Once an embryo has implanted, pregnancy has to be recognised, maintained and eventually ended at the right time. Each step involves signals passing between the conceptus (the embryo or fetus and its membranes) and the mother. Research on these signals has drawn on many species, from sheep and pigs to monkeys and humans, and has had to answer a long-standing puzzle: why the mother’s immune system tolerates a fetus that carries foreign genes from the father.
Signalling the pregnancy
The phrase “maternal recognition of pregnancy”, coined by the reproductive biologist Roger Short in 1969, describes how the conceptus announces its presence and prolongs the life of the corpus luteum, the ovarian structure that produces progesterone. Without that signal, the corpus luteum regresses at the end of the cycle and pregnancy cannot continue. Mammals have evolved strikingly different solutions:
- Sheep and other ruminants: the trophoblast secretes interferon tau, mainly between days 10 and 21–25 of pregnancy with a peak on days 14 to 16. It acts on the uterine lining to prevent the release of prostaglandin F2α, the hormone that would otherwise destroy the corpus luteum.
- Pigs: the conceptus produces oestrogen, which redirects prostaglandin F2α into the uterine lumen rather than into the bloodstream, keeping it away from the ovary.
- Primates, including humans: chorionic gonadotrophin from the conceptus maintains the corpus luteum until the placenta takes over hormone production, a transition known as the luteal–placental shift.
The immunological paradox
The immunologist Peter Medawar famously framed the fetus as a kind of graft that the mother should, in theory, reject. His essay steered decades of research toward the question of how maternal T cells become tolerant of the fetal allograft, and multiple mechanisms that dampen harmful T-cell responses to the fetus have since been described. A more recent line of research focuses on the uterine lining itself, where the most abundant immune cells are uterine natural killer cells. Rather than attacking placental cells, these cells appear to recognise them and help regulate how the placenta invades and remodels maternal blood vessels.
Genetic studies suggest that variation in natural killer cell receptors and their partner molecules may influence pregnancy success, but exactly how these cells work in normal and complicated pregnancies is still unclear. Researchers have warned that treatments aimed at suppressing natural killer cells should be viewed with caution in the absence of that understanding.
How labour begins
In every species, birth involves the same core events: the muscle of the uterus switches from a relaxed to a highly excitable state, the cervix softens and dilates, and the fetal membranes rupture. What sets the timing differs. In sheep, a surge of cortisol from the fetal adrenal glands, driven by the fetal hypothalamic–pituitary–adrenal axis, lowers placental progesterone production and triggers labour.
Humans do not follow this pattern. Progesterone production remains high throughout pregnancy and during labour, so researchers speak of a “functional” progesterone withdrawal, in which the target tissues become less responsive to the hormone. Several mechanisms are thought to contribute: production of corticotrophin-releasing hormone by the placenta, a positive feedback loop between cortisol and that hormone, inflammatory signalling (labour has been described as an inflammatory process, involving transcription factors such as NF-κB), mechanical stretch and, according to one recent hypothesis, the ageing of the fetal membranes. How these clocks and alarms are synchronised in human pregnancy is still described as a mystery.
When birth comes too early
Understanding labour has urgent practical stakes. The World Health Organization defines preterm birth as a live birth before 37 completed weeks of pregnancy. An estimated 13.4 million babies were born preterm in 2020, more than one in ten births, with national rates ranging from about 4% to 16%. Complications of preterm birth caused approximately 900 000 deaths in 2019 and are the leading cause of death among children under five. Most preterm births begin spontaneously; known risk factors include multiple pregnancies, infections and chronic conditions such as diabetes and high blood pressure, but often no cause is identified.
Long shadows: the womb and later health
Pregnancy affects more than the moment of birth. Epidemiological studies have found that smaller size or thinness at birth and in infancy is associated with higher rates of coronary heart disease in adulthood. The association is continuous and is seen across the normal range of birth weights, not only at the extremes. The relation between prenatal nutrition and later metabolic disease may even be U-shaped, with risks raised at both low and high birth weights.
The developmental-origins hypothesis interprets these findings through developmental plasticity: the fetus adjusts its development to cues from the mother, sometimes as a “predictive” adaptation to the environment it expects after birth. Disease risk may rise when the prediction proves wrong, for example when poor nutrition before birth is followed by abundance. Epigenetic mechanisms such as DNA methylation have been proposed as one way in which such early experiences are recorded.
