Side effects of Letrozole usage Headache (6.9%) Nausea (6.3%) Peripheral edema (6.2%) Fatigue (5.2%) Hot flushes (5.2%) Skin reactions (3.4%)

1. 1
of Letrozole
Dr. Jyoti Agarwal

2. Over 300 ppts are available on
slideshare.net ***for use of public/Doctors
www.slideshare.net / Lifecarecentre

3. Side effects of Letrozole usage
Headache (6.9%)
Nausea (6.3%)
Peripheral edema (6.2%)
Fatigue (5.2%)
Hot flushes (5.2%)
Skin reactions (3.4%)

4. Concerns have
been raised
regarding the use of
letrozole for
ovulation induction,
as it might interrupt
the normal
aromatase function
in tissues during
early fetal
development and
can be potentially
teratogenic

5. Authors reported that the use of letrozole
for infertility treatment might be associated
with a higher risk of congenital cardiac
and bone malformations in the
newborn
Biljan MM, Hemmings R, Brassard N (2005) Fertil Steril 84
(Suppl 1.1)O–231
This issue was raised at an abstract presentation at
the Annual Meetng of the American Society for
Reproductive Medicine in 2005
Outcome of 130 babies following the Rx with Letrazole

6. Novartis Pharmaceuticals 2005
Issued a warning to
infertility clinics
asserting that the
company does not
advocate the use of
Letrozole for infertility
treatment

7. Issued a directive to suspend the use of
letrozole in infertile women with
immediate effect , citing concerns regarding
its safety
Ministry of Health and Family Welfare ,
GOI October, 2011

8. Is the use of letrozole to
induce ovulation teratogenic ?

9. The use of letrozole to induce ovulation
does not appear to be associated with
an apparent increased risk of major
congenital malformations in humans
Simerpal Kaur Gill, MSc, Myla Moretti, MSc, and Gideon Koren, MD FRCPC

10. 10
• It is an effective oral agent for this purpose
• It has no significant active metabolites
• Has a short half-life of approximately 45 hours
( 30–60 hrs)
• Is cleared from the body completely by the time
embryo implantation takes place
Letrozole has been used for ovarian
stimulation since the late 1990s

11. ASRM Meeting 2005
Biljan et al (2005)
‘compared 130 letrozole pregnancies with
over 36,000 low risk spontaneous
pregnancies’
Concluded
letrozole might increase the risk of cardiac and
bone anomalies in the newborns
Heterogeneity between the two groups

12. Concerns
Biljan et al (2005)
• A huge disparity between the sizes of the two study
groups (130 vs 36,000)
• basically high-risk population was compared with a
low-risk fertile population who had spontaneous
conception
• Age of the control population
• They reported malformation rate of 1.8% in the
“control” population appears to be low
Heterogeneity between the two groups

13. Tulandi T, et al. Fertil Steril. 2006 Jun;85(6):1761-5
Letrozole & congenital malformation risk

14. 514 newborns
conceived after LTZ
397 newborns
conceived after CC
911babies born between 2001 - 2005 to
mothers who received either LTZ or CC for 5 days
Tulandi T, et al. Fertil Steril. 2006 Jun;85(6):1761-5.
Congenital malformation
Deformations
Chromosomal abnormalities

15. 514

16. 16
CC & congenital malformation risk
397

17. Number of newborns with major malformations
Percent of newborns with malformations

18. Tulandi T, et al. Fertil Steril. 2006
• No difference in overall rates of major & minor
congenital malformations among newborns from
mothers who conceived after LTZ or CC treatments
• It also appears that congenital cardiac anomalies
are less frequent in LTZ group
• The concern that LTZ use for ovulation induction
could be teratogenic is unfounded based on this
data

19. Latest evidence...2017!
Tatsumi T, et al. Hum Reprod. 2017 Jan;32(1):125-132.

20. Retrospective
cohort study:
Data collated
from Japanese
National ART
Registry
80,000
(2011-2013)

21. Neonatal
outcomes
Preterm
delivery
Low birth
weight
Small/large for
gestational age
Tatsumi T, et al. Hum Reprod. 2017 Jan;32(1):125-132.
Outcome Measures
Pregnancy
outcomes
Miscarriage
Ectopic
pregnancy
Still birth
Congenital
anomalies
Major
Minor

22. Risk of miscarriage was significantly lower in LTZ group
Tatsumi T, et al. Hum Reprod. 2017 Jan;32(1):125-132.
26.4%
12.2%
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
Percentageof
miscarriage
p<0.001
aOR, 0.37, 95% CI, 0.30–0.47
Pregnancy outcome: Miscarriage
Natural
cycle
LTZ

23. Tatsumi T, et al. Hum Reprod. 2017 Jan;32(1):125-132.
Characteristic Natural cycle
(n=3136)
LTZ
(n=792)
Miscarriage 827 (26.4) 97 (12.2)*
Ectopic pregnancy 22 (0.70) 1 (0.13)
Pregnancy termination (before 20 weeks
of gestation)
11 (0.35) 1 (0.12)
Still birth (after 22 weeks of gestation) 12 (0.38) 3 (0.37)
Live birth 2264 (72.2) 690 (87.1)
Other Pregnancy outcomes
*p<0.001

