Invited Lecture in Hands-on IUI Workshop by Genome Fertility Centre in September 2018 at Kolkata

1. Role of IUI in the Era of IVF
Sujoy Dasgupta
MBBS (Gold Medalist, Hons)
MS (OBGY- Gold Medalist)
DNB (OBGY)
MRCOG (London)
Consultant, Reproductive Medicine, Genome: The Fertility Centre, Kolkata

2. Will you do IUI

3. NICE

4. IUI is beneficial undoubtedly in

6. Donor IUI
• obstructive azoospermia
• non-obstructive azoospermia
• severe deficits in semen quality in couples who do not wish to
undergo ICSI.
Donor insemination should be considered in conditions such as:
• where there is a high risk of transmitting a genetic disorder to the
offspring
• where there is a high risk of transmitting infectious disease to the
offspring or woman from the man
• severe rhesus isoimmunisation

7. Controversy

8. Bhattacharya S, Harrild K, Mollison J, Wordsworth S, et al. Clomifene citrate
or unstimulated intrauterine insemination compared with expectant
management for unexplained infertility: pragmatic randomised controlled
trial. BMJ. 2008 Aug 7;337:a716.
Compared with expectant management, the odds ratio
for a live birth was 0.79 (95% confidence interval 0.45 to
1.38) after clomifene citrate and 1.46 (0.88 to 2.43) after
unstimulated intrauterine insemination.
More women randomised to clomifene citrate (159/170,
94%) and unstimulated intrauterine insemination
(155/162, 96%) found the process of treatment
acceptable than those randomised to expectant
management (123/153, 80%) (P=0.001 and P<0.001,
respectively).

9. • arguments based on a single randomized
controlled trial (Bhattacharya et al., 2008) that
yielded an IUI pregnancy rate of 6% per cycle
compared with the mean pregnancy rate of
13% per IUI cycle reported in the UK for the
same time period (NICE guidelines, 2013;
HFEA website, 2015).

10. HFEA website
• UK, 2011 Data
IUI 48141 Women
treated
27.2% per woman
IVF 61726 cycles done 22.1% per cycle
ET 89648 embryos
transferred
15.3% per embryo
transfer

11. • A major assumption within NICE was that stimulated IUI cycles
increased multiple births
• The absolute rate of multiple pregnancies is 0.3% after
monofollicular, and 2.8% after multifollicular, growth van Rumste
MM, et al. Hum Reprod Update. 2008 Nov-Dec;14(6):563-70.
• While the risk for multiple births for IUI with 2-3 follicles has to be
much less than if 2-3 embryos were transferred in an IVF cycle, no
comparative study exists to answer this question of relative risk
between matched follicles and embryos during treatment (van
Rumste et al., 2008).
• Shifting from a unifollicular to bifollicular IUI cycles will potentially
increase the chance of achieving an IUI pregnancy by 3.4-fold
Tomlinson MJ, et al. Prognostic indicators for intrauterine
insemination (IUI): statistical model for IUI success. Hum Reprod.
1996 Sep;11(9):1892-6.

12. Veltman-Verhulst SM, Hughes E, Ayeleke RO, et al. Intra-uterine
insemination for unexplained subfertility. Cochrane Database Syst Rev.
2016;2:CD001838.
• stimulated cycle IUI comparing with IUI in a
natural cycle, a significant increase was found in
pregnancy rate per couple (415 women; OR 2.33,
95 %CI 1.46–3.71) in favour of stimulated cycle.
• A live birth rate (LBR) of 11.0 % (14/127) for
stimulated IUI compared to 2.2 % (4/184) for EM
was recorded giving an odds ratio of 5.6 (95 %
confidence interval 1.8–17.4) in favour of
superovulation and IUI.

13. • The pregnancy rates can be even higher if
most cycles were performed with 2 follicles
using hMG which also allows for a greater
thickness in the endometrium compared to CC
cycles.
• needs to be a strict cancellation policy if >3
mature follicles are present to minimise
multiple births.

14. Bahadur G, 2015
• 184 cycles with 109 women gave a pregnancy
rate of 20.1% per cycle, such that 34% of
women could expect a pregnancy.
• Furthermore, of women aged ≤35 years, 39%
of the cohort became pregnant.