Established findings and open questions
The diversity of maternal recognition signals among mammals, the importance of progesterone, the main definitions and global burden of preterm birth, and the statistical link between early growth and adult disease are well documented. Less settled are the precise triggers of human labour, the role of maternal immune cells in normal and failed pregnancies, and the extent to which epigenetic changes explain the long-term effects of the prenatal environment. Animal studies remain essential, but differences between species, especially in how labour is timed, mean that their results cannot simply be transferred to humans.
Sources
- Spencer TE, Bazer FW, Reproductive Biology and Endocrinology, 2004 — Conceptus signals for establishment and maintenance of pregnancy
- Ziegler TE et al., General and Comparative Endocrinology, 2023 — Timing of the luteal-placental shift is delayed with additional fetuses in litter-bearing callitrichid monkeys
- Moffett A, Colucci F, Journal of Clinical Investigation, 2014 — Uterine NK cells: active regulators at the maternal-fetal interface
- Menon R et al., Human Reproduction Update, 2016 — Novel concepts on pregnancy clocks and alarms: redundancy and synergy in human parturition
- World Health Organization, “Preterm birth” fact sheet, 2023
- Gluckman PD et al., New England Journal of Medicine, 2008 — Effect of in utero and early-life conditions on adult health and disease
References from the journal archive
These articles were published in Reproduction, the Journal of Reproduction and Fertility or Reviews of Reproduction and are still cited at their old addresses on this domain. Each link leads to the publisher’s version through its DOI.
- EFFECT OF CADMIUM CHLORIDE ON THE PREGNANT ALBINO MOUSE
- PREGNANCY DIAGNOSIS
- EVIDENCE OF PRECOCIOUS PUBERTY IN THE IMMATURE FEMALE RHESUS MONKEY ( MACACA MULATTA ) TREATED WITH PREGNANT MARE'S SERUM GONADOTROPHIN
- NEED OF LUTEINIZING HORMONE FOR EARLY PREGNANCY IN THE GOLDEN HAMSTER ( MESOCRICETUS AURATUS )
- EFFECT OF LH, FSH AND THEIR ANTISERA ON GESTATION IN THE HAMSTER ( MESOCRICETUS AURATUS )
- Mating in the rhesus monkey ( Macaca mulatta ) after conception and its relationship to oestradiol and progesterone levels throughout pregnancy
- Early pregnancy diagnosis in the ewe, based on milk progesterone levels
- Radioimmunoassay for PMSG and its application to in-vivo studies
- Reproductive asymmetry and unilateral pregnancy in Chiroptera
- Short-term variations in plasma LH and testosterone in bull calves from birth to 1 year of age
- Effects of active immunization against oestradiol-17β, testosterone or progesterone on receptivity in the female rabbit and evaluation of specificity
- Estimation of progesterone in buffalo milk and its application to pregnancy diagnosis
- Effect of breast-feeding patterns on human birth intervals
- Role of striated penile muscles in penile reflexes, copulation, and induction of pregnancy in the rat
- Effects on pregnancy in mice of passive immunization against ovine LH and human chorionic gonadotrophin
- Serum concentrations of chorionic gonadotrophin, oestradiol-17β and progesterone during early pregnancy in the south Indian bonnet monkey ( Macaca radiata )
- Role of conceptus secretory products in establishment of pregnancy
- An avidin—biotin micro-enzymeimmunoassay for monkey chorionic gonadotrophin
- Overfeeding during early pregnancy reduces peripheral progesterone concentration and pregnancy rate in sheep
- Endocrine changes during pregnancy, parturition and the early post-partum period in the llama ( Lama glama )
- Interactions between melatonin and prolactin during gestation in mink ( Mustela vison )
- Pregnancy-specific protein B and progesterone concentrations in French Alpine goats throughout gestation
- Termination of pregnancy and induction of premature luteolysis by the antiprogestagen, mifepristone, in dogs
- Rapid extraction of faecal steroids for measuring reproductive cyclicity and early pregnancy in free-ranging yellow baboons ( Papio cynocephalus cynocephalus )
- Development from birth to sexual maturity in a semi-free-ranging colony of mandrills ( Mandrillus sphinx ) in Gabon
- The endocrinology of gestation failure in foxes ( Vulpes vulpes )
- Identification of early pregnancy factor as chaperonin 10: implications for understanding its role
- Fetal undernutrition and disease in later life
- Dynamics of immunoglobulins at the feto-maternal interface
- Evolution of mammalian pregnancy in the presence of the maternal immune system
