Letrozole versus clomiphene citrate in polycystic ovary syndrome: systematic review and meta-analysis

Abstract

The objective of the present systematic review and meta-analysis was to examine the literature and to identify the results of randomized controlled trials (RCTs) comparing the use of letrozole to clomiphene citrate (CC) for ovulation induction in patients with polycystic ovary syndrome (PCOS). An exhaustive electronic literature search was performed using the MEDLINE and EMBASE databases until October 2014. Seven prospective RCTs comparing the use of letrozole to CC in PCOS patients met the inclusion criteria. Overall, the seven included studies accounted for 1833 patients (906 in the letrozole group and 927 in the CC group) and for 4999 ovulation induction cycles (2455 in the letrozole group and 2544 in the CC group). Five of the included studies reported data on live birth rates. There was a statistically significant increase in the live birth and pregnancy rates in the letrozole group when compared to the CC group, with a relative risk (RR) = 1.55 (95% confidence interval (CI): 1.26-1.90; I(2)( )= 0%) and RR = 1.38 (95% CI: 1.05-1.83; I(2)( )= 61%), respectively. There were no differences in the multiple pregnancy, miscarriage and ovulation rates between the two groups. Our study found that letrozole is superior to CC when considering the live birth and pregnancy rates in patients with PCOS.

Full text

Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=igye20
Download by: [Matheus Roque] Date: 23 November 2015, At: 09:09
Gynecological Endocrinology
ISSN: 0951-3590 (Print) 1473-0766 (Online) Journal homepage: http://www.tandfonline.com/loi/igye20
Letrozole versus clomiphene citrate in polycystic
ovary syndrome: systematic review and meta-
analysis
Matheus Roque, Ana C. I. Tostes, Marcello Valle, Marcos Sampaio & Selmo
Geber
To cite this article: Matheus Roque, Ana C. I. Tostes, Marcello Valle, Marcos Sampaio & Selmo
Geber (2015): Letrozole versus clomiphene citrate in polycystic ovary syndrome: systematic
review and meta-analysis, Gynecological Endocrinology, DOI: 10.3109/09513590.2015.1096337
To link to this article: http://dx.doi.org/10.3109/09513590.2015.1096337
Published online: 19 Oct 2015.
Submit your article to this journal
Article views: 162
View related articles
View Crossmark data

http://informahealthcare.com/gye
ISSN: 0951-3590 (print), 1473-0766 (electronic)
Gynecol Endocrinol, Early Online: 1–5
!2015 Taylor & Francis. DOI: 10.3109/09513590.2015.1096337
REVIEW ARTICLE
Letrozole versus clomiphene citrate in polycystic ovary syndrome:
systematic review and meta-analysis
Matheus Roque
1
, Ana C. I. Tostes
1
, Marcello Valle
1
, Marcos Sampaio
2
, and Selmo Geber
2,3
1
Origen–Center for Reproductive Medicine, Av Rodolfo de Amoedo, 140, Barra da Tijuca, Rio de Janeiro, Brazil,
2
Origen–Center for Reproductive
Medicine, Av do Contorno, 7747, Lourdes, Belo Horizonte, Brazil, and
3
Universidade Federal de Minas Gerais, Avenida Alfredo Balena, 190,
Belo Horizonte, Brazil
Abstract
The objective of the present systematic review and meta-analysis was to examine the literature
and to identify the results of randomized controlled trials (RCTs) comparing the use of letrozole
to clomiphene citrate (CC) for ovulation induction in patients with polycystic ovary syndrome
(PCOS). An exhaustive electronic literature search was performed using the MEDLINE and
EMBASE databases until October 2014. Seven prospective RCTs comparing the use of letrozole
to CC in PCOS patients met the inclusion criteria. Overall, the seven included studies accounted
for 1833 patients (906 in the letrozole group and 927 in the CC group) and for 4999 ovulation
induction cycles (2455 in the letrozole group and 2544 in the CC group). Five of the included
studies reported data on live birth rates. There was a statistically significant increase in the live
birth and pregnancy rates in the letrozole group when compared to the CC group, with a
relative risk (RR) ¼1.55 (95% confidence interval (CI): 1.26–1.90; I
2
¼0%) and RR ¼1.38 (95% CI:
1.05–1.83; I
2
¼61%), respectively. There were no differences in the multiple pregnancy,
miscarriage and ovulation rates between the two groups. Our study found that letrozole is
superior to CC when considering the live birth and pregnancy rates in patients with PCOS.
