for Human Genetics, Cambridge, MA, USA
3Tufts University School of Medicine, Boston, MA, USA
Introduction
Amniotic fluid (AF) represents a constantly changing environment that simultaneously reflects and contributes to fetal development. Constituents include growth‐promoting and growth‐protective factors, and sufficient AF volume (AFV) provides mechanical cushioning and space for fetal movement. Biochemical and molecular components may also reflect fetal disease and maturity and, on occasion, maternal disease or environmental exposures. Analysis of the chemical constituents of AF has yielded valuable information for prenatal diagnosis, allowing assessment of fetal physiology and metabolism. Because the AF can be viewed as an extension of the fetal extracellular space,1, 2 an understanding of its origin, formation, and chemical constitution is crucial to prenatal diagnosis and fetal therapy. Sampling of extracoelomic fluid and AF during the 8th–16th weeks of pregnancy for the purpose of prenatal diagnosis has added valuable knowledge about the origin, formation, and content of AF.
Amniotic fluid
Formation and circulation
Fluid exchange between the fetus and the mother occurs via several routes and through different mechanisms, and varies throughout pregnancy. Large volumes of fluid are transferred across the fetal membranes, which are made up of five layers of amnion and four layers of chorion.3 Electron microscopy of the amnion has revealed a complex system of tiny intracellular canals that are connected to the intercellular canalicular system and the base of the cell.4 Studies in primates suggest that the AF is a transudate of the maternal plasma and becomes like other fetal fluids in the presence of the fetus, which contributes urine and other body secretions to the AF.5
Osmotic or diffusion permeability, hydrostatic pressure, chemical gradients, and other mechanisms are responsible for the fluid exchange between fetus and mother.6 In normal pregnancies, intra‐amniotic pressure at 16 weeks ranges between 1 and 14 mmHg.7 Fisk et al.8 studied AF pressure from 7 to 38 weeks and found that it increased with gestational age and may be determined by anatomic and hormonal influences or gravid uterine musculature, but was not influenced by the deepest vertical pool, AF index, maternal age, parity, gravity, fetal sex, twinning, or time of delivery. These authors suggested that AF pressure did not change significantly after removing fluid samples in early or late amniocentesis.9 During the second trimester, total AF turnover is complete within about 3 hours.10 About 20 mL of AF/hour is swallowed by the fetus; that is, approximately 500 mL/day.11 At term, the exchange rate between fetus and mother may approach 500 mL/h.10, 12
Although the fetus depends largely on the placenta for nutrient transport, it is also protected from marked fluctuations in maternal metabolism. The increase of creatinine, α‐glutamyl transferase, and β2‐microglobulin concentrations in AF after 10 weeks confirms the maturation of fetal glomerular function and reflects the fetal kidney development from the mesonephros to the metanephros.13 Active renal function is evident from the ability of the fetal kidney to concentrate radiopaque substances given intravenously to the mother, thereby allowing visualization of a fetal pyelogram.14 AF is mainly produced by the fetal kidney as pregnancy progresses and oligohydramnios may reflect renal structural anomalies, impaired swallowing, placental pathology, or general growth restriction.15
Volume
Brace16 described three determinants of AFV: (i) movement of water and solutes across the membranes; (ii) physiologic regulation of flow rates, such as fetal urine production and swallowing; and (iii) maternal effects on transplacental fluid movement. Total water accumulation in utero during pregnancy reaches about 4 L (fetus 2,800 mL; placenta 400 mL; AF 800 mL).8 Urine production per kg of body weight increases from 110 mL/kg/24 hour at 25 weeks to 190 mL/kg/24 hour at 35 weeks.17 Interference with disposal in the routes of fluid production by a factor affecting only 1 percent of the volume may increase or decrease total AFV by as much as 1 L in 10 days. AF turnover continues even after fetal death, but it is reduced by about 50 percent,18 implying that membranes may be responsible for about half of the water exchange. This suggests that the membranes play a larger role in water disposal than in production. Indeed, electron microscopic studies19 correlate with an absorptive function of the membranes. It is unlikely that excess AF production results solely from excess urine production or a failure of the fetus to swallow AF.20 The amnion must play a role in the maintenance of AFV and composition. Earlier studies concluded that 25–50 percent of the fluid turnover takes place through the fetus in late pregnancy.21 Abramovich22 challenged the concept that swallowing and voiding are important in controlling the AFV. He showed that some anencephalics may swallow considerable amounts of AF and that normal volumes were found in esophageal atresia and in the absence of fetal kidneys. Thus, other factors are involved in controlling the AFV. Chamberlain23 has reviewed the studies done on abnormalities of AFV and altered perinatal outcome.
Ultrasonic assessment of fetal kidney function in normal and complicated pregnancies revealed that the fetal urinary production rate was 2.2 mL/h at 22 weeks, increasing to 26.3 mL/h at 40 weeks.24 The authors concluded that regulation by the central nervous system does not play a large role in fetal urination control, and that fetal polyuria does not explain polyhydramnios. Polyhydramnios was accompanied by elevated AF pressures.25
Various techniques have been used for the direct estimation of AFV. Comparable results have been reported using dilution techniques, radioactive materials, or various dyes or chemicals.26–33 Abnormal AFV is associated with increased maternal risk and perinatal morbidity and mortality, but the invasive nature of AFV assessment limited its clinical utility.34 The vertical pocket measurement (VPM) is simple but remains semiquantitative with limited accuracy. The AF Index (AFI) is the result of the sum of the four maximum vertical pockets (MVP) from each quadrant of the uterus. A meta‐analysis concluded that both AFI and VPM identified abnormal AFVs poorly. The AFI led to more false‐positive oligohydramnios findings, and more interventions without improvement in perinatal outcome.35 Population differences for the AFI may also exist.36 Sandlin et al.37 established reference ranges for AFV from 16 to 41 weeks, using dye‐dilution techniques and a quantile regression statistical approach (Table 3.1). Refinements in quantifying the noninvasive sonographic assessment of AFV have not significantly improved the predictive ability to identify at‐risk pregnancies.38, 39
Table 3.1 Amniotic fluid volume percentile values in relation to gestational age by second‐order quantile regression
| Weeks of gestation | 5th | 25th | 50th | 75th | 95th |
|---|---|---|---|---|---|
| 16 | 134.0 | 334.5 | 377.1 | 503.2 | 694.7 |
| 17 | 132.3 | 322.0 | 389.6 | 552.2 | 937.2 |
| 18 | 130.9 | 311.1 |
