Fetal Water Balance

Water is the major component of cells and tissues and “is the basis for the physical and chemical conditions of life.” Within the body, water is distributed into two major compartments, intracellular water (ICW) and extracellular water (ECW). ECW is further divided into the plasma water (intravascular water) and interstitial water. The total amount of body water, as well as the distribution within the two major compartments, is developmentally regulated. During the first few months of fetal development, total body water (TBW) comprises over 90% of total body weight. By 6 months of gestation, TBW has decreased to approximately 86% and by term is approximately 76% of the body weight. During the last trimester, distribution of body water also changes; ECW decreases from 54% to 44% of body weight while ICW increases from 27% to 34% ( Fig. 10.1 ).

Total body water (TBW) content and fluid distribution between extracellular fluid (ECF) and intracellular fluid (ICF) compartments during fetal and postnatal life.

(Data modified from Friis-Hansen B. Body water compartments in children: changes during growth and selected changes in body composition. Pediatrics . 1961;28:169-181.)

Fluid balance in the fetus is dependent upon the movement of water from the maternal circulation across the placenta, primarily at the level of the syncytiotrophoblast. This water flow increases with advancing gestation to meet increasing fetal water needs for sustaining fetal cell growth and plasma volume, as well as amniotic fluid volume. Osmotic and hydrostatic forces promote placental water flow, although the contribution of each of these mechanisms during normal pregnancy is not known. Transcellular flow of solute-free water involves a family of cell membrane water channel proteins named aquaporins (AQPs), many of which appear to be developmentally regulated. Water exchange between the placenta, fetus, and amniotic fluid is poorly understood, although intramembranous flow across the amnion to the fetal circulation is important.

In humans the fetal metanephric kidney develops and begins to produce urine by 8 to 10 weeks of gestation. Fetal urine is the primary contributor to amniotic fluid volume during the last half of gestation. It has been estimated that in the healthy fetus, urine flow rate increases 10-fold, from 0.1 mL/min at 20 weeks to 1 mL/min at 40 weeks’ gestation. Fetal urine is typically hypotonic with respect to fetal plasma, the range of osmolality being 100 to 250 mOsm/kg H ₂ O. Although capable of producing diluted urine, the concentrating capacity of the fetal kidney is limited. Decreased sensitivity to arginine vasopressin (AVP), structural immaturity of the kidney, as well as the distribution of blood flow within the kidney likely contribute to this inability to concentrate urine.

Newborn Water Balance

Maintaining water and sodium balance following birth poses a unique challenge because the kidney is relatively immature, lacking fully functional regulatory systems. The ability to concentrate urine develops progressively during postnatal life. The term neonate can maximally concentrate urine to approximately half that of the older child or adult. Maturation of concentrating abilities occurs over the first 2 years of life, with urine osmolality exceeding 600 mOsm/L within a week of life, greater than 1000 mOsm/L by 1 month of age, and reaching adult values of 1300 to 1400 mOsm/L by 2 years of age. This limited concentrating ability of the infant kidney is of little importance unless the infant is provided formula with a high solute load, as occurred with some milk-based formulas in the 1950s to 1960s, in the presence of excessive water loss from diarrhea and/or fever or if intake is insufficient to cover obligatory water loss (e.g., insensible water loss, IWL). The preterm infant has a greater impairment of urine concentrating ability than the term infant likely related to a variety of functional and anatomic factors, although functional maturation progresses at a greater rate ex utero than in utero.

Infants born prematurely have higher TBW and ECW per kilogram than do term infants, whereas small-for-gestational-age infants have higher TBW and ECW than appropriate-for-gestational-age infants. After birth, TBW content continues to fall, primarily due to contraction of the extracellular space. The degree of contraction of the ECW compartment is inversely proportional to gestational age and greater in small-for-gestational-age than appropriate-for-gestational-age infants. Preterm infants may exhibit a 10% to 15% weight loss during the first week of life related to loss of ECW, whereas term infants generally exhibit a 5% to 7% weight loss. Failure to allow the normal postnatal contraction in ECW and weight loss in preterm infants may increase the risk of patent ductus arteriosus, necrotizing enterocolitis, and bronchopulmonary dysplasia. However, the optimal amount of weight loss is not known. ICW increases, decreases, or remains unchanged immediately after birth, although ICW increases approximately in proportion to body weight in the first few weeks of postnatal life. ICW continues to increase as a percent of body weight until exceeding that of ECW by 3 months of life.