Keywords
Clomiphene citrate, letrozole, PCOS
History
Received 8 May 2015
Accepted 16 September 2015
Published online 15 October 2015
Introduction
Polycystic ovary syndrome (PCOS) affects 5–10% of women of
reproductive age and is considered the most common cause of
ovulatory dysfunction [1]. The syndrome is related to a complex
reproductive–metabolic disorder and is diagnosed on the basis of
hyperandrogenism, oligomenorrhea and polycystic ovaries on
ultrasonography [2,3]. In 2003, experts held a meeting and they
arrived at a consensus regarding the diagnosis of PCOS [4,5].
Various treatments were proposed for infertile women with PCOS;
however, the optimal treatment option has yet to be defined.
Clomiphene citrate (CC) remains the first-line pharmacological
treatment for ovulation induction in most patients with PCOS [1].
CC is an antiestrogenic drug, and it has been used for over 40
years as an ovulatory inductor [6]. In around 15–20% of patients,
anovulation persists even after standard CC therapy and is defined
as CC resistance [7,8]. Furthermore, the antiestrogenic effects of
CC may be related to some adverse effects over the endometrium
and cervical mucus that may decrease the pregnancy rates [9].
The patients that failed to respond to CC, and the adverse effects
of CC over the endometrium, have encouraged the research of an
alternative ovulation inductor [10].
Letrozole is an aromatase inhibitor that was originally used for
the treatment of breast cancer. It was first described as an
ovulation inductor in 2001 in anovulatory women who failed to
ovulate with the use of CC, or those who ovulated but did not
conceive because of an endometrial thickness 56 mm [11].
Letrozole inhibits estrogen production by inhibiting the enzyme
aromatase, which is responsible for the conversion of androgens
to estrogens. It has been found to inhibit estrogen levels by at least
97–99% [12]. With this inhibitory effect, it avoids estrogenic-
based negative feedback in the hypothalamus and increases
follicle-stimulating hormone (FSH) secretion by the pituitary. It
still increases follicular sensitivity to FSH, as there is an
accumulation of androgens in the ovary [13]. As an ovulation
inductor, it is an off-label drug that is generally prescribed
for 5 days at the beginning of the follicular phase at doses of
2.5–7.5 mg/day [14].
The purpose of the present systematic review and meta-
analysis was to examine the literature and identify the results
of randomized controlled trials (RCTs) comparing the
use of letrozole to CC for ovulation induction in patients with
PCOS.
Materials and methods
Given that this was a systematic review and meta-analysis, and
that it did not involve any interventions in humans, the study was
exempt from institutional review board approval. To report the
results of this meta-analysis, we utilized the preferred reporting
items for systematic reviews and meta-analysis (PRISMA)
statement [15].
Search strategy
An exhaustive electronic search was performed using the
MEDLINE and EMBASE databases until October 2014.
Address for correspondence: Matheus Roque, ORIGEN–Center for
Reproductive Medicine, Avenida Rodolfo de Amoedo, 140, Barra da
Tijuca, Rio de Janeiro, Brazil. Tel: +55 21 21285351. Fax: +55 21
21285352. E-mail: matheusroque@hotmail.com
Downloaded by [Matheus Roque] at 09:09 23 November 2015

We also searched among the references of the identified
articles and we restricted the search to articles published in
English. The search combined relevant terms and descriptors
related to PCOS, anovulation, ovulation induction, clomiphene
citrate, letrozole, aromatase inhibitors and randomized controlled
trials.
Eligibility criteria and data extraction
The review included only RCTs of women with PCOS diagnosed
by fulfilling the Rotterdam 2003 criteria [4,5], those who
submitted to ovulation induction with CC versus letrozole, those
with no previous ovulation induction treatment and those without
any drugs associated with CC or letrozole. The selection criteria
are described in Table 1. In a first screening, two independent
authors (A.C.I.T; M.R.) assessed all of the abstracts retrieved
from the search, and they then obtained the full manuscripts of the
citations that met the inclusion criteria. These authors evaluated
the studies’ eligibility and quality, and they subsequently extracted
the data. Any discrepancies were solved by agreement and, if
needed, they reached consensus with a third author (S.G.). We
extracted the outcome results of women randomized in an
intention-to-treat analysis.
Outcome measures
The primary outcome of interest for this systematic review was
the live birth rate per woman randomized. The secondary
outcomes included ovulation rate per cycle, clinical pregnancy
rate per woman randomized, miscarriage rate and multiple
pregnancy rates. Clinical pregnancy was defined by the observa-
tion of a fetal heart beat by 7 weeks of gestation. Miscarriage
included any pregnancy that did not become an ongoing
pregnancy.
