Regulation Of Amniotic Fluid Volume Research Articles

Recurrence of idiopathic polyhydramnios: A nationwide population study.

Polyhydramnios occurs in approximately 1% of pregnancies, and idiopathic polyhydramnios (IPH) manifests with an unknown cause in 40–50% of all cases.1 Elucidating whether there is a recurrence risk will add to a better and more complete understanding of IPH.2 The objective of the present study was to calculate an odds ratio (OR) for recurrence of IPH in parous women and across generations. This was achieved by utilizing data from the compulsory Medical Birth Registry of Norway (MBRN), including all singleton births between 1967 and 2017 (n = 2 741 480). The midwife or physician attending the birth clinically judged the amount of amniotic fluid and reported this (oligohydramnios, normal, or polyhydramnios) in their notification to the registry. Polyhydramnios without fetal syndromes, malformations, infections, immunization, or maternal diabetes mellitus was defined as IPH. The authors linked the subsequent births of each woman, and across generations, by using unique national identification numbers. We calculated ORs (with 95% confidence intervals [CI]) and adjusted ORs (AOR) for recurrent IPH in subsequent births and across generations using multilevel logistic regression analysis. Possible confounding factors included: maternal age, body mass index, medical conditions, parity, smoking habits, year of birth, birthweight, placental weight, and sex of the neonate. The Regional Ethics Committee (2013/1484) and the registry owners provided ethical approval for the study protocol. SPSS version 26 (IBM Corp.) and MLwiN version 3.05 was used for analysis. IPH occurred in 0.6% of births and increased in incidence during the study period in question (0.4–1.1%). Women with a history of IPH in the first pregnancy had a seven-fold risk of IPH in the second pregnancy (Table 1). The OR of recurrence in subsequent births increased according to IPH status in the previous births. The OR of inter-generational recurrence was three-fold. Including the year of birth in the model attenuated the risk of recurrence, while including maternal or pregnancy factors did not significantly alter the results, and, therefore, were not included in the final model. A sensitivity-analysis, performed with Bayesian regression, suggested that recurrence of IPH was robust for unknown confounding factors. IPH tended to recur in subsequent births in a dose-response pattern according to history of IPH, and between generations, suggesting an influence of hereditary and/or sustained environmental factors in the regulation of amniotic fluid volume. Although validation studies have shown that the MBRN holds high quality data and is suitable for epidemiological research,3 the clinical variables describing amniotic fluid volume remains to be validated. The strengths of the present study are its prospective data collection, the population-based design, and essentially complete record linkage. The Medical Birth Registry of Norway for providing the datafile. The authors have no conflicts of interest. SR contributed to the study methodology, data curation, validation, manuscript drafting, review and editing of the manuscript, and study supervision. LL was responsible for the study methodology, data curation, formal analysis, drafting of the manuscript, and review and editing of the manuscript. CE contributed to the study conceptualization, methodology, formal analysis, project administration, writing of the original draft of the manuscript, and review and editing of the manuscript. All authors contributed to and approved of the version of the manuscript to be published.

Regulation of amniotic fluid volume: insights derived from amniotic fluid volume function curves.

Recent advances in understanding the regulation of amniotic fluid volume (AFV) include that AFV is determined primarily by the rate of intramembranous absorption (IMA) of amniotic fluid across the amnion and into fetal blood. In turn, IMA rate is dependent on the concentrations of yet-to-be identified stimulator(s) and inhibitor(s) that are present in amniotic fluid. To put these concepts in perspective, this review 1) discusses the evolution of discoveries that form the current basis for understanding the regulation of AFV, 2) reviews the contribution of IMA to this regulation, and 3) interprets experimentally induced shifts in AFV function curves and amnioinfusion function curves in terms of the activity of the amniotic fluid stimulator and inhibitor of IMA. In the early 1980s, it was not known whether AFV was regulated. However, by the late 1980s, IMA was discovered to be a "missing link" in understanding the regulation of AFV. Over the next 25 years the concept of IMA evolved from being a passive process to being an active, unidirectional transport of amniotic fluid water and solutes by vesicles within the amnion. In the 2010s, it was demonstrated that a renally derived stimulator and a fetal membrane-derived inhibitor are present in amniotic fluid that regulate IMA rate and hence are the primary determinants of AFV. Furthermore, AFV function curves and amnioinfusion function curves provide new insights into the relative efficacy of the stimulator and inhibitor of IMA.