Newborn water loss may occur by sensible (urine and stool) and insensible (evaporation from skin and with respiration) mechanisms. Urine production is necessitated by the need to excrete soluble waste products. The amount of urine produced is therefore governed by the renal solute load, comprised primarily of nitrogenous compounds and electrolytes, as well as the ability of the kidney to concentrate urine. Urine water loss is primarily regulated by water channels, or AQPs, which allow transcellular water reabsorption along the nephron segment. The majority of water from glomerular ultrafiltrate is reabsorbed in the proximal nephron via AQP1. Further refinement of water absorption and urinary concentrating ability is regulated by AQP2, located on collecting duct principal cells. AQP2 is the primary target for AVP, an antidiuretic hormone produced by the posterior pituitary gland in response to activation of osmoreceptors in the hypothalamus or baroreceptors in selected vasculature. The ontogenic pattern of AQP2 in the kidney parallels the development of AVP responsiveness and urinary-concentrating ability. The limited ability of the newborn kidney to concentrate urine in the presence of elevated AVP levels likely reflects the decreased number of AVP receptors or decreased responsiveness of downstream mechanisms following vasopressin receptor activation. The lack of concentration ability of the immature kidney results in higher obligate water losses and may predispose to hypertonic dehydration.

Fetal Sodium Balance

The fetus experiences an intake (net transplacental transfer) of sodium that greatly exceeds that of the newborn. Using a sodium tracer method, sodium transfer across the human placenta has been estimated to be approximately 130 mEq/day at term. Although a certain amount of water and sodium is retained by the fetus for growth, the healthy fetus excretes a large amount of sodium because renal mechanisms to retain sodium are relatively immature. Urinary excretion of sodium (U _Na V), and U _Na V normalized to glomerular filtration rate (GFR) and expressed as fractional excretion of sodium (FE _Na ), is greater in the fetus than the newborn. In fact, FE _Na is greater in the fetal sheep at 0.75 gestation (14%–15%) than 0.9 gestation (11%) or near term (5%, 145 days), suggesting developmental changes in renal tubular sodium transport occurs in utero.

Limited data regarding human fetal renal function are available, although they provide important insight into maturational changes in renal sodium metabolism. Analysis of fetal urine obtained from infants diagnosed prenatally with obstructive uropathy demonstrated that urine sodium concentration decreases whereas creatinine increases as gestational age advances between 20 and 38 weeks. Urine sodium concentrations ranged from 60 to 65 mmol/L before 25 weeks’ gestation to 40 to 50 mmol/L near term. In contrast, protein and phosphorus concentrations are low and remain unchanged over this period of time. Similar developmental changes in urine sodium concentration were reported from fetuses whose urine was obtained prior to elective termination or red blood cell transfusion for Rh isoimmunization. Along with a decreasing urine sodium concentration, the fractional excretion of sodium similarly decreases during the second half of gestation.

Neonatal Sodium Balance

Following birth, significant changes in renal sodium handling occur, the extent of which is dependent upon gestational age as well as postnatal age. Studies in term fetal sheep delivered by cesarean section demonstrate U _Na V and FE _Na are initially maintained at fetal levels, although they rapidly decrease during the first few hours of postnatal life. This rapid increase in renal tubular absorption was associated with increased GFR but not aldosterone levels.

