In Memory of Ivo Brosens: Reflections on the Pathophysiology of Neonatal Uterine Bleeding

BACKGROUND: The occurrence of vaginal bleeding in early neonatal life has been observed for centuries and was considered a consequence of the sudden drop in circulating hormones following birth. As such, neonatal uterine bleeding was dismissed as having no clinical significance. Interest in the phenomenon was renewed when a new theory suggested a link between neonatal uterine bleeding (NUB) and accelerated endometrial maturation. This theory was based on the observation of a higher incidence of NUB in babies born post-term or after pregnancies complicated by intrauterine growth restriction, preeclampsia, or blood group incompatibility. OBJECTIVE: The objective of this study was to review of available evidence on the pathogenesis of NUB. METHOD: Review of available literature using Medline search (August 2022, no limit on start date or language) to identify articles that may link NUB with features of the uterus and/or endometrium. OUTCOME: The fetal endometrial responses differ from that of the adult. In the fetus, the endometrium features progestogenic response only in a minority of cases. The endometrium in most newborn girls does not exhibit secretory or decidual changes which indicate lack of progesterone response. Most newborn girls do not have visible bleeding. Animal studies linked exogenous progestogen exposure during the period of organogenesis to poor endometrial gland development, progesterone resistance, and to alterations of reproductive performance. Although the fetal endometrium may not exhibit a full proliferative response, it is clearly sensitive to circulating estrogens. Molecular mechanisms involved in NUB may include "ontogenetic progesterone resistance." CONCLUSION AND OUTLOOK: Endometrial development and its response to withdrawal of hormones at birth varies and may be affected by intrauterine stressors and gestational age. Factors that affect endometrial development during fetal life and in preterm neonates can have implications on future reproductive performance.