Genetic Disorders and the Fetus. Группа авторов
cautioned that decreased AFV is especially of concern when it occurs in conjunction with structural fetal anomalies, fetal growth restriction, or maternal disease, and others have noted an increased risk of fetal heart rate abnormalities.49 However, a normal AFV may occur even in the presence of urinary tract obstruction or bilateral renal agenesis.26 A normal AFV was found in 13 cases of hydronephrosis, eight of which had confirmed urinary tract obstruction at birth; the other five were normal.50 The authors suggest that fetal hydronephrosis associated with normal amounts of AF does not require intrauterine treatment. Appropriate intervention after birth should lead to normal renal function. Rarely, oligohydramnios may be extreme, even to the point at which there is virtually no AF. These extreme cases are frequently associated with amnion nodosum, fetal defects or placental problems.43
Origin
Much of the evidence that AF is derived largely (but not only) from maternal sources comes from the study of constituent proteins in the fluid.51 To some extent at least, the AF in early gestation is probably a dialysate of maternal serum, the total solute concentration being similar.6 It is likely that the relative contributions from maternal and fetal sources change as pregnancy progresses. Although urine is present in the fetal bladder at least as early as 12 weeks of gestation, its contribution to AFV is likely to be significant only later.28
Sutcliffe and Brock52 observed that the maternal serum protein group‐specific component (Gc) is present in AF early in gestation, suggesting that this protein enters the AF through the placenta or the fetal membranes. For this reason, they cautioned against attempts at prenatal genetic diagnosis by examination of serum proteins or by linkage analysis using serum protein polymorphisms. Most of the albumin in AF, at least near term, is of maternal origin.53 Nevertheless, some AF albumin probably derives from the fetus because its concentration in fetal serum is greater than in maternal serum. In addition, at least after 30 weeks of gestation, most of the AF antitrypsin, ceruloplasmin, Gc, orosomucoid, and transferrin are of maternal origin.51
Cholesterol and its precursors derive from the mother, likely until at least the 15th gestational week.54 Hemopexin, a β‐glycoprotein, in AF55 is believed to be of maternal origin.56 β1‐Glycoprotein (SP1), produced by the syncytiotrophoblast, is elevated in AF in Meckel syndrome, but not in open NTDs and several other fetal disorders.57 Another glycoprotein, β2‐microglobulin, has been noted to have concentrations in the AF in excess of those in maternal serum,51 although the exact tissue(s) of origin is unknown. Because synthesis of β2‐microglobulin has been shown in lymphocytes, and other glycoproteins are found on the surface of most cells, adjacent maternal tissues may be the most important source of AF β2‐microglobulin.
Brace16 suggested that the fetus may have a substantial volume of fluid of salivary origin. A significant fraction of the secreted lung fluid seems to enter the AF. The phospholipids measured in AF, when lecithin/sphingomyelin (L/S) ratios are determined, are of pulmonary origin and are not passed in significant quantities through the urine.
α‐Fetoprotein (AFP) is feto‐specific, and acetylcholinesterase (AChE) is an extracellular component found in high concentration in the fetal brain (see discussion later). Other neuronal proteins found in the AF of fetuses with NTDs include D2‐protein,58 an “S‐100 protein,”59 and neuron‐specific enolase.60
Gogiel et al.61 studied the degradation products of collagen in AF. They suggested that nondialyzable collagenous polypeptides may be the products of the proteolytic conversion of procollagen into the monomeric form of this protein.
Biochemical and other characteristics of amniotic fluid
One of the earliest of the physical and chemical properties of AF was reported from Japan in 1919.62 Campbell and co‐workers63 studied the composition of AF and extraembryonic coelomic fluid (Figure 3.1) between 8 and 12 weeks of gestation. Sodium, potassium, and bicarbonate were higher in AF, whereas chloride, urea, protein, bilirubin, albumin, glucose, creatinine, calcium, and phosphate were present in higher concentrations in extraembryonic coelomic fluid. Those observations underline the significant difference in composition between the two embryonic fluids.
Figure 3.1 The coelomic and amniotic fluid spaces during the first trimester of gestation.
Cell‐free DNA and RNA
Circulating cell‐free DNA in AF is potentially useful for prenatal diagnosis, although its presence in maternal serum has already been widely adopted64 (see Chapter 7). A whole‐genome microarray analysis of RNA isolated from AF obtained at term and second trimester identified nearly 3,000 significant differences in gene transcripts.65 Many of the differences reflected enrichment of transcripts associated with fetal maturity, and may have value in studies of normal and abnormal fetal development.
Proteins
Decades ago, the mean protein concentration in AF at term was observed to be less than one‐tenth that in maternal serum.63 Subsequently, the ratios of albumin, transferrin, γ‐globulin, ceruloplasmin, α1‐antitrypsin, and Gc51 have been established, and provide direct evidence as to their maternal or fetal origin.51 Many maternal serum proteins gain access to the AF, thereby complicating the use of this fluid for prenatal diagnosis. Proteins of fetal origin probably derive from skin, amnion, chorion, umbilical cord, urine, and bronchial, buccal, and gastrointestinal secretions, and may be cellular, free organelles, or in solution.51, 66 Protein constituents of basement membrane have been detected,67 as has Tamm–Horsfall glycoprotein.68
The glycosaminoglycan composition of human AF reveals the major constituent to be hyaluronic acid at 12–21 weeks; the rest is mostly chondroitins and small amounts of heparan sulfate.69, 70 Gestational age is an important variable affecting glycosaminoglycan composition in both normal and pathologic pregnancies.69 The determination of glycosaminoglycan composition for prenatal diagnosis of the mucopolysaccharidoses is not recommended. The prenatal detection of hemophilia B by assay of factor IX and prothrombin in AF was unsuccessful,71 but direct analysis of DNA is successful (see Chapter 14).
There is striking variability in the total protein concentration during pregnancy, increasing from a mean of about 3.5 mg/mL at 12 weeks to a maximum of about 8 mg/mL at 25 weeks.72, 73 The concentration gradually falls to about 3 mg/mL between 25 and 35 weeks, with little change occurring thereafter. The highest concentrations of albumin, α1‐antitrypsin, Gc, and transferrin have been noted between 20 and 30 weeks of gestation.
Although most proteins in AF may be of maternal serum origin, nonserum proteins derived from the epithelial cells of the amnion74, 75 or from the maternal uterine decidua,51 as well as other α2‐proteins and α1‐fetoprotein, have been described. Chitayat et al.76 used a colon epithelial‐specific monoclonal antibody (Mc‐Ab) to determine the contribution of fetal colonic mucosal cells to the amniocyte population, and concluded that cell‐specific Mc‐Ab can be used to detect colon cells and that colonocytes are an important component of the AF cell population. The S100B protein, a product of nervous system glia77 and the amnion,78 can be elevated in preeclampsia, intrauterine restriction,78