MAGED2: a novel form of antenatal Bartter's syndrome.

Antenatal Bartter's syndrome (aBS) is the most severe form of Bartter's syndrome, requiring close follow-up, in particular during the neonatal period, primarily because of prematurity. The recent identification of a novel and very severe form of aBS merits an update on this topic. Despite the identification of several genes involved in Bartter's syndrome, about 20% of patients clinically diagnosed with aBS remained without genetic explanation for decades. We recently identified mutations in MAGED2 as a cause of an X-linked form of aBS characterized by a very early onset of severe polyhydramnios and extreme prematurity leading to high mortality. Remarkably, all symptoms in surviving patients with MAGE-D2 mutations resolve spontaneously, within weeks after preterm birth. Interestingly, MAGE-D2 affects the expression of the sodium chloride cotransporters NKCC2 and NCC, explaining thereby the severity of the disease. Importantly, a more recent analysis of MAGED2 in a large French cohort of patients with aBS confirmed our data and showed that females can also be affected. MAGE-D2 is critical for renal salt reabsorption in the fetus, amniotic fluid volume regulation, and maintenance of pregnancy. Most importantly, MAGED2 must be included in the genetic screening of every form of aBS.

Aquaporin 1 gene deletion affects the amniotic fluid volume and composition as well as the expression of other aquaporin water channels in placenta and fetal membranes

ObjectiveTo explore the role of aquaporin 1 (AQP1) in regulation of amniotic fluid volume and composition. To investigate the effects of AQP1 gene knockout on expression of other aquaporin water channels (AQP3, AQP8 and AQP9) in placentas and fetal membranes. MethodsMice were sacrificed at 9.5, 13.5 and 16.5 gestational day (GD). Amniotic fluid volume, osmolality and composition, fetal membranes, placental and fetal weights as well as placenta areas were recorded in Aqp1 homozygote conceptus group, heterozygote conceptus group and wild-type group, respectively. The expression of AQP1, AQP3, AQP8 and AQP9 mRNA and protein in placenta and fetal membranes were examined by quantitative Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and Western blotting. ResultsAqp1 homozygote conceptus had a greater volume of amniotic fluid, lower osmolality and calcium concentration than their wild-type counterparts at 16.5 GD. There was no significant difference in expression of AQP1, AQP3, AQP8 and AQP9 in placentas among three groups. While expression of AQP8 was increased at 13.5 and 16.5 GD in fetal membranes, the expression of AQP9 was significantly decreased in fetal membranes in Aqp1 homozygote group compared with Aqp1 heterozygote and wild-type groups. ConclusionAQP1 may play an important role in the homeostasis of maternal-fetal fluid at late gestation days. The mechanism of mutual compensation among AQPs gene needs further investigation.