16. Timing of Insemination
• little evidence-based information exists to decipher
what is critical for an optimal success rate, so it is
rather surprising that few studies were designed to find
the optimal time for insemination
• In the majority of studies, IUI is done 32–36 h following
hCG administration
• In one pilot study it appears that optimal time post-
hCG trigger for a pregnancy was 30 hour.
Bahadur G, Almossawi O, IIlahibuccus A, Al-Habib A,
Okolo S. Factors leading to pregnancies in stimulated
IUI cycles and the use of consecutive ejaculations
within a small clinic environment. JOGI. 2016

17. Timing Of Insemination
Fixed protocol
Single planned insemination: 36-38 hrs post hCG
Double insemination:
1st : 24 hrs. post hCG
2nd : 48 hrs. post-hCG
Variable protocol:
TVS 36 h post hCG:- Ovulated  single IUI
Not Ovulated  IUI at once
 IUI 24 hrs later

18. Exact timing of IUI
Conclusion:Postponing IUI until observation of follicle rupture
may yield a higher pregnancy rate.(25% Vs 8%)
(Kucuk ,2008).

19. No difference in PR between single vs double
Cantinaeu AE Cochrane 2009, Polyzos 2010
An exception suggested is if the TMC is less than 1 million
on insemination day, a second IUI can be offered within
the next 24 hours
Double vs single IUI

20. Mohamad E. Ghanem et al.,Human Reproduction, Vol.0, No.0 pp. 1–
8, 2010
The study included a total 1146 first-stimulated cycles in infertile couples due to
male factor, anovulation or unexplained infertility.
Conclusion: Single IUI timed post-ovulation gives a better CPR when
compared with single pre-ovulation IUI for non-male infertility whereas for
male factors, pre-ovulation, double IUI gives a better CPR when compared
with single IUI.

21. Reproductive BioMedicine Online (2014) 28, 300–
309
• Double Insemination significantly improves
the chance of pregnancy in male factor
subfertility

22. Diameter of leading follicle
• Data suggest that the pregnancy-related
diameter of the leading follicle in CC cycles is
significantly larger than that in gonadotropin
cycles
• The best time for hCG trigger in the CC cycle is
when the leading follicle reaches 20 mm,
whereas in hMG cycles 18 mm appears
optimal

23. Unexplained Subfertility
• Women assigned to IUI had a higher cumulative
livebirth rate than women assigned to expectant
management (risk ratio [RR] 3·41, 95% CI 1·71-6·79;
p=0·0003).
• Farquhar CM, Liu E, Armstrong S, Arroll N, Lensen S,
Brown J. Intrauterine insemination with ovarian
stimulation versus expectant management for
unexplained infertility (TUI): a pragmatic, open-label,
randomised, controlled, two-centre trial. Lancet. 2018
Feb 3;391(10119):441-450.

24. Unexplained Subfertility

25. Poor Ovarian reserve
Any 2 out of 3
• Advanced maternal age (≥40 years) or any
other risk factor for POR
• A previous POR (≤3 oocytes with a
conventional stimulation protocol)
• An abnormal ORT (i.e. AFC, 5–7 follicles or
AMH, 0.5–1.1 ng/ml)

26. IUI in POR

27. • As the pregnancy rates difference between
both groups was not statistically significant
the conversion to IUI could be considered a
useful substitute to the oocyte retrieval
procedure in the poor responder cases.

28. Age <35yrs 35-37 yrs 38-40yrs 41-42yrs >42yrs
No. of
cycles
2351 947 614 160 120
Success
rate
10.1% 8.2% 6.5% 3.6% 0%
*IUI seems to be a poor treatment option for women over 40 years of age
Dovey S et al,2008
Old Age

29. IUI in Male factor
• A total motile sperm count of 10 million may
be a useful threshold value for decisions
regarding the treatment of a couple with IUI
or IVF
• although 5 million is widely accepted
• The use of ‘consecutive ejaculate’ is a new
concept in overcoming male factor problems
in IUI.

30. • obtaining a second semen sample when the
motile sperm yield of the first semen sample
is 1 million to 5 million significantly increases
the total motile sperm count in the final
inseminate.