Risk of bias assessment
We followed the guidance suggested by the Cochrane
Collaboration [16] to assess the risk of bias from the included
studies. We evaluated sequence generation, allocation conceal-
ment, blinding and incomplete outcome data for each trial
included in the review. A low risk of bias was considered when a
judgment of ‘‘yes’’ for all domains was obtained, whereas a high
risk of bias was considered when a judgment of ‘‘no’’ for one or
more domains was obtained. An unclear risk of bias was defined
when an ‘‘unclear’’ judgment in any domain was considered. The
quality assessment of the included trials is shown in Table 2 of
Supplementary material.
Analysis
We pooled the data of the dichotomous outcomes from the
original studies to obtain the relative risk (RR) for the occurrence
of an outcome event and presented their corresponding 95%
confidence intervals (CIs). We used the intention-to-treat analysis
principles to extract the event data. Statistical significance was set
at p50.05. To quantify statistical heterogeneity, we used the I
2
statistic in order to describe the variations across trials that were
due to heterogeneity and not to sampling error. We pooled the
outcome data from each study using a Mantel–Haenszel model
and applied the fixed-effects model. When the heterogeneity was
greater than 50% (I
2
450%), we applied the random-effects model
[17]. We used the Review Manager 5 software (The Nordic
Cochrane Centre, The Cochrane Collaboration, Copenhagen,
Denmark) to conduct the meta-analysis.
Results
Our electronic search retrieved 232 articles. After screening the
titles and abstracts, one or both reviewers determined that 10
articles were eligible for inclusion. Among these, three articles
were excluded. One of them included patients that were resistant
to CC at a dose of 100 mg/day [18], and the other two included
patients who submitted to intrauterine insemination [19,20]. The
complete selection process is depicted in Figure 1.
Seven prospective RCTs comparing the use of letrozole to CC
in patients with PCOS met the inclusion criteria. Overall, the
seven included studies accounted for 1833 patients (906 in the
letrozole group and 927 in the CC group) and for 4999 ovulation
induction cycles (2455 in the letrozole group and 2544 in the CC
group). The characteristics of the studies included in this review
are found in Table 3 of Supplementary material.
Outcomes
Live birth rate per woman randomized
Five of the included studies reported data on the live birth rate
[3,21–24]. There was a statistically significant increase in the live
birth rate in the letrozole group when compared to the CC group
(RR ¼1.55; 95% CI: 1.26–1.90; I
2
¼0%) (Figure 2a).
Pregnancy rate per woman randomized
All seven included studies reported data on the pregnancy rate
[3,21–26]. There was a statistically significant increase in the
pregnancy rate in the letrozole group when compared to the CC
group (RR ¼1.38; 95% CI: 1.05–1.83; I
2
¼61%), which was
evaluated by the random-effects model due to the higher
heterogeneity rate observed among the studies (Figure 2b).
Table 1. Selection criteria of included studies (PICOS).
Included Excluded
Population * Patients diagnosed with PCOS by the Rotterdam criteria, without
tubal factor infertility and normal semen analysis
AND
* those that had never been exposed to any treatment for infertility
(therapy naı
¨ve)
* Proposed treatment: ovulation induction with timed intercourse
* Patients without a diagnosis of PCOS
* Infertility of unknown cause
* CC resistance
* Intrauterine insemination
Intervention * Any dose of letrozole * Placebo or another aromatase inhibitor
* Association of drugs to letrozol
Comparison * Any dose of CC * Association of drugs to CC
Outcomes * Primary: live birth rate per woman randomized
* Secondary: pregnancy rate, ovulation rate, miscarriage rate,
multiple pregnancy rate
Study type RCTs Not RCT
2M. Roque et al. Gynecol Endocrinol, Early Online: 1–5
Downloaded by [Matheus Roque] at 09:09 23 November 2015

Multiple pregnancy rates per woman randomized
There were six studies that evaluated the multiple pregnancy rates
between the two groups [3,21,22,24–26]. There was no statistic-
ally significant difference between the two groups when
comparing the multiple pregnancy rates (RR ¼0.43; 95% CI:
0.17–1.06; I
2
¼0%) (Figure 3a, supplementary material).
Miscarriage rate per woman randomized
There were six studies that evaluated the multiple pregnancy rates
between the two groups [3,21–24,26]. There was no statistically
significant difference between the two groups when comparing
the miscarriage rates (RR ¼1.43; 95% CI: 0.98–2.06; I
2
¼0%)
(Figure 3b, supplementary material).
