No increased risk of major congenital anomalies or adverse pregnancy or neonatal outcomes following letrozole use in assisted reproductive technology.
Does letrozole use increase the risk of major congenital anomalies and adverse pregnancy and neonatal outcomes in fresh, single-embryo transfer?



Letrozole significantly decreases the risk of miscarriage and does not increase the risk of major congenital anomalies or adverse pregnancy or neonatal outcomes compared with natural cycles in patients undergoing ART.



Letrozole is the most commonly used aromatase inhibitor for mild ovarian stimulation in ART. However, its safety in terms of pregnancy and neonatal outcomes is unclear.



This retrospective cohort study used data from the Japanese national ART registry from 2011 to 2013.



A total of 3136 natural cycles and 792 letrozole-induced cycles associated with fresh, single-embryo transfer and resulting in a clinical pregnancy were included in the analysis. The main pregnancy outcomes were miscarriage, ectopic pregnancy and still birth, and the neonatal outcomes were preterm delivery, low birth weight, small/large for gestational age and major congenital anomalies. Terminated pregnancies were included in the analysis of major congenital anomalies. Odds ratios (ORs) and 95% CIs were calculated using multivariate logistic regression analysis adjusted for maternal age and calendar year.



The risk of miscarriage was significantly lower in women administered letrozole (adjusted OR [aOR], 0.37, 95% CI, 0.30-0.47, P < 0.001). There was no significant difference in the overall risk of major congenital anomalies between the two groups (natural cycle 1.5% vs letrozole 1.9%, aOR, 1.24, 95% CI, 0.64-2.40, P = 0.52), and no increased risk for any specific organ system. Subgroup analysis demonstrated that the risk of major congenital anomalies was not increased in patients who underwent either in vitro fertilization or ICSI, or in those who received early cleavage stage or blastocyst embryo transfer. All other pregnancy and neonatal outcomes were comparable between the two groups.



Despite the large sample size, we were only able to rule out the possibility that letrozole might cause large increases in birth-defect risks in ART patients.



The results suggest that letrozole stimulation reduces the risk of miscarriage, with no increase in the risk of major congenital anomalies or adverse pregnancy or neonatal outcomes compared with natural cycles in women undergoing ART. Letrozole may thus be a safe option for mild ovarian stimulation.



None.



Not applicable.
Division of Reproductive Medicine, Center of Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo 157-8535, Japan.|Comprehensive Reproductive Medicine, Regulation of Internal Environment and Reproduction, Graduate School, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-0034, Japan.
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Tatsumi
Division of Reproductive Medicine, Center of Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo 157-8535, Japan jwa-s@ncchd.go.jp.|Sora no Mori Clinic, 229-1, Yagibaru, Yaese-cho, Shimajiri-gun, Okinawa 901-0406, Japan.
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Jwa
Department of Obstetrics and Gynecology, School of Medicine, University of Tokushima, 3-18-15, Kuramoto-chou, Tokushima-shi, Tokushima 770-8503, Japan.
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Kuwahara
Department of Obstetrics and Gynecology, School of Medicine, University of Tokushima, 3-18-15, Kuramoto-chou, Tokushima-shi, Tokushima 770-8503, Japan.
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Irahara
Comprehensive Reproductive Medicine, Regulation of Internal Environment and Reproduction, Graduate School, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-0034, Japan.
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Kubota
Division of Reproductive Medicine, Center of Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo 157-8535, Japan.
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Saito
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000022:Abortion, Spontaneous / Q000209:etiology*; D000328:Adult; D047072:Aromatase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D005307:Fertilization in Vitro / Q000009:adverse effects; D006801:Humans; D007231:Infant, Newborn; D000077289:Letrozole; D008423:Maternal Age; D009570:Nitriles / Q000009:adverse effects* / Q000627:therapeutic use; D010062:Ovulation Induction / Q000009:adverse effects* / Q000379:methods; D011247:Pregnancy; D011256:Pregnancy Outcome; D012189:Retrospective Studies; D012306:Risk; D014230:Triazoles / Q000009:adverse effects* / Q000627:therapeutic use
D047072:Aromatase Inhibitors; D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole
congenital anomaly; letrozole; mild ovarian stimulation; neonatal outcome; ovulation-induction method; pregnancy outcome