Optimizing iui results

1. Dr Vandana Bansal
MS, D. Phil. (Gold Medalist), DGO, FCGP
Senior Gynaecologist & Obstetrician
Gynaecological Endoscopic Surgeon
Infertility & IVF Specialist
Director
Arpit Test Tube Baby Centre
Jeevan Jyoti Hospital
PRAYAGRAJ

2. IUI is a relatively simple, low-tech, safe and inexpensive treatment modality
compared to IVF-ET
Rationale behind IUI is to bypass cervical-mucous barrier to increase gamete
density at site of fertilization.
First line management for couples with unexplained infertility as most
popular treatment
Male factor infertility with mild OAT’s
Couples requiring donor insemination can benefit from first line IUI
treatment.
Mild to minimal endometriosisWilliam Ombelet: Reproductive Biomedicine Online-vol 7. Comp1,66-72 1995
(Practice Committee ASRM 2006)

3. The Technique of IUI has essentially remained the same, several
advances in the type of stimulation protocols, gonadotropins, sperm
preparation techniques and ultrasound monitoring have led to
promising success rates with IUI.
Strict patient selection criteria and individualized stimulation
protocols tailored according to the age and etiology of the patient
with a strict cycle cancelation policy will help to reduce the
associated complications, such as multiple pregnancies and OHSS,
while maximizing the overall pregnancy outcome.
Three to six IUI cycles may be offered before considering alternate
therapy.

4.  The rationale behind intrauterine insemination (IUI) with
homologeous sperm is bypassing the cervical – mucus barrier and
increasing the number of motile spermatozoa with a high
proportion of normal forms at the site of fertilization.
 Artificial insemination was only performed in cases of male
subfertility and psychologic dysfunction, such as retrograde
ejaculation, vaginismus, hypospadias and impotence. Routine use
of post-coital tests, other indications were added such as hostile
cervical mucus.
 Interest in IUI is undoubtedly associated with the refinement of
techniques for the preparation of washed motile spermatozoa.
 These washing procedures are necessary to remove
prostaglandins, infections agents, antigenic proteins, non-motile
spermatozoa, leucocytes and immature germ cells.

5. Will benefit from direct referral to IVF/ICSI.

6.  Unexplained infertility
 Male factor infertility

7.  253 couples with unexplained infertility and a 30 – 40%
probability of a spontaneous pregnancy within 12 months were
randomly assigned either OH/IUI for 6 months or expectant
management for 6 months
 (RR 0.85, 95% CI 0.63—1.1) Steures P et al (CECERM), Lancet 2006
Pregnancy rate (%) On-going PR (%)
OH/IUI 33 23
Expectant
Management
32 27

8.  IUI in a natural cycle vs. expectant management (n = 334)  no
evidence of increased live birth (OR 1.60, 95% CI 0.92 – 2,8)
 IUI vs. TI (both in stimulated cycles)  increase chance of
pregnancy after IUI (6 RCTs, n = 517, OR 1.68, 95% CI 1.13 – 2.50)
 IUI + OH vs. IUI in a natural cycle  a significant increase in live
birth rate (4 RCTs, n = 396, OR 2.07, 95% CI 1.22 – 3.50)
 IUI alone vs. TI + OH (one RCT, N = 342)  a marginal significant
increase in live births for IUI
Veltman-Verhulst SM et al, Cochrane Sys Rev 2012, Issue 9, CD001838

9.  Better pregnancy rates (PR) per couple but not statistically
significant :-
 There were insufficient data available for adverse outcomes such
as OHSS, multiple pregnancy, miscarriage rate and ectopic
pregnancy to perform a statistical analysis.
(Pooled)Peto OR 95% CI
IUI vs. TI 5.3 0.42 – 67
OH/IUI vs. IUI 1.47 0.92 – 2.37
OH/IUI vs. OH 1.67 0.83 – 3.37
Bensdorp A et al, Cochrane database of systematic reviews, 2007

10. 0%
5%
10%
15%
20%
25%
1 2 3 4
Series1 Series2
*
*
* P < 0.05
On-going PR 3.9%
LBR
3.1%
Live birth rate between 3 and 4% for women over 40 years