Vesicular uptake of macromolecules by human placental amniotic epithelial cells

IntroductionStudies in animal models have shown that unidirectional vesicular transport of amniotic fluid across the amnion plays a primary role in regulating amniotic fluid volume. Our objective was to explore vesicle type, vesicular uptake and intracellular distribution of vesicles in human amnion cells using high- and super-resolution fluorescence microscopy. MethodsPlacental amnion was obtained at cesarean section and amnion cells were prepared and cultured. At 20%–50% confluence, the cells were incubated with fluorophore conjugated macromolecules for 1–30 min at 22 °C or 37 °C. Fluorophore labeled macromolecules were selected as markers of receptor-mediated caveolar and clathrin-coated vesicular uptake as well as non-specific endocytosis. After fluorophore treatment, the cells were fixed, imaged and vesicles counted using Imaris® software. ResultsVesicular uptake displayed first order saturation kinetics with half saturation times averaging 1.3 min at 37 °C compared to 4.9 min at 22 °C, with non-specific endocytotic uptake being more rapid at both temperatures. There was extensive cell-to-cell variability in uptake rate. Under super-resolution microscopy, the pattern of intracellular spatial distribution was distinct for each macromolecule. Co-localization of fluorescently labeled macromolecules was very low at vesicular dimensions. ConclusionsIn human placental amnion cells, 1) vesicular uptake of macromolecules is rapid, consistent with the concept that vesicular transcytosis across the amnion plays a role in the regulation of amniotic fluid volume; 2) uptake is temperature dependent and variable among individual cells; 3) the unique intracellular distributions suggest distinct functions for each vesicle type; 4) non-receptor mediated vesicular uptake may be a primary vesicular uptake mechanism.

Регуляция объема амниотической жидкости

Регуляция объема амниотической жидкости

Regulation of amniotic fluid volume: mathematical model based on intramembranous transport mechanisms.

Experimentation in late-gestation fetal sheep has suggested that regulation of amniotic fluid (AF) volume occurs primarily by modulating the rate of intramembranous transport of water and solutes across the amnion into underlying fetal blood vessels. In order to gain insight into intramembranous transport mechanisms, we developed a computer model that allows simulation of experimentally measured changes in AF volume and composition over time. The model included fetal urine excretion and lung liquid secretion as inflows into the amniotic compartment plus fetal swallowing and intramembranous absorption as outflows. By using experimental flows and solute concentrations for urine, lung liquid, and swallowed fluid in combination with the passive and active transport mechanisms of the intramembranous pathway, we simulated AF responses to basal conditions, intra-amniotic fluid infusions, fetal intravascular infusions, urine replacement, and tracheoesophageal occlusion. The experimental data are consistent with four intramembranous transport mechanisms acting in concert: 1) an active unidirectional bulk transport of AF with all dissolved solutes out of AF into fetal blood presumably by vesicles; 2) passive bidirectional diffusion of solutes, such as sodium and chloride, between fetal blood and AF; 3) passive bidirectional water movement between AF and fetal blood; and 4) unidirectional transport of lactate into the AF. Further, only unidirectional bulk transport is dynamically regulated. The simulations also identified areas for future study: 1) identifying intramembranous stimulators and inhibitors, 2) determining the semipermeability characteristics of the intramembranous pathway, and 3) characterizing the vesicles that are the primary mediators of intramembranous transport.

Regulation of amniotic fluid volume: evolving concepts.

Studies in late gestation fetal sheep have provided several new insights into the regulation of amniotic fluid (AF) volume (AFV): There are four quantitatively important amniotic inflows and outflows that include fetal urine production, lung liquid secretion, swallowing, and intramembranous absorption. Of these, AFV is regulated primarily by modulating the rate of intramembranous absorption of AF water and solutes across the amniotic epithelial cells into the underlying fetal vasculature. Modulation of the rate of intramembranous absorption depends on the presence of stimulators and inhibitors present in the AF. A stimulator of intramembranous absorption is present in fetal urine. In addition, AF contains a non-renal, non-pulmonary inhibitor of intramembranous absorption presumably secreted by the fetal membranes. Although passive bidirectional movements of water and solutes occur across the intramembranous pathway, intramembranous absorption is primarily a unidirectional, vesicular, bulk transport process mediated through VEGF activation of transcytotic transport via caveolae. Further, the stimulators and inhibitors of intramembranous absorption alter only the active, unidirectional component of intramembranous absorption while the passive components are not altered under experimental conditions studied thus far. Future progress depends on identifying the cellular and molecular mechanisms that regulate active and passive intramembranous absorption as well as their regulatory components.

