Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate
Open accessAbstract
Objective To evaluate the incidence of congenital malformations among offspring of mothers who conceived with clomiphene citrate (CC) or with letrozole treatment for infertility.Design Retrospective study.Setting 5 fertility centers in Canada.Patients 911 newborns from women who conceived following CC or letrozole treatment.Interventions Examination of medical files of both mother and newborn, and cross-checked with the parents by telephone calls.Main outcome measures Identified major and minor congenital malformations, birth weight, age of the mother, and type of treatment that led to the conception.Results Overall, congenital malformations and chromosomal abnormalities were found in 14 of 514 newborns in the letrozole group (2.4%) and in 19 of 397 newborns in the CC group (4.8%). The major malformation rate in the letrozole group was 1.2% (6/514) and in the CC group was 3.0% (12/397). One newborn in the letrozole group was found to have a ventricular septal defect (0.2%) compared to 4 newborns in the CC group (1.0%). In addition, the rate of all congenital cardiac anomalies was significantly higher (P: 0.02) in the CC group (1.8%) compared to the letrozole group (0.2%).Conclusion There was no difference in the overall rates of major and minor congenital malformations among newborns from mothers who conceived after letrozole or CC treatments. However, it appears that congenital cardiac anomaly is less frequent in the letrozole group. The concern that letrozole use for ovulation induction could be teratogenic is unfounded based on our data.
AI snapshot
Written from the paper’s full text.
TL;DR
In a retrospective multicenter study of 911 newborns, overall congenital malformation/chromosomal abnormality rates were 2.4% after letrozole and 4.8% after clomiphene citrate, with no significant difference in major malformations. Congenital cardiac anomalies were significantly less frequent in the letrozole group (0.2%) than in the CC group (1.8%; P=0.02).
Key findings
- Overall congenital malformations or chromosomal abnormalities occurred in 14/514 letrozole newborns (2.4%) versus 19/397 CC newborns (4.8%).
- Major malformation rates were 1.2% (6/514) in the letrozole group and 3.0% (12/397) in the CC group; this difference was non-significant.
- All congenital cardiac anomalies were significantly higher in the CC group (1.8%) than in the letrozole group (0.2%; P=0.02); ventricular septal defect occurred in 1 letrozole newborn (0.2%) versus 4 CC newborns (1.0%).
- Minor malformation rates were similar: letrozole 1.6%, CC 1.8%.
Methods
- Retrospective study at 5 fertility centers in Canada; 931 babies were identified from women who conceived after CC or letrozole treatment, with complete data for 911 babies (98%) after 20 were lost to follow-up. Babies born after IVF were excluded.
- Women received letrozole or CC orally for 5 days from day 3 to 7 of the cycle for ovulation induction or augmentation for timed intercourse or intrauterine insemination. Data were retrieved from medical files of mother and newborn and cross-checked with parents by telephone.
- Outcomes included major and minor congenital malformations, chromosomal abnormalities, birth weight, maternal age, and treatment type, using WHO ICD-10 Chapter XVII definitions. Analysis used Shapiro-Wilks, Kruskal-Wallis, Chi-Square or Fisher’s exact tests, with P<0.05 considered significant.
Limitations
- The paper does not include a dedicated limitations section. It states that the low anomaly rates in both groups may reflect that infertile women are generally health conscious, with high folic acid/prenatal vitamin use and low smoking or drug use during pregnancy.
- Evident from the text: the study is retrospective, relies on medical records cross-checked by telephone, had 20 babies lost to follow-up, excluded IVF pregnancies, and compared two infertility treatment groups rather than randomized groups.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 21 cited sources checked · 0 supported · 0 flagged
- Findingown data
Overall congenital malformations or chromosomal abnormalities were found in 14 of 514 newborns in the letrozole group (2.4%) and in 19 of 397 newborns in the CC group (4.8%).
“Overall, congenital malformations and chromosomal abnormalities were found in 14 of 514 newborns in the letrozole group (2.4%) and in 19 of 397 newborns in the CC group (4.8%).”
