predictors of successful intra...

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


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


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.


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.


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]

• [email protected] • 012-3301400 • 03-79674761

mailto:[email protected]

mailto:[email protected]

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

predictors of successful intra...

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