English

BACKGROUND: Due to active involvement of fetal system in regulation of amniotic fluid volume, AFI has been identified as indicator of intrauterine fetal status. USG has revolutionized the process of assessment of amniotic fluid thus becoming an integral part of fetal surveillance. Polyhydramnios is an obstetrical condition associated with significant perinatal and maternal morbidity and mortality. In a low resource health facility as India with poor coverage of antenatal care and malnutrition it still becomes more important to screen pregnancies for such high risk factors. AIMS: 1. To study incidence of polyhydramnios. 2. To identify major etiological factors of polyhydramnios. 3. To study perinatal outcome. SETTINGS AND DESIGN: A hospital based cross section study for duration from 1 st May 2009 to 31 st October 2010. MATERIAL & METHOD: All the cases identified as polyhydramnios according to AFI in four pocket were included in the study. The cases identified as having polyhydramnios but not delivered at the facility were excluded. OBSERVATION: Incidence of polyhydramnios is 0.72% of the total antenatal cases, multiparous ie, 52% more than primiparous cases. Majority were unbooked (77.3%) 63% were from rural set up. 76% belonged to low socio economic status. Majority 66% of the cases had their 1 st antenatal visit at term. Increased incidence of operative delivery was seen in the study. Associated maternal factors found with polyhydramnios were gestation hypertension (8.4%), preeclampsia (2.9%), eclampsia (2.9%), anaemia (11%), twins (8.4%), malpresentation (5%), RH negative factor (3.7%), and diabetes (1.9%). Fetal complication include prematurity 21.6%, IUFT 20.7%, congenital malformation 21.6%, cord prolapse 3.7%, birth asphyxia 1.9%. Most common congenital anomaly was anencephaly i.e., 11%. CONCLUSION: The study gives us the understanding of the impact of polyhydramnios on the maternal and fetal outcome. Our study demonstrates that careful fetal examination has to be performed when polyhydramnios is diagnosed as congenital malformations are often associated with this condition. These anomalies if detected early timely termination of pregnancy can be done hence less physical and psychological trauma to mother. Also antenatal visits play important role in early diagnosis of high risk pregnancy like polyhydramnios.

Regulation of intramembranous absorption and amniotic fluid volume by constituents in fetal sheep urine

Our objective was to test the hypothesis that fetal urine contains a substance(s) that regulates amniotic fluid volume by altering the rate of intramembranous absorption of amniotic fluid. In late gestation ovine fetuses, amniotic fluid volumes, urine, and lung liquid production rates, swallowed volumes and intramembranous volume and solute absorption rates were measured over 2-day periods under control conditions and when urine was removed and continuously replaced at an equal rate with exogenous fluid. Intramembranous volume absorption rate decreased by 40% when urine was replaced with lactated Ringer solution or lactated Ringer solution diluted 50% with water. Amniotic fluid volume doubled under both conditions. Analysis of the intramembranous sodium and chloride fluxes suggests that the active but not passive component of intramembranous volume absorption was altered by urine replacement, whereas both active and passive components of solute fluxes were altered. We conclude that fetal urine contains an unidentified substance(s) that stimulates active intramembranous transport of amniotic fluid across the amnion into the underlying fetal vasculature and thereby functions as a regulator of amniotic fluid volume.

The expression of aquaporin 8 and aquaporin 9 in fetal membranes and placenta in term pregnancies complicated by idiopathic polyhydramnios

Background Aquaporins are a family of membrane-bound water channel proteins that regulate the flow of water across a variety of biological membranes. The expression of aquaporin 8 and aquaporin 9 has been demonstrated in human chorioamniotic membrane and placenta. But their roles in the pathophysiology of polyhydramnios are unclear. Aims To study the expression of aquaporin 8 and aquaporin 9 in fetal membranes and placenta in term pregnancies complicated by idiopathic polyhydramnios and to explore the association between aquaporin expressions and polyhydramnios. Subjects The placentas were collected from 51 patients who underwent elective Cesarean sections at term, of which 21 cases had idiopathic polyhydramnios and the other 30 had normal amniotic fluid volume. Outcome measures Real-time polymerase chain reaction and immunohistochemistry techniques were used to determine the expression and localization of aquaporin 8 and aquaporin 9 in the amnion, chorion and placenta. Results Expression of aquaporin 8 and aquaporin 9 was detected in the amnion, chorion and placenta and located in amnion epithelia, chorion cytotrophoblasts and placental trophoblast. Compared to normal amniotic fluid volume group, the expression of aquaporin 8 in amnion, and aquaporin 9 in amnion and chorion, were significantly increased in idiopathic polyhydramnios group; however, their expression in the placenta was significantly decreased. Conclusions When polyhydramnios occurs, expression of aquaporin 8 and aquaporin 9 in fetal membranes and placenta is an adaptive change, which may be involved in the regulation of amniotic fluid volume. However, the modulation factors of the aquaporin 8 and aquaporin 9 expressions need further study.