- Also stated in: § RESULTS · plain
“Overall, congenital malformations or chromosomal abnormalities were found in 14 of 514 newborns in the letrozole group (2.4%) and in 19 of 397 newborns in CC group (4.8%) (Tables 2 and 3).”
- Also stated in: § DISCUSSION · plain
“In the present study of 911 babies born after infertility treatment, congenital malformations were encountered in 2.4% of newborns in the letrozole group and 4.8% of newborns in the CC group.”
Quote in the paperSubstantial claim - Also stated in: § RESULTS · plain
- Findingown data
The rate of all congenital cardiac anomalies was significantly higher (P=0.02) in the CC group (1.8%) compared to the letrozole group (0.2%).
“In addition, the rate of all congenital cardiac anomalies was significantly higher (P: 0.02) in the CC group (1.8%) compared to the letrozole group (0.2%).”
- Also stated in: § RESULTS · plain
“In addition, the rate of all congenital cardiac anomalies was significantly higher (P: 0.02) in the CC group (1.8%) compared to the letrozole group (0.2%).”
- Also stated in: § DISCUSSION · plain
“7 newborns in the CC group (1.8%) and only one in the letrozole group (0.2%) were found to have congenital cardiac anomalies (P: 0.02).”
Quote in the paperSubstantial claim - Also stated in: § RESULTS · plain
- Findingown data
The rates of minor congenital malformations were similar between the letrozole (1.6%) and CC (1.8%) groups.
“The rates of minor congenital malformations were similar (letrozole: 1.6%, CC: 1.8%).”
Quote in the paperNot a substantial claim - Findingown data
Ventricular septal defect was the predominant cardiac anomaly (5 of 8 newborns with cardiac anomalies).
“Ventricular septal defect was the predominant cardiac anomaly (5 of 8 newborns with cardiac anomalies), similar to the findings in spontaneously conceived pregnancies (16,17).”
Quote in the paperNot a substantial claim - Findingown data
There was no difference in the overall rates of major and minor congenital malformations among newborns from mothers who conceived after letrozole or CC treatments.
“There was no difference in the overall rates of major and minor congenital malformations among newborns from mothers who conceived after letrozole or CC treatments.”
- Also stated in: § DISCUSSION · plain
“We conclude that there is no difference in the overall rates of major and minor malformations or chromosomal abnormalities between newborns of mothers who conceived after letrozole or after clomiphene citrate treatments.”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · plain
- Findingown data
The major malformation rates were not statistically different between the letrozole and CC groups.
“The major malformation rate in the letrozole group was 1.2% (6/514) and in the CC group was 3.0% (12/397) (non-significant).”
- Also stated in: § DISCUSSION · plain
“These rates of major anomalies were not statistically different between the 2 groups”
- Also stated in: § DISCUSSION · plain
“Although we did not find any significant difference in the rates of major and minor malformations between newborns in the letrozole and CC groups”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · plain
- Findingown data
Congenital cardiac anomalies are less frequent in the letrozole group than in the CC group.
“However, it appears that congenital cardiac anomaly is less frequent in the letrozole group.”
- Also stated in: § DISCUSSION · hedged
“These findings suggest that congenital cardiac anomalies are less frequent in the letrozole group than in the CC group and general population, and refute the conclusion of the ASRM abstract (3).”
- Also stated in: § DISCUSSION · boosted
“However, the present study demonstrated that congenital cardiac anomalies are statistically less frequent in the letrozole group than in the CC group.”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · hedged
- Findingown data
One newborn in the letrozole group had a ventricular septal defect (0.2%) compared to 4 newborns in the CC group (1.0%).
“One newborn in the letrozole group was found to have a ventricular septal defect (0.2%) compared to 4 newborns in the CC group (1.0%).”
- Also stated in: § RESULTS · plain
“One newborn in the letrozole group was found to have a ventricular septal defect (VSD) (0.2%) compared to 4 newborns in the CC group (1.0%).”
Quote in the paperSubstantial claim - Also stated in: § RESULTS · plain
- Interpretationcitation
The rates of major anomalies in the study were similar to the quoted rates of anomalies found in the general population (2-3%).