Figure 1. Flowchart for trial identification
and selection process.
Figure 2. Forest plot – Letrozole versus CC – (a) Live birth rate; (b) Pregnancy rate.
DOI: 10.3109/09513590.2015.1096337 Letrozole versus CC 3
Downloaded by [Matheus Roque] at 09:09 23 November 2015

Ovulation rate per cycle
All seven included studies reported data on the ovulation rate
[3,21–26]. There was no statistically significant difference in the
ovulation rates when comparing the letrozole and CC groups
(RR ¼1.15; 95% CI: 0.98–1.34; I
2
¼89%); this was evaluated by
the random-effects model due to the higher heterogeneity
observed among the studies (Figure 3c, supplementary material).
Discussion
Although CC is still the first-line treatment for patients with
PCOS, this systematic review and meta-analysis showed that the
use of letrozole for ovulation induction followed by timed
intercourse in patients with PCOS significantly improved the live
birth and pregnancy rates when compared to CC. These findings
are important because previous recent meta-analyses did not show
differences in these outcomes when comparing the two drugs
[6,9,13], and these results are in accordance to another recent
published study [27]. Our study was specifically designed for
evaluating letrozole (no other aromatase inhibitors were included
in the analysis) compared to CC for ovulation induction without
any other intervention. The search strategy was different from the
Franik et al. [27]. Thus, there are different studies included in the
analysis when compared to Franik et al.
Three of the five studies included in this meta-analysis that had
evaluated live birth rates [3,23,24] were published after 2012, and
these studies had a weight of 89% in the live birth analysis. We
found a statistically significant increase in the live birth rates in
patients in the letrozole group (RR ¼1.55; 95% CI: 1.26–1.90),
and although there was no heterogeneity among the studies
(I
2
¼0), one study alone [3] was responsible for 58% of the
included patients. Our results differed from those of the study by
Misso et al., which did not show differences in the live birth rates
between the letrozole and CC groups. When considering the
pregnancy rates, all seven studies [3,21–26] included in this meta-
analysis evaluated this outcome and we found a statistically
significant increase in these rates, favoring the letrozole group
(RR ¼1.38; 95% CI: 1.05–1.83). This analysis was performed
using random-effects modeling due the high heterogeneity
(I
2
¼61%) observed among the studies. The weight of the studies
included in the analysis was better distributed, with the highest
weight attributed to the Badawy et al. study (24.1%) [26]. This
finding is contrary to those of two previous meta-analyses [9,6],
which did not show differences in the pregnancy rates between the
letrozole and CC groups. There were also no differences in the
multiple pregnancy and miscarriage rates among the groups,
which is in accordance with the literature.
As we did not find differences in the ovulation rates per cycle
when comparing the letrozole and CC groups (RR ¼1.15; 95%
CI: 0.98–1.34), we hypothesized that these improved live birth
and pregnancy rates observed among the patients that used
letrozole would be explained by differences in the pharmaco-
dynamics between the two drugs, as well as by the differential
alterations in endometrial gene expression. The half-life of
letrozole is 45 h [12] and it features rapid clearance, preventing
accumulation of the drug with repeated cycles. This is in contrast
to CC, which has a longer plasma and tissue retention time
(plasma levels are measurable up to 1 month after a single 50 mg
dose of CC) [28], leading to prolonged depletion of the estrogen
receptors. This depletion may lead to the development of adverse
effects, such as endometrial thinning as well as poor quality and
quantity of the cervical mucus [10]. There are numerous proteins
that can be used as biomarkers of endometrial receptivity (ER),
and integrin is one of the most well-established markers of ER
[29]. Some previous studies have shown that letrozole might
improve integrin expression, resulting in improvements in
ER [30]. Furthermore, letrozole may increase the gene expression
of some important genes during implantation, improving the
results of women undergoing ovulation induction with this drug
rather than CC [31].
There is great concern about the safety of letrozole for
ovulation induction. This concern was raised during an oral
presentation at an American Society for Reproductive Medicine
meeting in 2005, as findings regarding its safety were based on a
small number of newborns conceived after ovulation induction
with letrozole, either alone or in combination with gonadotropin
[32]. However, several studies have shown that there are no
increases in congenital or cardiac malformations when comparing
letrozole to CC [3,33–36]. In fact, recent studies showed that there
is an increase in cardiac malformations and birth defects in
newborns conceived after mothers use CC [37,38]. Only one of
the studies included in this meta-analysis [3] evaluated fetal
anomalies and malformations in newborns conceived after the use
of letrozole or CC, and the authors did not find any differences
between the two groups. Although there is increasing evidence
about the effectiveness of letrozole for treating patients with
PCOS, at this moment, it cannot be considered the first-line
treatment for these patients. It is necessary more studies
evaluating the letrozole effectiveness related to PCOS phenotype
and genetic differences [39].
