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by 18 weeks, they are producing 7 to 14 mL per day. Fetal urinecontains more urea, creatinine, and uric acid than fetal plasma.Amnionic fluid also contains desquamated fetal cells, vernix,lanugo, and various secretions. Because these are hypotonic, thenet effect is that amnionic fluid osmolality decreases with ad-vancing gestation. Pulmonary fluid contributes a small propor-tion of the amnionic volume, and fluid filtering through theplacenta accounts for the rest.

The volume of amnionic fluid at each week is quite variable. Ingeneral, the volume increases by 10 mL per week at 8 weeks andincreases up to 60 mL per week at 21 weeks, then declines gradu-ally back to a steady state by 33 weeks (Brace and Wolf, 1989).

Amnionic fluid serves to cushion the fetus, allowing muscu-loskeletal development and protecting it from trauma. It alsomaintains temperature and has a minimal nutritive function.Epidermal growth factor (EGF) and EGF-like growth factors,such as transforming growth factor- , are present in amnionicfluid. Ingestion of fluid into the gastrointestinal tract and in-halation into the lung may promote growth and differentiationof these tissues. Animal studies have shown that pulmonary hy-poplasia can be produced by draining off amnionic fluid, bychronically draining pulmonary fluid through the trachea, andby physically preventing the prenatal chest excursions thatmimic breathing (Adzick and associates, 1984; Alcorn and col-leagues, 1977). Thus, the formation of intrapulmonary fluidand, at least as important, the alternating egress and retention offluid in the lungs by breathing movements are essential to nor-mal pulmonary development. Clinical implications of oligohy-dramnios and pulmonary hypoplasia are discussed in Chapter21 (p. 496).

Fetal CirculationThe fetal circulation is substantially different from that ofthe adult and functions until the moment of birth, when it isrequired to change dramatically. For example, because fetalblood does not need to enter the pulmonary vasculature tobe oxygenated, most of the right ventricular output bypassesthe lungs. In addition, the fetal heart chambers work in par-allel, not in series, which effectively supplies the brain andheart with more highly oxygenated blood than the rest of thebody.

Oxygen and nutrient materials required for fetal growthand maturation are delivered from the placenta by the singleumbilical vein (Fig. 4-12). The vein then divides into the duc-tus venosus and the portal sinus. The ductus venosus is the ma-jor branch of the umbilical vein and traverses the liver to enterthe inferior vena cava directly. Because it does not supply oxy-gen to the intervening tissues, it carries well-oxygenated blooddirectly to the heart. In contrast, the portal sinus carries bloodto the hepatic veins primarily on the left side of the liver whereoxygen is extracted. The relatively deoxygenated blood fromthe liver then flows back into the inferior vena cava, which alsoreceives less oxygenated blood returning from the lower body.Blood flowing to the fetal heart from the inferior vena cava,therefore, consists of an admixture of arterial-like blood thatpasses directly through the ductus venosus and less well-oxy-genated blood that returns from most of the veins below the

level of the diaphragm. The oxygen content of blood deliveredto the heart from the inferior vena cava is thus lower than thatleaving the placenta.

In contrast to postnatal life, the ventricles of the fetal heartwork in parallel, not in series. Well-oxygenated blood enters theleft ventricle, which supplies the heart and brain, and less oxy-genated blood enters the right ventricle, which supplies the restof the body. The two separate circulations are maintained by thestructure of the right atrium, which effectively directs enteringblood to either the left atrium or the right ventricle, dependingon its oxygen content. This separation of blood according to itsoxygen content is aided by the pattern of blood flow in the in-ferior vena cava. The well-oxygenated blood tends to coursealong the medial aspect of the inferior vena cava and the lessoxygenated blood stays along the lateral vessel wall. This aidstheir shunting into opposite sides of the heart. Once this bloodenters the right atrium, the configuration of the upper intera-trial septumthe crista dividensis such that it preferentiallyshunts the well-oxygenated blood from the medial side of theinferior vena cava and the ductus venosus through the foramenovale into the left heart and then to the heart and brain (Dawes,1962). After these tissues have extracted needed oxygen, the re-sulting less oxygenated blood returns to the right heart throughthe superior vena cava.

The less oxygenated blood coursing along the lateral wallof the inferior vena cava enters the right atrium and is de-flected through the tricuspid valve to the right ventricle. Thesuperior vena cava courses inferiorly and anteriorly as it en-ters the right atrium, ensuring that less well-oxygenatedblood returning from the brain and upper body also will beshunted directly to the right ventricle. Similarly, the ostiumof the coronary sinus lies just superior to the tricuspid valveso that less oxygenated blood from the heart also returns tothe right ventricle. As a result of this blood flow pattern,blood in the right ventricle is 15 to 20 percent less saturatedthan blood in the left ventricle.

Almost 90 percent of blood exiting the right ventricle isshunted through the ductus arteriosus to the descending aorta.High pulmonary vascular resistance and comparatively lower re-sistance in the ductus arteriosus and the umbilicalplacental vas-culature ensure that only about 15 percent of right ventricularoutput8 percent of the combined ventricular outputgoes tothe lungs (Teitel, 1992). Thus, one third of the blood passingthrough the ductus arteriosus is delivered to the body. The re-maining right ventricular output returns to the placenta throughthe two hypogastric arteries, which distally become the umbilicalarteries. In the placenta, this blood picks up oxygen and othernutrients and is recirculated through the umbilical vein.

