ABSTRACT The oxygen supply of the fetus depends on the blood oxygen content and flow rate in the uterine and umbilical arteries and the diffusing capacity of the placenta. Oxygen consumption by the placenta is a significant factor and a potential limitation on availability to the fetus. The relevance of these several factors as well as responses to acute or sustained hypoxia has been explored in the sheep model. In addition, much has been learned in the context of hypobaric hypoxia by studying human populations that have resided at high altitude for varying periods of time. Embryonic development occurs under anaerobic conditions and even the fetus is adapted to a low oxygen environment. Nevertheless, there is a reserve capacity, and during acute hypoxia the fetus can counter a 50% reduction in oxygen delivery by increasing fractional extraction. During sustained hypoxia, on the other hand, fetal growth is slowed, although oxygen consumption is unaltered when corrected for fetal mass. Similarly, birth weight is reduced in humans living at high altitude even if the effect is tempered in those with a long highland ancestry. Placental mass changes little during sustained hypoxia in sheep or humans at high altitude. This conceals the fact that there are structural changes and that placental oxygen consumption is reduced. The underlying mechanisms are a current focus of research. One intriguing possibility is that increased anaerobic metabolism of glucose in the placenta spares oxygen for the fetus but reduces its supply of substrate and thereby limits fetal growth. © 2015 American Physiological Society. Compr Physiol 5:1381‐1403, 2015.

Amniotic fluid is a complex biological medium that surrounds the fetus and offers not only mechanical protection but also provides nutrition and plays a critical role in normal fetal growth, organogenesis, and potentially fetal programming. Despite its importance, the biology of amniotic fluid has been understudied because of ethical and technical challenges in obtaining amniotic fluid samples from healthy human pregnancies, translational limitations of animal models to humans due to species-specific differences. Recent progress in understanding its dynamic physiology, composition, and clinical applications has advanced prenatal care and facilitated improved diagnostic and therapeutic strategies. As research continues to elucidate the complexities and evolutionary function of amniotic fluid, its increasingly recognized role in maternal-fetal medicine and its potential to transform clinical practice will only become more evident. The purpose of this review is to underscore the key roles of amniotic fluid in shaping fetal development and therapeutic potential. Despite its importance, the biology of amniotic fluid has been understudied because of ethical and technical challenges in obtaining amniotic fluid samples from healthy human pregnancies, translational limitations of animal models to humans due to species-specific differences. Recent progress in understanding its dynamic physiology, composition, and clinical applications has advanced prenatal care and facilitated improved diagnostic and therapeutic strategies. Its composition and function undergo significant temporal changes that reflect its multifactorial contributions to maternal-fetal health 2 . Historically, amniotic fluid has been understudied compared to other elements at the maternal-fetal interface, such as the placenta, because of the challenges in obtaining amniotic fluid samples throughout pregnancy. However, advances in ultrasonography and biology have substantially enhanced our understanding of its physiologic importance. Beyond serving as a protective biological medium, amniotic fluid has also emerged as a potential diagnostic and therapeutic resource. Fetuses with gastrointestinal obstruction, either anatomic or functional, that prevents fetal amniotic fluid digestion are frequently growth restricted 23 , 24 , 25 . Ligation of the esophagus in animal models results in reduced intestinal growth, villus blunting, mucosal atrophy, and enterocyte structural changes 26 , 27 —human infants with intestinal obstruction preventing gastrointestinal amniotic fluid intake demonstrate similar intestinal epithelial changes distal to the obstruction 23 . In human fetuses, it is unclear whether lung fluid flow is two-way, with lung fluid flowing out of the lungs into the amniotic fluid and amniotic fluid returning into the lungs with fetal breathing movements or is one-way, in which the trachea acts as a one-way valve that prevents amniotic fluid from entering the lung 35 . Late-gestation The maintenance of amniotic fluid volume depends on an equilibrium between production, absorption, and circulation ( Figure 3 ). Fetal swallowing plays a critical role in both regulating fluid volume and contributing to gastrointestinal maturation. Evidence suggests that specific fetal stimuli can decrease pulmonary fluid production, including increased levels of epinephrine, cortisol, and other hormones released during labor 37 . This may potentially explain the greater fluid clearance observed in neonates delivered vaginally compared to those delivered via cesarean section 38 . Because active stimuli primarily lead to decreased production, it is unlikely that these mechanisms play a significant role in amniotic fluid regulation, but rather primarily facilitate fetal airway development 39 , 40 , 41 , 42 . Clinical Applications Amniotic fluid has several clinical applications, including pregnancy monitoring and evaluation. Challenges to Research There is limited knowledge regarding amniotic fluid because it is understudied. Barriers to amniotic fluid research include the difficulties in obtaining amniotic fluid samples from healthy human pregnancies, lack of longitudinal profiling, and the prior absence of a relevant animal model. More recently, the non-human primate has shown promise as a translational platform for amniotic fluid studies 2 , 68 . The impacts of amnioinfusion with a fluid that more closely mimics amniotic fluid remain to be investigated. The advances in neonatal intensive care support combined with the significant morbidity and mortality associated with extreme prematurity have inspired development of artificial womb and artificial placenta technologies, in which systems incorporate a fluid filled bag with artificial amniotic fluid consisting of slow continuous normal saline fluid exchange that mixes with fetal lung fluid and urine produced by the fetus 88 , 89 . Notably, the mechanisms by which some fetuses with congenital anomalies—particularly those expected to alter fluid turnover—maintain normal amniotic fluid volumes remain poorly understood. The identification of additional regulatory pathways, including maternal, placental, and fetal contributions to fluid volume and composition, represents an important area for future investigation. Furthermore, renewed attention to previously underexplored strategies, such as intraamniotic drug delivery and computational modeling of amniotic fluid dynamics, may yield novel insights and therapeutic avenues. Jang Y, Kim EK, Shim WS, Song KM, Kim SM. Amniotic fluid exerts a neurotrophic influence on fetal neurodevelopment via the ERK/GSK-3 pathway. Biol Res 2015, 48(1): 44. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 95. Brace RA. Physiology of amniotic fluid volume regulation. Clin Obstet Gynecol 1997, 40(2): 280–289. [ DOI ] [ PubMed ] [ Google Scholar ] 96. Abramovich DR, Garden A, Jandial L, Page KR. Fetal swallowing and voiding in relation to hydramnios. Obstet

Amniotic fluid (AF) is a biological fluid in which metabolite transport is regulated by the placenta, the permeable skin, fetal lung egress and gastric fluid. During pregnancy, the composition of AF changes from similar to the interstitial fluid of the mother, to a more complex system, influenced by the fetus's urine. Since AF reflects the mother's and the fetus's health status at the same time, it may be an important diagnostic tool for a wider spectrum of clinical conditions. Indeed, the metabolic characterization of AF in relation to pathological occurrences may lead to the discovery of new biomarkers for a better clinical practice. For this reason, metabolomics may be the most suitable strategy for this task. In this review, research works on metabolomic AF analysis are discussed according to the morbidity of interest, being preterm birth/labor, gestational age and diabetes and fetal malformations, along with a number of other important studies.