Publication:

Injectable natural progesterone: a physiologic alternative following the withdrawal of 17α-hydroxyprogesterone caproate for preterm birth prevention

Following the withdrawal of 17-alpha hydroxyprogesterone caproate (17-OHPC; formerly marketed as MAKENA) there is a therapeutic gap in the prevention of recurrent spontaneous preterm birth (PTB) in women with singleton pregnancies and a history of prior PTB. Originally granted accelerated approval based on the Meis trial, 17-OHPC failed to demonstrate clinical benefit in the confirmatory PROLONG trial and raised long-term safety concerns regarding childhood cancer risk. In contrast, natural progesterone, an endogenous hormone essential for pregnancy maintenance, can provide strong biological plausibility for myometrial quiescence through evident genomic and non-genomic mechanisms. Although no head-to-head trials exist comparing intramuscular (IM) natural progesterone with 17-OHPC for PTB, physiological reasoning, pharmacokinetic advantages of the native molecule, and indirect evidence from historical and contemporary progestogen studies support its consideration as a viable alternative. In this short communication we highlight the mechanistic rationale for IM natural progesterone while acknowledging the need for dedicated clinical trials to establish efficacy and optimal dosing in modern obstetric practice.