11. Age Clinical Pregnancy Rate (%)
< 30 years 13.6
30 – 34 years 13.5
35 – 39 years 12.6
 40 years 5.0
• Statistically significant, age-related decline in pregnancy rate (P < 0.05)
very low pregnancy in women > 40 years
(Wainer R et al, 2004)
• PR 24.9% (66/265) (< 30 yr) vs. 12.9% (11/85) ( 30yr) per cycle
(Zadehmodarres S et al, 2009)

12. The rationale behind the use of Ovarian
Stimulation in IUI is :
 Increase in number of available oocytes
 Correction of subtle endocrinological or
ovulatory dysfunction

13. 1. Clomiphene: Day 3 to 7 for 5 days 100 mg/day
2. Tamoxifen: Day 3 to 7 for 5 days 40 mg/day
3. Letrozole: Day 3 to 7 for 5 days 2.5 to 5mg/day
4. Gonadotropins: Daily dosing starting with 50 to 75
units/day from day 3 or 4 of cycle till dominant
follicle is made

14.  43RCTs, n=3957
• CC with letrozole: no significant difference (OR 1.2)
• Gonadotrophins with CC: Significant higher PR with gonadotrophins (OR 1.8)
• Different gonadotrophins: no significant difference
• No evidence of benefit in doubling the dose of gonadotrophins (OR 1.2), multiple
pregnancy rates and OHSS rates increased.
 Cochrane Jan 21 2009 (up to date: January 23, 2007)

15.  Gonadotrophins vs. anti-estrogens (7 studies, n = 556)  significant
higher pregnancy rates with gonadotrophins (OR 1.8, 95% CI 1.2 – 2.7)
Cantineau & Cohlen, Cochrane Sys Rev, 2011, Issue 2, CD005356)

16.  2 – 3 follicles with 18 – 19 mm
 Endometrium ≥ 9 mm thick & trilaminar
 IUI between Cycle D13 and D16, 36-40 hrs. from
HCG inj
1.Cantineau AE et al. Cochrane Database Syst Rev. 2007;(2):CD005356.2.Sinha SP. Apollo Medicine 2012. 9(3): 228-238

17. 1.Sinha SP. Optimization of ovarian stimulation to improve success rate in ‘ART’. Apollo Medicine 2012; 9(3): 228-238.
CC - 50mg dose per day
From cycle day 2 for 5 days
of the menstrual cycle
LH surge - Starts from 5 to 12 days after the last
day of CC administration

18. Clinically not > than
150mg is usedPractice Committee of the American Society for Reproductive Medicine. Fertil Steril 2003; 5:1302-8
How many cycles and How?

19.  Transvaginal U/Sn
 A baseline scan on D2 or D3 and thereafter from the
 D9 or D10 onwards till the follicle shows a growth and
 maturtion
 BBT
 LH kits
 Day 21 Progesterone
 Serum E2 levels
Lobo RA, et al. Fertil Steril 1982; 37:168.

20. CC Resistance CC Failure
Failure to ovulate with 3
months of use at 150mg/day
of 5 days
Most common cause -PCOS
Patients who ovulate but fail
to conceive on CC therapy
To start on alternative
therapy
Practice Committee of the American Society for Reproductive Medicine..Fertil Steril 2003; 80:1302.
Alternative

21. Unripe
follicle
Ripening
follicle
Ovulation Corpus
luteum
Regression
of Corpus
luteum
Clomiphene
100 mg day2
for 5 days
Gonadotrophin
stimulation from
day 4 to day of
HCG Leading follicle > 18mm
Oocyte mature
38 hrs
HCG
1. Emam MA. Ovarian Stimulation An overview. Accessed from website http://ebookbrowse.com/ovarian-stimulation-ppt-d152627873.

22. 73%
36%
20%
13%
0
20
40
60
80
1 2 3 4
Percentof
patients(%)
Clomiphene achieves about 70% ovulation
and combining it with timed intercourse will
achieve pregnancy of up to 25% per cycle.
Homburg R.Hum Reprod. 2005;20(8):2043.
Stimulation protocols in IUI- CC+Gn

23. FSH - 37.5 to 75 IU/day SC/IM(rec-Human FSH)
Step up the dose by 37.5 IU if no follicles >10mm after 7 days (response on U/sn)
Step up every 7 days until dominant follicle appear
Maximum of 225 IU
HCG > 18mm and endometrium > 7mm
White DM, et al. J Clin Endocrinol Metab 1996; 81:3821.
Low-dose
Step-up Protocol

24. Step-down protocol
FSH – 150 IU/day SC/IM; after spontaneous or progesterone
-induced bleeding, continued -dominant follicle (>10 mm) on U/sn
Dose decreased to 112.5 int. units/day, further decreased to
75 int. units/day three days later
Imani B, et al. Fertil Steril 2002; 77:83.