In term infants, FE _Na decreases from 3.4% to 1.5% in the first few hours of life and continues to decrease to adult values (<1%) over subsequent days. Several studies have shown in preterm infants that FE _Na and U _Na V are inversely associated with gestational age at birth and postnatal age ( Fig. 10.2 ). Siegel and Oh found the magnitude of urinary sodium excretion decreased from approximately 200 µEq/kg per hour in infants at 27 weeks’ gestation to less than 25 µEq/kg per hour at term. In addition, Gubhaju and coworkers reported FE _Na exceeded 6% in infants less than 28 weeks’ gestation on day of life 3, decreasing to approximately 4% by the end of the first week of life and 2% at a month of age. Less premature infants (29–36 weeks’ gestation at birth) had lower FE _Na at 3 days of age and showed a similar maturational decrease in FE _Na over the first month of life. By 28 days of life, there was no statistically significant difference in FE _Na among the gestation age groups, although infants born at less than 28 weeks’ gestation appeared to have an FE _Na twice that of older infants.

Fractional excretion of sodium during the first weeks of life.

(Reprinted by permission from Macmillan Publishers Ltd: Pediatr Res. 1994;36:572-577 copyright [1994].)

Term infants have a diminished ability to excrete a sodium load compared with adults, as a result of the inability of the newborn to increase GFR to the similar extent as an adult. In term infants provided an oral sodium load, the urinary sodium excretion rate is only approximately 10% of that found in older children. Preterm infants demonstrate a greater ability to excrete a sodium load compared with term infants because a lower percentage of the sodium load presented to the distal tubule is reabsorbed in preterm infants than in term infants.

Multiple factors likely contribute to the changes in renal sodium excretion with development, including but not limited to a redistribution of renal blood flow, increased oxygen availability, increased proximal tubular length, increased expression and activity of the basolateral sodium-potassium ATPase and luminal membrane sodium-hydrogen exchanger, and response to hormones. Relative to the newborn, the fetus displays a state of high renal vascular resistance. In the first day after birth, there is little change in total renal blood flow or renal vascular resistance, although GFR increases significantly as a result of the redistribution of intrarenal blood flow in favor of outer cortical nephrons. The rise in arterial oxygen content and renal oxygen delivery, with an associated increase in available renal energy, likely enhances the ability of the newborn kidney to reabsorb sodium. Oxygen delivered to the newborn sheep kidney is five to seven times that to the fetal kidney, and there is a positive relationship between the quantities of sodium reabsorbed and renal oxygen delivery and consumption. In fetal sheep, in utero ventilation, which increased fetal arterial p o ₂ values from 18 to 86 mm Hg, decreased urine flow rate and FE _Na without changes in atrial natriuretic peptide (ANP), vasopressin, angiotensin II, or GFR.

Calculations of Fluid Requirement

Water is life’s matter and matrix, mother and medium. There is no life without water.

The provision of water is the most basic concept in sustaining life. Although hundreds of thousands of infants receive parenteral fluids each year, studies to guide the clinicians approach are limited. Recent Cochrane reviews highlight that, although more than 4000 infants were involved in more than 20 trials of antenatal steroids to decrease the incidence of respiratory distress syndrome, fewer than 600 preterm infants have been involved in a total of five randomized controlled trials of restricted versus liberal water intake for preventing morbidity and mortality.

To determine daily maintenance water requirements, one must consider IWL, urine volume, fecal water loss, metabolically derived water, and water retained for growth. For practical purposes, stool water need not be included in calculations of initial fluid needs because stool water losses are minimal in the first few days of life. Water produced by oxidation is approximately 5 to 10 mL/kg per day and is ignored in fluid calculations because it essentially offsets fecal losses. Water necessary for growth is approximately 10 to 15 mL/kg per day, assuming a weight gain of 10 to 20 mL/kg per day and 60% to 70% of cellular growth is water. However, in the first week of life, during which time there is a physiologic weight loss and minimal somatic growth, the calculation of maintenance fluid is based primarily on IWL and urine water loss.