Expression of aquaporin 8 in human fetal membrane and placenta of idiopathic polyhydramnios

To determine the expression of Aquaporin 8(AQP8) in the fetal membrane and placenta of idiopathic polyhydramnios. The amnion, chorion and placenta were collected from 12 term pregnancies with idiopathic polyhydramnios( polyhydramnios group) and 12 term pregnancies who were normal (control group). The expression of AQP8 mRNA was detected by reverse transcription-polymerase chain reaction (RT-PCR). The expression of AQP8 protein was detected by immunohistochemistry. The expression of AQP8 mRNA in amnion, chorion and placenta of polyhydramnios group was (0.78 +/- 0.13), (0.58 +/- 0.10), and (0.86 +/- 0.15) respectively, and that of control group was (0. 39 0.07), (0.45 +/- 0.09), and (0.34 +/- 0.09) respectively. The expression of AQP8 protein in amnion, chorion and placenta of polyhydramnios group was (0.195 +/- 0.024), (0.170 +/- 0.028), and (0.193 +/- 0.024) respectively, and that of control group was (0.151 +/- 0.018), (0.156 +/- 0.024), and (0.152 +/- 0.023) respectively. In all 3 types of tissues the expression of AQP8 mRNA of polyhydramnios group was higher than that of control group (P < 0.05). In amnion and placenta the expression of AQP8 protein of polyhydramnios group was also increased compared to that of control group (P < 0.05), but in chorion the difference in AQP8 protein expression between the two groups was not significant (P > 0.05). The expression of AQP8 mRNA and protein is significantly increased in the amnion and placenta of polyhydramnios, suggesting that AQP8 may play an important role in the regulation of amniotic fluid volume.

Regulation of Amniotic Fluid Volume

Water arrives in the mammalian gestation from the maternal circulation across the placenta. It then circulates between the fetal water compartments, including the fetal body compartments, the placenta and the amniotic fluid. Amniotic fluid is created by the flow of fluid from the fetal lung and bladder. A major pathway for amniotic fluid resorption is fetal swallowing; however, in many cases the amounts of fluid produced and absorbed do not balance. A second resorption pathway, the intramembranous pathway (across the amnion to the fetal circulation), has been proposed to explain the maintenance of normal amniotic fluid volume. Amniotic fluid volume is thus a function both of the amount of water transferred to the gestation across the placental membrane, and the flux of water across the amnion. Water flux across biologic membranes may be driven by osmotic or hydrostatic forces; existing data suggest that intramembranous flow in humans is driven by the osmotic difference between the amniotic fluid and the fetal serum. The driving force for placental flow is more controversial, and both forces may be in effect. The mechanism(s) responsible for regulating water flow to and from the amniotic fluid is unknown. In other parts of the body, notably the kidney, water flux is regulated by the expression of aquaporin water channels on the cell membrane. We hypothesize that aquaporins have a role in regulating water flux across both the amnion and the placenta, and present evidence in support of this theory. Current knowledge of gestational water flow is sufficient to allow prediction of fetal outcome when water flow is abnormal, as in twin–twin transfusion syndrome. Further insight into these mechanisms may allow novel treatments for amniotic fluid volume abnormalities with resultant improvement in clinical outcome.

