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Lior Segev,1,2,* Avigail Ben Zimra,1,* Gideon A Weitzman,2 Naamah Bloch,1 Itay Pitussi,3 Tatiana Alkhazov,4 Natalya M Kogan,4 David Peleg,1,5 Abraham O Samson,1 Inbar Ben Shachar1,5 1Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel; 2PUAH Institute: Fertility, Medicine, Halacha, Jerusalem, Israel; 3Department of Chemical Sciences, Ariel University, Ariel, Israel; 4Institute of Personalized and Translational Medicine, Department of Molecular Biology, Ariel University, Ariel, Israel; 5Department of Obstetrics and Gynecology, Ziv Medical Center, Safed, Israel*These authors contributed equally to this workCorrespondence: Abraham O Samson, Email avraham.samson@biu.ac.ilIntroduction: Few studies have examined the transfer of Ethinylestradiol (EE) into breastmilk in women using Combined Hormonal Contraception (CHC). Most studies are decades old, from when EE doses (≈50 μg) were higher than today (≤ 35 μg).Methods: Here, we asses EE levels in milk from breastfeeding women on CHC with low-dose EE (15– 35 μg/day EE) using mass spectrometry (MS). Our study included 14 breastfeeding women: 6 using oral CHC (15, 20, or 30 μg/day EE), 7 using a vaginal ring (15 μg/day EE), and 1 using a transdermal patch (35 μg/day EE). A control group of 8 breastfeeding women not using hormonal contraceptives was also included. All participants completed a background questionnaire and provided 5mL of breast-milk. Samples were lyophilized and extracted with methyl tert-butyl ether (MTBE) for Liquid Chromatography-Mass Spectrometry (LC-MS) analysis. EE levels were assessed using high-resolution LC-MS, with a limit of quantification (LOQ) of 3.5 ng/mL.Results: No measurable peak of the compound was found in any of the CHC users. To confirm that EE was not lost during sample preparation, pure EE was added to control breast milk and successfully detected.Conclusion: These findings suggest that EE transfer into breastmilk is less than 3.5 ng/mL, and therefore negligible compared to endogenous estradiol. This first LC-MS–based study provides novel evidence supporting the lactation safety of modern low-dose CHC, though larger studies with lower detection limits are needed for confirmation.Plain Language Summary: Our findings suggest that the breast milk transfer of Ethinylestradiol (EE) from current low-dose combined hormonal contraception (CHC) is negligible. As such, our findings suggest that modern low-dose CHC can be safely used during breastfeeding, offering reassurance to both mothers, and healthcare providers.Keywords: combined hormonal contraception, ethinylestradiol, breast-milk, lactation safety, mass spectrometry