Circulatory Changes at Birth

After birth, the umbilical vessels, ductus arteriosus, foramenovale, and ductus venosus normally constrict or collapse. Withthe functional closure of the ductus arteriosus and the expan-sion of the lungs, blood leaving the right ventricle preferen-tially enters the pulmonary vasculature to become oxygenatedbefore it returns to the left heart. Virtually instantaneously,the ventricles, which had worked in parallel in fetal life, noweffectively work in series. The more distal portions of the

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hypogastric arteries, which course from the level of the blad-der along the abdominal wall to the umbilical ring and intothe cord as the umbilical arteries, undergo atrophy andobliteration within 3 to 4 days after birth. These becomethe umbilical ligaments, whereas the intra-abdominal rem-

nants of the umbilical vein form the ligamentum teres. Theductus venosus constricts by 10 to 96 hours after birth andis anatomically closed by 2 to 3 weeks, resulting in the for-mation of the ligamentum venosum (Clymann and Hey-mann, 1981).

LVRV

RA

Ductusarteriosus

LA

Superior vena cava

Foramen ovale

Inferior vena cava

Ductus venosus

Portal sinus

Portal v.

Aorta

Umbilical aa.

Umbilical v.Hypogastric

aa.

Placenta

Oxygenated

Mixed

Deoxygenated

FIGURE 4-12 The intricate nature of the fetal circulation is evident. The degree of oxygenation of blood in various vessels differs appre-ciably from that in the postnatal state as the consequences of oxygenation being provided by the placenta rather than the lungs and thepresence of three major vascular shuntsthe ductus venosus, foramen ovale, and ductus arteriosus. (aa ! arteries; LA ! left atrium; LV ! left ventricle; RA ! right atrium; RV ! right ventricle; v ! vein.)

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Fetal Blood

Hemopoiesis

In the very early embryo, hemopoiesis is demonstrable first inthe yolk sac. The next major site is the liver, and finally the bonemarrow. The contributions made by each site are depicted inFigure 4-13.

The first erythrocytes released into the fetal circulation are nu-cleated and macrocytic. Mean cell volumes are expressed in fem-toliters (fL), and one femtoliter equals one cubic micrometer.The mean cell volume is at least 180 fL in the embryo and de-creases to 105 to 115 fL at term. The erythrocytes of aneuploidfetuses generally do not undergo this maturation and maintainhigh mean cell volumes130 fL on average (Sipes and associates,1991). As fetal development progresses, more and more of thecirculating erythrocytes are smaller and nonnucleated. As the fe-tus grows, both the volume of blood in the common fetoplacen-tal circulation and hemoglobin concentration increase. Hemo-globin content of fetal blood increases to about 12 g/dL atmidpregnancy and to 18 g/dL at term (Walker and Turnbull,1953). Because of their large size, fetal erythrocytes have a shortlife span, which progressively lengthens to approximately 90 daysat term (Pearson, 1966). As a consequence, red blood cell pro-duction is increased. Reticulocytes are initially present at high lev-els, but decrease to 4 to 5 percent of the total at term. The fetalerythrocytes differ structurally and metabolically from those ofthe adult. They are more deformable, which serves to offset theirhigher viscosity, and contain several enzymes with appreciablydifferent activities (Smith and co-workers, 1981).

Erythropoiesis

This process is controlled primarily by fetal erythropoietin be-cause maternal erythropoietin does not cross the placenta. Fetalerythropoietin production is influenced by testosterone, estrogen,prostaglandins, thyroid hormone, and lipoproteins (Stockmanand deAlarcon, 1992). Serum levels of erythropoietin increasewith fetal maturity, as do the numbers of responsive erythrocytes.The exact site of erythropoietin production is disputed, but thefetal liver appears to be an important source until renal produc-tion begins. There is a close correlation between the concentra-tion of erythropoietin in amnionic fluid and that in umbilical ve-nous blood obtained by cordocentesis. After birth, erythropoietinnormally may not be detectable for up to 3 months.

Fetal Blood Volume

Although precise measurements of human fetoplacental volumeare lacking, Usher and associates (1963) reported values in termnormal newborns to average 78 mL/kg when immediate cord-clamping was conducted. Gruenwald (1967) found the volume offetal blood contained in the placenta after prompt cord clampingto average 45 mL/kg of fetal weight. Thus, fetoplacental blood vol-ume at term is approximately 125 mL/kg of fetal weight.

Fetal Hemoglobin

This tetrameric protein is composed of two copies of two differ-ent peptide chains, which determine the type of hemoglobinproduced. Normal adult hemoglobin A is made of " and chains.During embryonic and fetal life, a variety of " and chain

Days

First hepaticcolonization

Circulation established

Yolk sac

17 19 21 23 27 30 40 10.5Weeks

Second hepaticcolonization Bone marrow

colonization

FIGURE 4-13 Chronological appearance of hemopoietic stem cells in the human embryo. (Modified from Tavian and Pault, 2005.)