Amniotic Fluid Water Dynamics

Water arrives in the mammalian gestation from the maternal circulation across the placenta. It then circulates between the fetal water compartments, including the fetal body compartments, the placenta and the amniotic fluid. Amniotic fluid is created by the flow of fluid from the fetal lung and bladder. A major pathway for amniotic fluid resorption is fetal swallowing; however in many cases the amounts of fluid produced and absorbed do not balance. A second resorption pathway, the intramembranous pathway (across the amnion to the fetal circulation), has been proposed to explain the maintenance of normal amniotic fluid volume. Amniotic fluid volume is thus a function both of the amount of water transferred to the gestation across the placental membrane, and the flux of water across the amnion. Membrane water flux is a function of the water permeability of the membrane; available data suggests that the amnion is the structure limiting intramembranous water flow. In the placenta, the syncytiotrophoblast is likely to be responsible for limiting water flow across the placenta. In human tissues, placental trophoblast membrane permeability increases with gestational age, suggesting a mechanism for the increased water flow necessary in late gestation. Membrane water flow can be driven by both hydrostatic and osmotic forces. Changes in both osmotic/oncotic and hydrostatic forces in the placenta my alter maternal-fetal water flow. A normal amniotic fluid volume is critical for normal fetal growth and development. The study of amniotic fluid volume regulation may yield important insights into the mechanisms used by the fetus to maintain water homeostasis. Knowledge of these mechanisms may allow novel treatments for amniotic fluid volume abnormalities with resultant improvement in clinical outcome.

Reduction of aquaporin‐8 on fetal membranes under oligohydramnios in mice lacking prostaglandin F2α receptor

To investigate the association between aquaporin-8 (AQP-8: a water channel protein) expression in fetal membranes and oligohydramnios during near-term and postdate pregnancy, we set up an oligohydramnios model using prostaglandin F2 alpha receptor (FP)-deficient mice. Pregnant FP-deficient mice from 14 to 21 gestational days (GD) were killed to measure the amniotic fluid volume (AFV), and fetal membranes were collected for the analysis of aquaporin-8 expression. The AFV was highest at 14 GD, and was significantly decreased to 28% and 0% at 20 GD and 21 GD, respectively, compared with the volume at 14 GD. Immunohistochemistry and immunoblot analysis showed that aquaporin-8 was expressed in the basal component of fetal membranes, and that the protein level was significantly decreased to 60% at 20 GD compared with that at 14 GD. We demonstrated that AQP-8 expression in the fetal membrane was decreased at post term in FP-deficient mice. Our findings suggest that aquaporin-8 in fetal membranes may be involved in the regulation of AFV, especially when oligohydramnios occurs.

Amniotic Fluid Dynamics

After completing this article, readers should be able to: 1. Describe clinical assessments of amniotic fluid volume. 2. Explain the processes of amniotic fluid formation and removal. 3. Describe the presentations and treatments for oligohydramnios and polyhydramnios. Fortunately for most healthy pregnant women, amniotic fluid (AF) is an unimportant byproduct of the delivery. Little attention, if any, is paid to the AF unless meconium staining occurs in labor. It is only in the presence of certain complications that may compromise fetal well-being that any interest is taken in the AF. When there is too much AF (polyhydramnios) or too little (oligohydramnios), perinatal morbidity or mortality may be increased significantly, raising sudden concern among patients and clinicians. When severe oligohydramnios occurs in the second trimester, the perinatal mortality rate approaches 90% to 100%. (1)(2)(3) Similarly, with severe polyhydramnios in mid-pregnancy, the perinatal mortality rate can be greater than 50%. (4)(5) Attempts to study abnormalities of AF are hindered by the realization that little is known about the processes involved in the regulation of normal amniotic fluid volume (AFV). This review examines the limited information available on the normal physiology of AFV regulation, including routes of formation, removal, and regulation and the changes in AF composition across gestation. Additionally, the clinical impact and treatment options on disease conditions are discussed. Attempts to measure actual AFV are limited by the invasiveness required to access the amniotic cavity. The most common method is injection of an inert dye into the amniotic cavity via amniocentesis, followed by timed removals of AF to determine a dilution curve. (6)(7)(8)(9) This method has been shown to be accurate compared with actual measurement of AF, but because of its invasive nature, has limited application to clinical practice. Brace and Wolf …