“These rates of major anomalies were not statistically different between the 2 groups, and were similar to the quoted rates of anomalies found in the general population (2-3%) (6, 7).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [6] 2005
Not checked in the free run.
- cites [7] 2002
Not checked in the free run.
- Interpretationown data
The study findings refute the conclusion of the ASRM abstract.
“These findings suggest that congenital cardiac anomalies are less frequent in the letrozole group than in the CC group and general population, and refute the conclusion of the ASRM abstract (3).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] Biljan, 2005, The outcome of 150 babies following the treatment with letrozole or letrozole and gonadotropins, Fertil Steril
Not checked in the free run.
- Interpretationcitation
The predominance of ventricular septal defect is similar to the findings in spontaneously conceived pregnancies.
“Ventricular septal defect was the predominant cardiac anomaly (5 of 8 newborns with cardiac anomalies), similar to the findings in spontaneously conceived pregnancies (16,17).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [16] Samson, 2004, A study of congenital cardiac disease in a neonatal population–the validity of echocardiography undertaken by a neonatologist, Cardiol in the Young source
Not checked in the free run.
- cites [17] Hoffman, 1995, Incidence of congenital heart disease: I. Postnatal incidence, Pediatr Cardiol source
Not checked in the free run.
- Interpretationown data
Congenital cardiac anomalies are less frequent in the letrozole group than in the general population.
“These findings suggest that congenital cardiac anomalies are less frequent in the letrozole group than in the CC group and general population, and refute the conclusion of the ASRM abstract (3).”
Quote in the paperSubstantial claim - Interpretationown data
The CC rates of cardiac anomalies are slightly higher than the rate reported among all births.
“The incidence of cardiac anomalies in the letrozole group was slightly lower than the rate of congenital cardiac anomalies reported among all births (0.4 -1.2%) (13)(14)(15)(16), and the CC rates are slightly higher.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [13] Stephensen, 2004, Congenital cardiac malformations in Iceland from 1990 through 1999, Cardiol in the Young source
Not checked in the free run.
- cites [14] Wren, 1999, Presentation of congenital heart disease in infancy, Arch Dis Child Fetal Neonatal Ed source
Not checked in the free run.
- cites [15] Bower, 1994, Congenital heart disease, J Pediatr Child Health source
Not checked in the free run.
- Interpretationown data
The concern that letrozole use for ovulation induction could be teratogenic is unfounded based on the study data.
“The concern that letrozole use for ovulation induction could be teratogenic is unfounded based on our data.”
- Also stated in: § DISCUSSION · plain
“The concern that letrozole use for ovulation induction could be teratogenic is unfounded based on our data.”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · plain
- Interpretationown data
The incidence of cardiac anomalies in the letrozole group was slightly lower than the rate of congenital cardiac anomalies reported among all births (0.4-1.2%).
“The incidence of cardiac anomalies in the letrozole group was slightly lower than the rate of congenital cardiac anomalies reported among all births (0.4 -1.2%) (13)(14)(15)(16), and the CC rates are slightly higher.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [13] Stephensen, 2004, Congenital cardiac malformations in Iceland from 1990 through 1999, Cardiol in the Young source
Not checked in the free run.
- cites [14] Wren, 1999, Presentation of congenital heart disease in infancy, Arch Dis Child Fetal Neonatal Ed source
Not checked in the free run.
- cites [15] Bower, 1994, Congenital heart disease, J Pediatr Child Health source
Not checked in the free run.
- Interpretationreasoning
Letrozole should be cleared from the body completely by the time of embryo implantation.
“Letrozole should be cleared from the body completely by the time of embryo implantation.”
Quote in the paperSubstantial claim - Study design and conductnone given
None of the patients were exposed to either letrozole or CC during pregnancy.
“None of our patients were exposed to either letrozole or CC during pregnancy.”
Quote in the paperSubstantial claim
- May combine two claims. 10
- Classified as probably not a substantial claim. 7
- The quote only partly states this claim. 1
May combine two claims.
Findingown dataThe major malformation rate in the letrozole group was 1.2% (6/514) and in the CC group was 3.0% (12/397).
