Mumps (husband)•H/O Post Appendicectomyin wife
Female Factor•Menarche Duration mensus•Dysmenorrhea Interval mensus•Intermenstrual bleed Contraception•Discharge Postcoital bleed•Galactorrhea Dyspareunia
• Parity • Total number of IUI cycles
Lifestyle•BMI wife•Smoking status of husband•Frequency of sexual intercourse
Socio-demographic•Duration of Infertility•Types of Infertility•Age of wife•Ethnicity •Occupation•Family Income
Male Factor•Sperm count•Sperm motility
Biological•Thickness of Endometrium•Number of ovarian follicles
WEB OF CAUSATION: PREDICTORS OF IUI SUCCESS
IUI SUCCESS/PREGNANCY RATE
Medical history wife &
husband•H/O of DM/HT•H/O of Asthma•H/O Mumps (husband)•H/O Post Appendicectomyin wife
Female Factor•Menarche Duration mensus•Dysmenorrhea Interval mensus•Intermenstrual bleed Contraception•Discharge Postcoital bleed•Galactorrhea Dyspareunia
• Parity • Total number of IUI cycles
Lifestyle•BMI wife•Smoking status of husband•Frequency of sexual intercourse
Socio-demographic•Duration of Infertility•Types of Infertility•Age of wife•Ethnicity •Occupation•Family Income
Male Factor•Sperm count•Sperm motility
Biological•Thickness of Endometrium•Number of ovarian follicles