N-Methyl-D-Aspartate Glutamate Receptor Mediates Spontaneous and Angiotensin II-Stimulated Ovine Fetal Swallowing

In adult rats, N-methyl-D-aspartate (NMDA) receptors have been implicated in the central control of body fluid homeostasis, as intracerebroventricular (ICV) injection of NMDA receptor antagonists suppresses stimulated drinking behavior. Fetal swallowing occurs at a significantly higher rate as compared to adult drinking, contributing to amniotic fluid volume regulation and fetal gastrointestinal development. The aim of present study was to determine the role of central NMDA receptors in the modulation of fetal swallowing activity. Eight time-dated pregnant ewes and fetuses were chronically prepared with fetal vascular and ICV catheters, electrocorticogram (ECoG), and esophageal electromyogram electrodes and studied at 130 +/- 1 days' gestation. Following an initial 2-hour baseline period (time 2 h), the NMDA receptor antagonist, dizocipline (1 mg), was injected ICV. At time 4 h, the dose of dizocipline was repeated, together with angiotensin II (AngII, 6.4 microg). Fetal swallowing was monitored for 2 hours after each injection. Four of these fetuses also received an identical control study (on an alternate day) in which dizocipline was replaced with artificial cerebrospinal fluid (aCSF). ICV dizocipline injection nearly abolished spontaneous fetal swallowing activities (0.6 +/- 0.1 to 0.2 +/- 0.1 swallows/min; P < .001). ICV AngII in the presence of dizocipline did not demonstrate a dipsogenic effect on fetal swallowing (0.1 +/- 0.1; P < .001). In the control study, ICV injection of aCSF did not change fetal swallowing activity (1.0 +/- 0.1 swallows/min), while ICV AngII resulted in a significant increase in fetal swallowing (2.0 +/- 0.1 swallows/min; P < .001). This study demonstrates that central NMDA-glutamate receptor-mediated activity contributes to the high rate of spontaneous and AngII-stimulated fetal swallowing. We speculate that reduced NMDA receptor expression within the forebrain dipsogenic neurons may account for observed differences in drinking activities between the fetus/neonate and the adult.

A novel model of polyhydramnios: amniotic fluid volume is increased in aquaporin 1 knockout mice

To test the hypothesis that amniotic fluid volume is increased in aquaporin 1 knockout mice. Transgenic mice deficient in aquaporin 1 protein were generated by targeted gene disruption, as described previously. After a cesarean section was performed, intact, individual gestational sacs were removed from the uterus and weighed. Amniotic fluid volume, osmolality, and fetal and placental weights were determined. Data were analyzed by a 1-way analysis of variance for ranks; Dunn's post hoc test was used to analyze significant trends. Analysis of 16 litters showed 35 wild-type, 52 heterozygote, and 33 aquaporin 1 knockout mice. The knockout mice had a greater volume of amniotic fluid and lower amniotic fluid osmolality than their wild-type and heterozygote counterparts. There were no significant differences in fetal or placental weights among the groups. Aquaporin 1 null fetuses produce a greater volume of more dilute amniotic fluid. Our findings show that aquaporin 1 water channels in fetal membranes may contribute to amniotic fluid volume regulation. We speculate that idiopathic polyhydramnios may be associated with a deficiency of aquaporin 1 channels in human fetal membranes. Transgenic aquaporin 1 knockout mice provide a unique animal of polyhydramnios.