25. Low dose step-
up
Step down P value
No. of patients 85 72
Duration of
treatment (days)
15.2 ± 7 9.7 ± 3.1 < 0.001
Total dose of
rec-FSH (IU)
951 ± 586 967 ± 458 NS
Mono-follicular
growth
68.2% 32% < 0.0001
Ovulation rate 70.3% 61.7% 0.02
Pregnancies/cyc
le
18.7% 15.8% NS
OHSS 2.25% 11% <0.001
Christin-Maitre S, et al. Hum Reprod. 2003 Aug;18(8):1626-31

26. Live birth rate per couple following IUI with or without FSH ovarian
stimulation (Verhulst et al., 2006).
1.Hum Reprod Update. Intrauterine insemination. ESHRE Capri Workshop Group.2009;15(3):265-277.

27. Pregnancy rates following IUI combined with ovarian stimulation using
either anti-estrogens or FSH.
In a meta-analysis of the remaining six trials involving 456 couples, the 5.7%
difference in pregnancy rates was not significant
1.Hum Reprod Update. Intrauterine insemination. ESHRE Capri Workshop Group.2009;15(3):265-277.

28.  Premature LH surges also occur in 25–30% of stimulated
IUI cycles and theoretically may interfere with timing of the
IUI or result in cancellation and more treatment failures
 Administration of a GnRH antagonist almost completely
abolishes premature luteinization but does not substantially
improve the pregnancy rate
 One of the consequences of the poor quality of the growing
follicle
1.Hum Reprod Update. Intrauterine insemination. ESHRE Capri Workshop Group.2009;15(3):265-277.

29.  Unexpected rise or surge of LH
 Too early & too late for IUI
 Improper timing of IUI may lead to lower pregnancy
rates
Benefits of agonist/ antagonist in IUI
 Controls LH surge and times ovulation better
 Proper synchronization with single IUI
 May be used to tide over a weekend

30. Unlike GnRH agonists, the antagonists do not
induce an initial hypersecretion of gonadotropins
but instead cause an immediate and rapid,
reversible suppression of gonadotropin secretion
The principal MOA of GnRH antagonists is competitive
occupancy of the GnRH-receptor
van Loenen AC, et al. Semin Reprod Med. 2002 Nov;20(4):349-64.

31. Cantineau & Cohlen, Cochrane Sys Rev, 2011, Issue 2, CD005356)

32. van Loenen AC, et al. Semin Reprod Med. 2002 Nov;20(4):349-64.

33. Fertil Steril. 2013 Nov;100(5):1373-80.
Iatrogenic disruptions in the hypothalamic-pituitary-
gonadal axis may occur during ovulation induction ,
manifested by a shortened luteal phase with low
concentrations of Progesterone.
As many as 20% of women undergoing gonadotropin-
stimulated ovulation induction experience luteal
phase defects.
Ultimately, alterations in the luteal phase create
suboptimal environments for blastocysts implantation
and maintenance of early pregnancy

34. Fertil Steril. 2009 Jun;91(6):2508-13

35. Fertil Steril. 2013 Nov;100(5):1373-80.
Luteal phase P
support improved
the likelihood of
clinical pregnancy and
live birth in IUI cycles
where ovulation
induction was
achieved with
gonadotropins

36. The time interval from the end of sperm processing to AIH-IUI is 20-39
minutes.
Washed sperms fertilize oocyte only within 2 to 3 hours from preparation
time
No sperm reservoir in cervical mucous in IUI, only forms after coitus for 48
hours or more

Editorial :J Obstet Gynecol India Vol. 59, No. 5 : September/October 2009 pg 407-409
Relationship between the time interval from semen collection to sperm wash and IUI
outcome Fertil Steril Vol 92, Issue 3, Supplement , Page S145, September 2009

37. WHO probit analysis of natural cycles:
Ovulation 24 to 56 hours after onset of LH surge
After hCG injection ovulation after 36 hours & is
sequential over several hours
Oocytes fertilizable within 12 -16 hrs of releaseTherefore best time of insemination appears 46 to 48 hours
post hCG trigger in absence starting of LH surge