24. Tatsumi T, et al. Hum Reprod. 2017 Jan;32(1):125-132.
Neonatal outcome

25. Tatsumi T, et al. Hum Reprod. 2017 Jan;32(1):125-132.
Congenital Anomalies

26. LTZ
stimulation
Reduces risk of
miscarriage
No increase in risk of
Major congenital
anomalies
Adverse pregnancy
outcomes
Adverse neonatal
outcomes
Concluded
Safest option for
mild ovarian
stimulation

27. “…it is the 1st study of such kind in
Asian subcontinent”
Sharma S, et al. PLoS ONE. 2014; 9(10): e108219

28.  Retrospective
study
 Babies born:
Jan 2007 & Dec
2011
 646
 Infertile women
between 21–35
years of age who
conceived
naturally or who
received: LTZ or CC
Sharma S, et a PLoS ONE. 2014; 28

29. Demographic details & birth weight
Characters Natural
conception
LTZ CC P
value
No. of newborns 171 201 251
Twins None 9 15 NS
Age of mother (years) 29.3  3.85 29.83 
3.73
29.84 
4.05
NS
Birth weight of
singleton newborn
(kg)
2.61  0.56 2.59 
0.41
2.50 
0.42
0.02

30. Structural
malformations
&
chromosomal
abnormalities
Natural
conception
5/171babies
(2.9%)
LTZ group
5 / 201 babies
(2.5%)
CC group
10 / 251 babies
(3.9%)
Sharma S, et al. PLoS ONE. 2014; 9(10): e108219
Congenital malformations

31. Congenital malformations found to be
comparable following natural conception,
LTZ & CC
Undue fear against LTZ
may be uncalled for
Key
Message
Concluded

32. Safety studies (2006 – 2017)

33. 33
Reference Patient
population
No of
patient
Conclusion
Tulandi T, et al.
Fertil Steril. 2006
Jun;85(6):1761-5.
Women
undergoing OI or
SO for timed
intercourse or
IUI
911 No difference in overall rates of major &
minor congenital malformations among
newborns from mothers who conceived after
LTZ or CC treatments
Tatsumi T, et al.
Hum Reprod.
2017
Jan;32(1):125-
132.
Women
undergoing
natural/LTZ
induced cycles
resulting in
pregancy after
FET
3928 LTZ stimulation reduces risk of miscarriage,
with no increase in risk of major congenital
anomalies or adverse pregnancy or neonatal
outcomes compared with natural cycles in
women undergoing ART. LTZ may be a safe
option for mild ovarian stimulation.
Sharma S, et al.
PLoS ONE. 2014;
9(10): e108219
Infertile women
who conceived
naturally or
undergoing OI
623 Congenital malformations found to be
comparable following natural conception, LTZ
& CC.
Forman R, et al. J
Obstet Gynaecol
Can 2007;29:668-
71.
Women
undergoing OI
430 No major congenital malformations in LTZ
group.

34. 34
Reference Patient
populatio
n
No of
patient
s
Conclusion
Dehbashi S, et al.
Iran J Med Sci
2009;34:23-8.
PCOS 100 No major congenital anomaly in LTZ group.
1 in CC (meningomyelocele). No minor
anomalies were observed in both groups.
Legro RS, et al. N
Engl J Med. 2014 Jul
10;371(2):119-29.
PCOS 750 Rates of neonatal complications (including
anomalies) were comparable between
groups. Overall birth-defect rate was similar.
Major congenital anomalies: LTZ 4; CC 1 (NS)
Banerjee Ray P, et
al. Arch Gynecol
Obstet. 2012
Mar;285(3):873-7.
PCOS 147 All babies delivered were healthy
without any known congenital
malformations.
Roy KK, et al. J Hum
Reprod Sci. 2012
Jan-Apr; 5(1): 20–25
PCOS 204 Congenital malformations found to be
comparable following natural conception, LTZ
& CC
Wu XK, et al. Fertil
Steril 2016;106:757-
765
PCOS 644 Two major congenital anomalies were
reported. One in LTZ (hydrocephalus,
terminated) another in LTZ/barberine
combination group (VSD+PS, infant death)

35. Reference No of
patients
Conclusion
Requena A, et al.
Hum Reprod Update.
2008 Nov-
Dec;14(6):571-82.
(Meta-analysis)
2573 No increase of congenital malformations among
offspring of mothers who conceived with letrozole
treatment for infertility.
Diamond MP, et al. N
Engl J Med
2015;373:1230-40.
900 No significant differences among groups in frequencies
of congenital anomalies or major fetal and neonatal
complications.
Letrozole use does not increase risk of
congenital anomalies in newborns
- Wang R, et al. BMJ. 2017; 356: j138.
According to current evidence

36. To summarise ……
• Better pregnancy outcome with LTZ
compared to CC in PCOS
• Effective even in patients with CC-
resistant PCOS
• Monofollicular development &
lower multiple pregnancies
• No anti-estrogenic effects on
endometrium & cervical mucus
• Lower cycle cancellation & risk of
hyperstimulation
Today safety
of LTZ is well
established
in clinical
studies

37. 37
Feb 2017

39. ADDRESS
11 Gagan Vihar, Near
Karkari Morh Flyover,
Delhi - 51
CONTACT US
9650588339
9599044257
011-22414049
WEBSITE :
www.lifecareivf.in
www.lifecarecentre.in
www.lifecareabs.in
ISO 14001:2004 (EMS)
…..Caring hearts, healing hands
ISO 9001:2008
Helpline : 9599044257
Web.www.lifecareivf.in
Helpline : 9910081484
26
Year
In
your
service