In conclusion, our study found that letrozole is superior to CC
when considering the live birth and pregnancy rates in patients
with PCOS. The findings of this meta-analysis and the factors
discussed herein should encourage the performance of more RCTs
and enforce discussions about the treatments available for patients
with PCOS.
Acknowledgements
English-language editing of this manuscript was provided by Journal
Prep.
Declaration of interests
The authors report no conflicts of interest.
References
1. The Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus
Workshop Group. Consensus on infertility treatment related to
polycystic ovary syndrome. Fertil Steril 2008;89:505–22.
2. Meirow D, Laufer N, Schenker JG. Ovulation induction in polycystic
ovary syndrome: a review of conservative and new treatment
modalities. Eur J Obstet Gynecol Reprod Biol 1993;50:123–31.
3. Legro RS, Brzysli RG, Diamond MP, et al. Letrozole versus
clomiphene for infertility in the polycystic ovary syndrome. N Engl J
Med 2014;371:119–29.
4. The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus
Workshop Group. Revised 2003 consensus on diagnostic criteria
and long-term health risks related to polycystic ovary syndrome.
Fertil Steril 2004;81:19–25.
5. The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus
Workshop Group. Revised 2003 consensus on diagnostic criteria
and long-term health risks related to polycystic ovary syndrome
(PCOS). Hum Reprod 2004;19:41–7.
6. Misso ML, Wong JLA, Teede HJ, et al. Aromatase inhibitors for
PCOS: a systematic review and meta-analysis. Hum Reprod Update
2012;18:301–12.
7. Franks S, Adams J, Mason H, Polson D. Ovulatory disorders in
women with polycystic ovary syndrome. Clin Obstet Gynecol 1985;
12:605–32.
8. Kurabayashi T, Suzuli M, Fujita K, et al. Prognostic factors for
ovulatory response with clomiphene citrate in polycystic ovary
syndrome. Eur J Obstet Gynecol Reprod Biol 2006;126:201–5.
4M. Roque et al. Gynecol Endocrinol, Early Online: 1–5
Downloaded by [Matheus Roque] at 09:09 23 November 2015

9. He D, Jiang F. Meta-analysis of letrozole versus clomiphene citrate
in polycystic ovary syndrome. Reprod Biomed Online 2011;23:
91–6.
10. Casper RF, Mitwally MF. A historical perspective of aromatase
inhibitors for ovulation induction. Fertil Steril 2012;98:1352–5.
11. Mitwally MF, Casper RF. Use of an aromatase inhibitor for
induction of ovulation in patients with an inadequate response to
clomiphene citrate. Fertil Steril 2001;75:305–9.
12. Pavone ME, Bulun SE. Clinical review: the use of aromatase
inhibitors for ovulation induction and superovulation. J Clin
Endocrinol Metab 2013;98:1838–44.
13. Requena A, Herrero J, Landeras J, et al. Reproductive
Endocrinology Interest Group of Spanish Society of Fertility. Use
of letrozole in assisted reproduction: a systematic review and meta-
analysis. Hum Reprod Update 2008;14:571–82.
14. Pritts E. Letrozole for ovulation induction and controlled ovarian
hyperstimulation. Curr Opin Obstet Gyn 2010;22:289–94.
15. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting
items for systematic reviews and meta-analyses: the PRISMA
statement. BMJ 2009;339:332–9.
16. Higgins JPT, Green S. Cochrane handbook for systematic reviews of
interventions version 5.1.0. London: The Cochrane Collaboration;
2011.
17. Higgins JP, Thompson SG, Deeks JJ, Altmann DG. Measuring
inconsistency in meta-analyses. BMJ 2003;327:557–60.
18. Begum MR, Ferdous J, Begum A, Quadir E. Comparison of efficacy
of aromatase inhibitor and clomiphene citrate in induction of
ovulation in polycystic ovarian syndrome. Fertil Steril 2009;92:
853–7.