38.  Over time, reference values for normal semen parameters have
changed
 Semen characteristics are highly variable among men, and are
not the sole determinants of a man’s fertility; (WHO Laboratory
Manual 5th edition, 2010)
WHO Laboratory Manual 1999 2010
Sperm conc. (× 106/mL) 20 15 (12 -16)
Total sperm number (106/ejaculate) 40 39 (33 – 46)
Total motility (PR + NP, %) - 40 (38 – 42)
Progressive motility (PR, %) 50 (a+b) or 25 (a) 32 (31 – 34)
Morphology (normal forms, %) 30 4 (3.0 – 4.0)

39.  > 1 million (7 studies): Makkar G et al, 2003, Ombelet W et al, 2003,
Saucedo de la Llata E et al, 2003, Lee VM et al, 2002, Ombelet W et al,
1997, Campana A et al, 1996, Horvath PM et al
 1 – 2 million (4 studies): De La Cuesta Benjumea R et al, 2008, Kdous M et
al, 2007, De La Cuesta R et al, 2004, Toner JP et al, 1995
 > 5 million (4 studies): Badawy A et al, 2009, Wainer R et al, 2004, Khalil
MR et al, 2001, Huang HY et al, 1996
Ombelet W et al, 2014

40. 5 RCT’s Swim up vs gradient Swim up vs wash
and centrifugation
Gradient vs wash
and centrifugation
Pregnancy rate 30.5% vs. 21.5% 22.2% vs. 38.1% 23.5% vs. 13.3%
Odds ratio OR 1.57 OR 0.41 OR 1.76
Confidence interval 95% CI 0.74 – 3.32) 95% CI 0.15 – 1.10 95% CI 0.57 – 5.44
Boomsma CM et al, Cochrane Sys Rev 2007, Issue 4, CD004507
Five RCTs (Dodson 1998; Xu 2000; Grigoriou 2005; Posada 2005; Soliman 2005) n = 262

41.  In IUI cycles for unexplained infertility OS appears to improve outcome in
terms of PR
 Significantly higher PR in IUI cycles seen with gonadotropin stimulation
compared to other drugs
 Addition of antagonist may improve outcome marginally by possibly better
timing of IUI
 Timing of IUI needs to be reviewed to optimize PR
 >5 million post wash MSC appears minimal requirement for successful IUI
 All methods of sperm wash show equal efficacy

42.  The goal of ovarian stimulation should be the development of a maximum of two
dominant follicles.
 Success rate of IUI is improved with an IMC above 1 million, a morphology score of more
than 4% normal forms, a TMCS of more than 5 million and an initial total motility of more
than 30%.
 In couples with cervical factor subfertility IUI in natural cycles significantly increases the
probability of conception while the combination of ovarian stimulation and IUI is
recommended in couples with unexplained subfertility.
 Double IUI results in higher pregnancy rates compared with single IUI in couples with male
factor subfertility, but not in unexplained infertility cases.
 The optimal time- interval between HCG injection and IUI seems between 12 and 36 h and
at least 10–15 min of immobilization should be applied after every insemination attempt
Middle East Fertility Society Journal 2013;18:74–7

43. When to start
treatment?
What order of
treatments is most
sensible?
When should the
couple shift to more
sophisticated and
costly treatment?
1.Hum Reprod Update. Intrauterine insemination. ESHRE Capri Workshop Group.2009;15(3):265-277.

44.  Unstimulated IUI: does not significantly increase pregnancy rates;
 CC/IUI: 5–7% pregnancy rate per cycle even after 7 cycles
 IUI/ovarian stimulation: modest effect and risks of multiple
pregnancy and OHSS;
 IUI/mild ovarian stimulation: the efficacy needs to be confirmed
by large studies;
 IVF: 7-fold higher likelihood of pregnancy (ESHRE Capri Workshop
Group, 2007);
 ICSI: is better that IVF only in couples with severe male infertility
1.Hum Reprod Update. Intrauterine insemination. ESHRE Capri Workshop Group.2009;15(3):265-277.

45.  Ovarian stimulation with IUI is a widely used, non-
invasive and relatively simple method of treatment for
a broad range of diagnostic categories.
 Success rates varies considerably and depends upon
age of the female partner, duration of infertility, sperm
quality and status of tubes.
 Its true place in terms of efficacy and cost
effectiveness is challenged and yet to be decided