Neonatal uterine bleeding as a biomarker for reproductive disorders during adolescence: a worldwide call for systematic registration by nurse midwife

Abstract

Neonatal uterine bleeding (NUB) occurs in approximately 5% of newborns, and is generally considered to be of little clinical significance. However, the real clinical importance of this condition and its long-term implications remain to be determined. The reason why NUB is rare despite high circulating levels of progesterone can be attributed to a progesterone resistance present in a majority of neonates. Recent work indicates that NUB represents a significant biomarker for events that can occur later-on during adolescence. Indeed, clinical studies have shown that “neonatal menstruation” constitutes a sign of fetal distress during late pregnancy, reflecting a stage of endometrium development that may subsequently have an impact on the reproductive life of the adolescent and the young adult. Via retrograde flow, NUB can cause endometrial stem/progenitor cells to arrive into the pelvic cavity and survive there, dormant underneath the peritoneal surface, until menarche activates them. Indeed, there is both clinical and epidemiological evidence of a link between NUB and adolescent endometriosis. In addition, if progesterone resistance persists till the onset of menarche, in case of an early teen pregnancy, it can result in a disorder of deep placentation. Therefore, we propose that NUB should be carefully recorded so that prospective studies can examine its links with reproductive disorders in adolescence and beyond.

Pathogenesis of endometriosis: the genetic/epigenetic theory

“…Microscopic and subtle lesions are considered to be the initial stages after implantation. Neonatal menstruation (208)(209)(210)(211), occurring in some 5% of neonates (208,(212)(213)(214)(215)(216)(217), especially in postmature and SGA babies, might explain premenarchal and severe adolescent (218,219) endometriosis. The behavior of endometriosis lesions and the aromatase activity or progesterone resistance are speculated to be caused by an abnormal environment, by immunology, or by implantation of basal endometrium (163).…”

Pathogenesis of deep endometriosis

“…The neonatal origin in the pathogenesis of early onset endometriosis remains hypothetical, but the hypothesis is falsifiable by the establishment of a registration of neonatal menstruation. Recently several investigators (26,54) have made a call for systematic registration of the neonatal uterine bleeding.…”

Progesterone Resistance and Adult Stem Cells’ Genomic and Epigenetic Changes in the Puzzle of Endometriosis

“…Endometrial stem cells have the characteristics of adult stem cells (ASCs), namely, the clonogenicity and high ability to proliferate, differentiate, and induce rapid angiogenesis, a fact that may contribute to consider their binary qualities in natural functions in the normal endometrium and in endometriosis [5,79]. Their involvement in endometriosis is from intrauterine life [64], with reactivation after a dormant period in adolescence years in the form of so-called early-onset endometriosis ( Figure 3) [80].…”

“…PR is discussed together with other hormones' resistances, and it is a clinical consequence of many gynecological disorders regarding the ovaries-PCOS, the endometrium-abnormal uterine bleeding associated with endometrial hyperplasia, the eutopic endometrium in endometriosis, the decidual causes of infertility or recurrent pregnancy loss, or the myometrium-for miscarriage and preterm birth, when it is lost the uterine quiescence. The fetal endometrium remains progesteroneresistant, except when fetal distress causes decidualization and menstruation at birth [80], or the "neonatal menstruation," which is a biomarker reflecting a stage of endometrium development that may subsequently have an impact on the reproductive life of the adolescent and the young adult.…”