“The major malformation rate in the letrozole group was 1.2% (6/514) and in the CC group was 3.0% (12/397).”
- Also stated in: § RESULTS · plain
“The major malformation rate in the letrozole group was 1.2% (6/514) and in the CC group was 3.0% (12/397) (non-significant).”
- Also stated in: § DISCUSSION · plain
“Major malformations were detected in 1.2% of the babies in the letrozole group and in 3.0% of the babies in the CC group.”
Quote in the paperSubstantial claim- Also stated in: § RESULTS · plain
May combine two claims.
PremisecitationThe control group in the ASRM abstract was composed of predominantly spontaneous conceptions, which are known to be associated with a lower risk of pregnancy complications and congenital malformations than an infertility population.
“First, the control group was composed of predominantly spontaneous conceptions, which are known to be associated with a lower risk of pregnancy complications and congenital malformations than an infertility population (18).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [18] Buckett, 2005, Congenital abnormalities in children born after assisted reproductive techniques, Fertil Steril source
Not checked in the free run.
May combine two claims.
Interpretationnone givenBoth the cardiac and bone differences reported in the ASRM abstract are solely related to type I error.
“We believe both these differences are solely related to type I error.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] Biljan, 2005, The outcome of 150 babies following the treatment with letrozole or letrozole and gonadotropins, Fertil Steril
Not checked in the free run.
May combine two claims.
InterpretationreasoningThe ASRM abstract had several methodologic problems that led to an erroneous conclusion.
“We believe there were several methodologic problems with the ASRM abstract as presented that led to an erroneous conclusion.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] Biljan, 2005, The outcome of 150 babies following the treatment with letrozole or letrozole and gonadotropins, Fertil Steril
Not checked in the free run.
May combine two claims.
Study design and conductown dataThe birth weights of the newborns and the incidence of multiple births among the four groups were similar.
“The birth weights of the newborns and the incidence of multiple births among the four groups were also similar (Table 1).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationNo teratogenicity has been observed among women who took CC inadvertently during pregnancy.
“Furthermore, no teratogenicity has been observed among women who took CC inadvertently during pregnancy (11).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] Carlier, 1996, Clomiphene-exposed pregnancies-analysis of 39 information requests including 25 cases with known outcome, Therapie
Not checked in the free run.
May combine two claims.
PremisecitationThe half-life of letrozole is approximately 45 hours (range 30-60 hours), which is shorter than that of clomiphene citrate (5-7 days).
“In the case of letrozole, the half life of approximately 45 hours (range 30 -60 hours) is shorter than that of clomiphene citrate (5-7 days) (1).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Holzer, 2006, A new era of ovulation induction, Fertil Steril source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationClomiphene citrate has been used for over four decades and several studies have shown that its use is not associated with an increased risk of congenital malformation.
“Clomiphene citrate has been used for over four decades and several studies have shown that its use is not associated with an increased risk of congenital malformation (8 -10).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [8] Correy, 1982, The outcome of pregnancy resulting from clomiphene-induced ovulation, Aust N Zealand J Obstet Gynaecol source
Not checked in the free run.
- cites [9] Schenker, 1981, Multiple pregnancies following induction of ovulation, Fertil Steril source
Not checked in the free run.
- cites [10] Whiteman, 2000, Reproductive factors, subfertility, and risk of neural tube defects, Am J Epidemiol source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataNone of the mothers in either group took recreational drugs or marijuana during pregnancy.
“None of the mothers in either group took recreational drugs or marijuana during pregnancy.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningThese abnormalities could be underrepresented in the 36,000 deliveries from the low risk hospital, making calculation of a relative risk for the letrozole group impossible.
“Therefore, these abnormalities could be underrepresented in the 36,000 deliveries from the low risk hospital making calculation of a relative risk for the letrozole group impossible.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
InterpretationreasoningThe low rate of anomalies in both groups may reflect that infertile women are generally very health conscious, with high utilization of folic acid and other prenatal vitamins and low incidence of cigarette smoking and other drug use in pregnancy.