- Impact of photoperiodic exposures during late gestation and lactation periods on the pineal and reproductive physiology of the Indian palm squirrel, Funambulus pennanti
- Fetal growth restriction: adaptations and consequences
- Fetomaternal interactions and influences during equine pregnancy
- Micronutrient programming of development throughout gestation
- Nutrient partitioning during adolescent pregnancy
- Modulation of sex hormone secretion in cows by acute infection with bovine viral diarrhoea virus
- Antioxidant enzymatic defence systems in sheep corpus luteum throughout pregnancy
- Effects of parity and body condition at parturition on endocrine and reproductive parameters of the cow
- Gene-nutrient interactions during fetal development
- Persistence of anti-zonae pellucidae antibodies following a single inoculation of porcine zonae pellucidae in the domestic equine
- The role of nuclear factor kappa B in human labour
- Induction of labour at the start of the new millennium
- Mouse pregnancy-specific glycoproteins: tissue-specific expression and evidence of association with maternal vasculature
- Regulation of leptin synthesis and secretion before birth: implications for the early programming of adult obesity
- Different effects of maternal parity, cold exposure and nutrient restriction in late pregnancy on the abundance of mitochondrial proteins in the kidney, liver and lung of postnatal sheep
- Follistatin serum concentrations during full-term labour in women – significant differences between spontaneous and induced labour
- Glucocorticoid exposure and tissue gene expression of 11β HSD-1, 11β HSD-2, and glucocorticoid receptor in a porcine model of differential fetal growth
- Leukotrienes modulate secretion of progesterone and prostaglandins during the estrous cycle and early pregnancy in cattle: an in vivo study
- Obesity, insulin resistance, and pregnancy outcome
- Obesity, pregnancy, inflammation, and vascular function
- Remodelling at the maternal–fetal interface: relevance to human pregnancy disorders
- Heifer nutrient intake during early- and mid-gestation programs adult offspring adiposity and mRNA expression of growth-related genes in adipose depots
- Molecular regulators of resolution of inflammation: potential therapeutic targets in the reproductive system
- Novel insights into the mechanisms of pregnancy establishment: regulation of prostaglandin synthesis and signaling in the pig
- Preconception omega-3 fatty acid supplementation of adult male mice with a history of developmental 2,3,7,8-tetrachlorodibenzo- p -dioxin exposure prevents preterm birth in unexposed female partners
- Suboptimal maternal nutrition, during early fetal liver development, promotes lipid accumulation in the liver of obese offspring
- Circulating microRNAs are elevated in plasma from severe preeclamptic pregnancies
- Investigations into the mechanisms controlling parturition in cattle
- Neonatal hormone changes and growth in lambs born to dams receiving differing nutritional intakes and selenium supplementation during gestation
- Influence of infection during pregnancy on fetal development
- Prokineticin 1 induces a pro-inflammatory response in murine fetal membranes but does not induce preterm delivery
- Prokineticin receptor variants ( PKR1-I379V and PKR2-V331M ) are protective genotypes in human early pregnancy
- The role of endocannabinoids in pregnancy
- Balanced levels of nerve growth factor are required for normal pregnancy progression
- Determinants of maternal pregnancy one-carbon metabolism and newborn human DNA methylation profiles
- Effects of cytokine-suppressive anti-inflammatory drugs on inflammatory activation in ex vivo human and ovine fetal membranes
- The evolution of viviparity: molecular and genomic data from squamate reptiles advance understanding of live birth in amniotes
- Exosomes, endogenous retroviruses and toll-like receptors: pregnancy recognition in ewes
- Regulation of postnatal pancreatic Pdx1 and downstream target genes after gestational exposure to protein restriction in rats
- Role of the endocannabinoid system in the mechanisms involved in the LPS-induced preterm labor
- Convergent evolution of pregnancy-specific glycoproteins in human and horse
- Early pregnancy modulates survival and apoptosis pathways in the corpus luteum in sheep
- Endocannabinoid system and pregnancy
- Marginal zone B cells emerge as a critical component of pregnancy well-being
- Altered miRNA-profile dependent on ART outcome in early pregnancy targets Wnt-pathway
- Progress in the understanding of the etiology and predictability of fetal growth restriction