Regulation of amniotic fluid volume: Intramembranous solute and volume fluxes in late gestation fetal sheep

Objective Recent studies suggest that amniotic fluid volume is regulated by the rate of intramembranous absorption of amniotic fluid into fetal blood. The purpose of the present study was to determine the simultaneous intramembranous solute and water fluxes to gain insight into the intramembranous transport and amniotic fluid volume regulatory mechanisms. Study design All major amniotic inflows and outflows, except intramembranous flow, were eliminated in 10 fetal sheep over 8 hours by occlusion of the fetal trachea and esophagus; the fetal urine was drained to the exterior. Amniotic fluid composition and volume were measured before and at the end of the 8 hours. Solute and volume fluxes through the intramembranous pathway were calculated from amniotic fluid concentration and volume changes. Statistical analyses included t-tests, linear regression, and analyses of variance. Results Amniotic fluid volume decreased by 128 ± 24 (SE) mL over 8 hours ( P < .001), which was correlated only marginally with the fetal to amniotic fluid osmotic gradient (r = 0.59; P >= >.072). Amniotic fluid sodium, chloride, calcium, and bicarbonate concentrations increased ( P < .0001), even though there were net outward fluxes of these solutes; these outward fluxes occurred against concentration gradients; and the clearances of these solutes were the same despite widely differing amniotic fluid concentrations and fetal blood to amniotic fluid concentration gradients. With the use of multivariate regression, intramembranous solute fluxes separated into 2 components, which were a primary outward flux that correlated with the volume flux and a minor inward component that correlated with the fetal plasma to amniotic fluid concentration gradient for sodium, chloride, calcium ( P < .001), and bicarbonate ( P < .02). The concentration-dependent fluxes averaged approximately one third of the bulk fluxes and were in the opposite direction. Conclusion The poor correlation of amniotic fluid volume reduction with the fetal-to-amniotic fluid osmotic gradient shows that the primary mechanism that mediates intramembranous volume flow is not passive osmosis in the normal fetus under basal conditions. The strong correlations of solute fluxes simultaneously with volume flux and concentration gradients suggest that intramembranous solute fluxes are mediated by both bulk flow and passive diffusion. The small size of the passive component relative to the size of the bulk component suggests that intramembranous solute transfer is mediated primarily by bulk flow with a smaller and usually oppositely directed contribution by diffusion down concentration gradients. Bulk flow by vesicular transport is the only known physiologic transport mechanism that is compatible with these data, but it is not known whether this occurs in the amnion or intramembranous blood vessels or both.

In utero development of fetal thirst and appetite: potential for programming.

Thirst and appetite-mediated ingestive behavior develop and are likely programmed in utero, thus preparing for newborn and adult ingestive behavior. Fetal swallowing activity is markedly different from that of the adult, as spontaneous fetal swallowing occurs at a markedly (six-fold) higher rate compared with spontaneous adult drinking activity. This high rate of fetal swallowing is critical for the regulation of amniotic fluid volume and the development of the fetal gastrointestinal tract. Disordered fetal swallowing has been associated with both a decrease (oligohydramnios) and increase (polyhydramnios) in amniotic fluid volume. Both conditions are associated with a significant increase in perinatal morbidity and mortality, and limited treatment modalities are currently available. The mechanisms underlying the high rate of human fetal swallowing are regulated, in part, by tonic activity of central angiotensin II, glutamate N-methyl-D-aspartate receptors, and neuronal nitric oxide synthase. Fetal hypertonicity-mediated dipsogenesis is likely programmed in utero, as offspring of water-restricted ewes demonstrate a programmed syndrome of plasma hypertonicity, with significant hematologic and cardiovascular alterations. Similar to dipsogenic mechanisms, peripheral and central fetal orexic mechanisms also develop in utero, as demonstrated by increased fetal swallowing after both oral sucrose infusion and central injection of neuropeptide Y. The role of leptin in regulating fetal ingestive behavior is interesting because, contrary to actions in adults, leptin does not suppress fetal ingestive behavior. Teleologically, this may be of value during the newborn period, as unopposed appetite stimulatory mechanisms may facilitate rapid fetal and newborn weight gain. An adverse intrauterine environment, with altered fetal orexic factors during the critical developmental period of fetal life, may alter the normal setpoints of appetitive behavior and potentially lead to programming of adulthood hyperphagia and obesity. Further research is needed to delineate the mechanistic relationship between the intrauterine environment and the development of the setpoints of adult appetite and thirst.