31. TMSC and motility– cut offs
TMSC PR/CYCLE
 10–20 million 18.29%
 5–10 million 5.63%
 <5million 2.7%
 TMSC should be 5-10 million
 If less than 5 million counsel and do IUI
(Guven et al, 2008;Abdelkader & Yeh)2009)

33. Endometriosis

34. Tubal Patency Checking before IUI
• Before starting treatment by donor insemination,
it is important to confirm that the woman is
ovulating.
• Women with a history that is suggestive of tubal
damage should be offered tubal assessment
before treatment.
• Women with no risk factors in their history
should be offered tubal assessment after 3
cycles if treatment by donor insemination has
been unsuccessful. (NICE, 2013)

35. IUI in Tube Block
• B/L- No
• U/L- ?

36. Berker B, Şükür YE, et al. Impact of unilateral tubal blockage diagnosed by
hysterosalpingography on the success rate of treatment with controlled
ovarian stimulation and intrauterine insemination. J Obstet Gynaecol. 2014
Feb;34(2):127-30.
• In conclusion, IVF
instead of IUI may
be a more
appropriate
approach for distal
unilateral tubal
blockage patients.
CPR after 3
cycles of IUI
U/L tube
block
26.3% P = 0.043
Unexplained
Infertility
44.7%
Proximal tube
block
38.1% P = 0.572
Distal tube
block
11.7% P= 0.01

37. Hydrosalpinx
• Within the group of women with mid-distal tubal
occlusion, the cumulative PR was similar between
those with and without hydrosalpinx or sactosalpinx
(1/7 or 14.3% versus 3/14 or 21.4%, respectively;
P=.694).

38. Male Sexual Dysfunction
• Erectile Dysfunction
• Retrograde Ejaculation
• Spinal Cord Injury

39. Female Sexual Dysfunction
• Vaginugmus
• Superficial Dysparaeunia

40. Sero-discordant couple
1. the man is compliant with highly active antiretroviral therapy (HAART)
2. the man has had a plasma viral load <50 copies/ml for >6 months
3. there are no other infections present
4. unprotected intercourse is limited to the time of ovulation.

41. Sero-discordant couple
1. the man is compliant with highly active antiretroviral therapy (HAART)
2. the man has had a plasma viral load <50 copies/ml for >6 months
3. there are no other infections present
4. unprotected intercourse is limited to the time of ovulation.
when all of the above
criteria are met
 Advise couples that the risk of HIV transmission to the female
partner is negligible through unprotected sexual intercourse
 Advise couples that, sperm washing may not further reduce the
risk of infection and may reduce the likelihood of pregnancy.
 If couples still perceive an unacceptable risk of HIV transmission
after discussion with their HIV specialist, consider sperm washing.
 Inform couples that there is insufficient evidence to recommend
that HIV negative women use pre-exposure prophylaxis

42. Sero-discordant couple
The man is HIV positive
and either not compliant
with HAART or viral load
≥50 copies/ ml
 offer sperm washing.
 Inform couples that sperm washing reduces, but does not
eliminate, the risk of HIV transmission.

43. Hepatitis B and Hepatitis C
• Do not offer sperm washing

44. Sperm Wash-IUI interval
• Exhaustion of energy sources in the sperm-washing
medium by the motile spermatozoa
• Premature (in vitro) capacitation of washed motile
spermatozoa

45. How many cycles?
 Pregnancies resulting from IUI occur during the first
3-6 treatment cycles (Morshedi et al,2003, Dickey et al
2002).
most women conceive after 4-6 cycles of IUI
cycle fecundability declines by ½ to 2/3 thereafter
(Khalil MR et al.; Acta Obstet Gynaecol Scand. 2001
Jan, 80(1): 74-81)

46. Endometrial Scratching in IUI
Endometrial scratching is useful in increasing pregnancy rates after failed
previous intra uterine insemination trials when it is performed in the mid
proliferative phase.

47. After IUI
• Bed rest
• Coitus
• Luteal Support

48. • The ongoing pregnancy rate per couple was not
found to be superior in the immobilization group
than in the immediate mobilization group
(relative risk 0.81; 95% CI [0.63, 1.02], risk
difference: −7.8%, 95% CI [−16.4%, 0.8%]).
• No difference was found in miscarriage rate,
multiple gestation rate, live birth rate and time to
pregnancy between the groups.

49. • Based on the study results available in the
literature, it appears to be beneficial to
supplement the luteal phase in gonadotropin-
stimulated IUI cycles that yield more than one
follicle.

50. • There were no differences in basic characteristics between two groups.
• Biochemical and clinical pregnancy were parallel in the study and control
groups.
• There were no statistically significant increases in abortion rate between
the study groups (P=0.49).
• Luteal phase support by progesterone suppository does not improve the
pregnancy rate of stimulated IUI cycles.

51. Take Home Messages
• IUI still have role in helping many infertile
couples to conceive
• Pocket-friendly, noninvasive, simple,
acceptable, effective
• Best results are obtained in mild male factor
subfertility and unexplained subfertility
• Needs further studies on many aspects