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One of the most significant problems facing maternal and children health worldwide is preterm birth (PTB). Although strategies to increase the survival of premature infants have significantly improved in the past few decades, they have yet to be successful. Nine years ago, the use of progesterone in pregnancy was approved by the United States Food and Drug Administration (FDA) for PTB prevention. This paper reviews the recent evidence supporting the use of progesterone in pregnancy for PTB prevention and provides guidelines for its use in daily clinical practice. The guidelines address multiple current controversial areas regarding the prevention of PTB to aid physicians with their clinical decision-making practice, including the use in multifetal gestation, different formulations, safety in pregnancy, dose and route of administration.Saudi Med J 2020; Vol. 41 (4): 333-340doi: 10.15537/smj.2020.4.25036How to cite this article:Alsulmi ES, Alfaraj M, Faden Y, Al Qahtani N. The use of progesterone during pregnancy to prevent preterm birth. Saudi Med J 2020; Vol. 41: 333-340. doi: 10.15537/smj.2020.4.25036.