The volume of water needed in the first few days of life is that which is necessary to avoid hypernatremia but also allows for the contraction of the extracellular space and physiologic weight loss. For the term infant under basal conditions, respiratory water loss is approximately 7 to 10 mL/kg per day and evaporative water loss is 10 to 30 mL/kg depending upon environmental conditions. Thus total IWL is approximately 20 to 40 mL/kg per day, and urine output also averages approximately 5 to 10 mL/kg per day for the first few days of life. The breastfed term infant loses on average 1% to 2% of his or her birth weight daily for the first few days of life, with a target weight loss of 7% to 10% of birth weight. Because 60% to 80% of this weight loss is likely extracellular fluid, a mild increase in extracellular sodium concentration develops. Although increased, serum sodium values remain in the “normal” range because newborns are often mildly hyponatremic at birth. However, excessive weight loss resulting from limited enteral intake, IWL and ongoing urine output increases the risk for development of dehydration and clinical hypernatremia. With hypernatremic dehydration, the extracellular fluid compartment becomes relatively less contracted than the intracellular compartment, making diagnosis on clinical evaluation more difficulty.

Moritz and coworkers reported up to 2% of neonatal hospital admissions of infants ≥35 weeks’ gestation are for breastfeeding-associated hypernatremic dehydration (serum sodium concentration ≥150 mEq/L), the vast majority of cases associated with primiparous mothers. Despite education and support from a lactation consultant, 16% of exclusively breastfed infants born to primiparous woman had greater than 10% weight loss by day 3 of life. Providers need to be aware of breastfeeding-associated hypernatremia and increased risk for hyperbilirubinemia and provide follow-up monitoring of those infants most at risk. Although there is a reluctance to provide supplemental formula to breastfed infants with insufficient lactation, judicious use of supplementation has been demonstrated to decrease the incidence of excessive weight loss (>10%). Although additional studies are needed to best identify infants at risk for breastfeeding-associated hypernatremia, consideration of supplemental feeds to breastfed infants may be given for greater than 7% to 8% weight loss.

Term infants receiving intravenous fluids soon after birth are typically provided sufficient water to replace IWL plus urine output. Initially, 50 to 60 mL/kg per day of fluid, often provided as 10% dextrose in water, is sufficient to meet these needs. With the provision of enteral or parenteral nutritional, which increases the renal solute load, fluid requirements increase. After the first few days of life, a need for water for growth (deposition in to new tissues) also exists. For example, a 3.5-kg infant receiving parenteral nutrition that provides 3.5 g protein/kg, 3 mEq NaCl/kg, 2 mEq KCl/kg, and 1 mEq NaPO ₄ /kg needs to excrete a potential renal solute load of 112 mOsm (70 mOsm urea [1 g protein = 5.7 mOsm urea], 14 mOsm Na ⁺ , 7 Osm K ⁺ , 17.5 mOsm Cl ⁻ , 3.5 mOsm PO ₄ ⁻³ ). Assuming a urine concentration of 300 mOsm/L, approximately 375 mL of urinary water is necessary. When 15 mL/kg are provided for growth and 30 mL/kg per day for IWL, approximately 375 + 52 + 105 = 532 mL, or 150 mL/kg per day, of water intake is necessary. Stool water loss and metabolically derived water are excluded from this calculation because they essentially offset each other.

The development of parenteral fluid therapy for preterm infants in the 1960s was a major turning point for the care of this population and generated several randomized and nonrandomized trials of early parenteral therapy versus no fluids for 24 to 72 hours. Meta-analysis of these trials showed a lower death rate in fluid-treated infants, with a relative risk of death of approximately 0.8, although the difference did not reach statistical significance. Premature infants have larger maintenance water requirements than term infants because of increased IWL, as discussed previously. Most often these fluids are provided by the parenteral route. The IWL replacement component of maintenance water should be increased with decreasing birth weight or gestation age and decreased with advancing postnatal age ( Table 10.1 ). However, careful attention to the prevention of excessive IWL is as important as the replacement of increased IWL. These efforts include maintenance environmental temperature in the thermoneutral zone and use of plastic shields/chambers/barriers and semipermeable membranes.

Table 10.1

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