“In addition, the low rate of anomalies in both groups may reflect the fact that infertile women are generally very health conscious with regard to their much desired pregnancies as reflected in high utilization of folic acid and other prenatal vitamins and a low incidence of cigarette smoking and other drug use in pregnancy.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningThese factors would all attenuate the risks of some congenital abnormalities.
“These factors would all attenuate the risks of some congenital abnormalities.”
Quote in the paperNot a substantial claimThe quote only partly states this claim.
Study design and conductown dataThere were no significant differences in the ages of the mothers among the letrozole, letrozole/FSH, CC, or CC/FSH groups.
“No significant difference in the results among the different treatment groups.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningExposure to letrozole predates the critical fetal development period, casting doubt on the biological plausibility of teratogenicity in the use of the drug for ovulation induction.
“Thus, the exposure to the drug predates the critical fetal development period, casting doubt on the biological plausibility of teratogenicity in the use of the drug for ovulation induction.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductown dataTwenty babies were lost to follow-up, resulting in complete data collection for 911 babies (98%).
“Twenty babies were lost to follow-up resulting in complete data collection for 911 babies (98%).”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationThe birth prevalence of congenital cardiac anomalies in Canada in 1999 was 104 per 10,000 births (1.04%).
“Similarly, the birth prevalence of congenital cardiac anomalies in Canada in 1999 was 104 per 10,000 births (1.04%) (7).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [7] 2002
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationFor a drug to have a teratogenic effect, it must be present at the time of organogenesis.
“Finally, for a drug to have a teratogenic effect, it must be present at the time of organogenesis (19).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [19] Shepard, 2001
Not checked in the free run.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Two subsequent publications suggest that letrozole may not be associated with fetal anomalies.
“However, two subsequent publications suggest that letrozole may not be associated with fetal anomalies. 241,242”
From Assessment and management of polycystic ovary syndrome: Summary of an evidence-based guideline (2011) · cites this paper as [242]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Letrozole-group overall malformation rate is miscalculated
MinorFourteen of 514 newborns is 2.7%, not 2.4%. The 2.4% figure is repeated in the results and discussion.
Reported 2.4 · recomputed 2.723735
“congenital malformations and chromosomal abnormalities were found in 14 of 514 newborns in the letrozole group (2.4%)”
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- Authors
- Tulandi, T., Martin, J., Al-Fadhli, R., Kabli, N., Forman, R., Hitkari, J., Librach, C., Greenblatt, E., & Casper, R. F.
- Affiliations
- McGill University (CA)
- Mount Sinai Hospital (CA)
- Corresponding author
- Casper, Robert F.
- Venue
- Fertility and Sterility
- Publisher
- Elsevier BV
- Published
- 2006-06
- Volume
- 85
- Issue
- 6
- Pages
- 1761-1765
- ISSN
- 0015-0282 (ISSN-L)
- OpenAlex
- W1995071598
- Semantic Scholar
- 5050356504fa0f209abcee8f6347fabf7645a4e5
- Cited by
- 370
- References
- 16
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 8 · 2023: 3 · 2022: 10 · 2021: 16 · 2020: 11 · 2019: 16 · 2018: 17 · 2017: 23 · 2016: 17 · 2015: 22 · 2014: 17 · 2013: 26 · 2012: 33
- FWCI
- 27.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Fertility and Sterility (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Assisted Reproductive Technology and Twin Pregnancy
- Health Sciences › Medicine › Reproductive Medicine › Reproductive Health and Technologies
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Pregnancy and Medication Impact
- Keywords
- congenital malformations, letrozole, clomiphene citrate, ovulation induction, infertility treatment, teratogenicity, congenital heart disease, ventricular septal defect, chromosomal abnormalities, birth weight, maternal age
- MeSH terms
- Congenital Abnormalities, Letrozole, Adult, Canada, Clomiphene, Female, Fertility Agents, Female, Humans, Infant, Newborn, Infertility, Female, Nitriles, Ovulation Induction, Pregnancy, Pregnancy Outcome, Retrospective Studies, Risk Factors, Triazoles, Comorbidity, Incidence, Treatment Outcome, Risk Assessment, Aromatase Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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