19. Zeinalzadeh M, Basirat Z, Esmailpour M. Efficacy of letrozole in
ovulation induction compared to that of clomiphene citrate in
patients with polycystic ovarian syndrome. J Reprod Med 2010;55:
36–40.
20. Kar S. Clomiphene citrate or letrozole as first-line ovulation
induction drug in infertile PCOS women: a prospective randomized
trial. J Hum Reprod Sci 2012;5:262–5.
21. Bayar U, Kiran S, Coskun A, Gezer S. Use of an aromatase inhibitor
in patients with polycystic ovary syndrome: a prospective rando-
mized trial. Fertil Steril 2006;5:1447–51.
22. Dehbashi S, Kazerooni T, Robati M, et al. Comparison of the effects
of letrozole and clomiphene citrate on ovulation and pregnancy rate
in patients with polycystic ovary syndrome. Iran J Med Sci 2009;1:
19–26.
23. Ray PB, Ray A, Chakraborti PS. Comparison of efficacy of letrozole
and clomiphene citrate in ovulation induction in Indian women with
polycystic ovarian syndrome. Arch Gynecol Obstet 2012;285:873–7.
24. Roy KK, Baruah J, Singla S, et al. A prospective randomized trial
comparing the efficacy of letrozole and clomiphene citrate in
induction of ovulation in polycystic ovarian syndrome. J Hum
Reprod Sci 2012;5:20–5.
25. Atay V, Cam C, Muhcu M, et al. Comparison of letrozole and
clomiphene citrate in women with polycystic ovaries undergoing
ovarian stimulation. J Int Med Res 2006;1:73–6.
26. Badawy A, Aal IA, Abulatta M, Caballero AE. Clomiphene citrate
or letrozole for ovulation induction in women with polycystic
ovarian syndrome: a prospective randomized trial. Fertil Steril 2009;
3:849–52.
27. Franik S, Kremer JA, Nelen WL, Farquhar C. Aromatase inhibitors
for subfertile women with polycystic ovary syndrome. Cochrane
Database Syst Rev 2014;2:CD010287.
28. Young SL, Opsahl MS, Fritz MA. Serum concentrations of
enclomiphene and zuclomiphene across consecutive cycles of
clomiphene citrate therapy in anovulatory infertile women. Fertil
Steril 1999;71:639–44.
29. Franasiak JM, Holoch KJ, Yuan L, et al. Prospective assessment of
midsecretory endometrial leukemia inhibitor factor expression
versus ab3 testing in women with unexplained infertility. Fertil
Steril 2014;101:1724–31.
30. Miller PB, Parnell BA, Bushnell G, et al. Endometrial receptivity
defects during IVF cycles with and without letrozole. Hum Reprod
2012;27:881–8.
31. Wallace KL, Johnson V, Sopelak V, Hines R. Clomiphene citrate
versus letrozole: molecular analysis of the endometrium in women
with polycystic ovary syndrome. Fertile Steril 2011;96:1051–6.
32. Biljan M, Hemmings R, Brassard N. The outcome of 150 babies
following the treatment with letrozole or letrozole and gonado-
tropins. Fertil Steril 2005;84: O–231, Abstract 1033.
33. Tiboni GM. Aromatase inhibitors and teratogenesis. Fertil Steril
2004;81:1158.
34. Tulandi T, Martin J, Al-Fadhii R, et al. Congenital malformations
among 911 newborns conceived after infertility treatment with
letrozole or clomiphene citrate. Fertil Steril 2006;85:1761–5.
35. Casper RF, Mitwally MF. Use of the aromatase inhibitor letrozole
for ovulation induction in women with polycystic ovarian syndrome.
Clin Obstet Gynecol 2011;54:685–95.
36. Sharma S, Ghosh S, Singh S, et al. Congenital malformations among
babies born following letrozole or clomiphene for infertility
treatment. PLoS One 2014;9:e108219.
37. Reefhuis J, Honein MA, Schieve LA, Rasmussen SA, National Birth
Defects Prevention Study. Use of clomiphene citrate and birth
defects, National birth defects prevention study, 1997-2005. Hum
Reprod 2011;26:451–7.
38. Davies MJ, Moore VM, Willson KL, et al. Reproductive
technologies and the risk of birth defects. N Engl J Med 2012;
366:1803–13.
39. Palomba S. Aromatase inhibitors for ovulation induction. J Clin
Endocrinol Metab 2015;100:1742–7.
Supplementary material available online.
DOI: 10.3109/09513590.2015.1096337 Letrozole versus CC 5
Downloaded by [Matheus Roque] at 09:09 23 November 2015