Developmental origins of pregnancy loss in cattle

Pregnancy losses constitute a major economic burden in cattle farming and are caused by developmental failures occurring mostly during the first month of gestation. This review integrates knowledge gathered from direct and indirect estimations of embryo survival at critical developmental periods with knowledge obtained from functional in vivo and in vitro studies to elucidate the developmental origins of pregnancy loss in cattle. Fertilization failures and embryonic arrest prior to the blastocyst stage, estimated based on morphological observation of flushed structures, average 10 to 20 and 10 to 30%, respectively. Reduced oocyte competence arises as the major driver of the underlying developmental failures, including impaired embryonic genome activation, loss of totipotency and defective first lineage differentiation. To estimate embryonic losses from blastocyst to implantation, direct observation of embryo development and indirect proxies of pregnancy have been employed. Indirect proxies such as nonreturn to oestrus or biochemical markers such as Interferon Stimulated Genes or Pregnancy Associated Glycoproteins inform on the development of extra-embryonic membranes, but do not distinguish between viable pregnancies and anembryonic pregnancies, where embryo-devoid structures formed by extra-embryonic membranes are able to maintain the corpus luteus to day 37. Merging data from recovery rates of early elongated structures and incidence of embryo-devoid structures, embryonic mortality from blastocyst hatching to pregnancy recognition oscillates between 12-79% for in vivo derived and 40-86% for in vitro produced embryos. The exclusion of anembryonic pregnancies diminishes embryonic mortality between day 16 and the time when the embryo proper is clearly identifiable by ultrasound (days 31-42) to less than 10%. The manuscript also provides an update on novel tools used to elucidate embryonic metabolic and signalling requirements, as well as on the molecular regulation of key developmental landmarks that must be achieved during developmental windows most susceptible to pregnancy loss.