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Articles ยป Amniotic fluid
2007-12-19-01 Amniotic fluid dynamic © Moghazy www.thefetus.net/
Amniotic fluid dynamic 

Mona Moghazy, MD.

Egypt

 

1.    Introduction

 

Amniotic fluid surrounds the fetus during intrauterine development. This fluid is in a dynamic state throughout pregnancy and is essential to fetal well-being. This article will review the physiology of amniotic fluid exchange regulation, content, clinical significance, and abnormalities in both volume and content.

 

2.    Physiology of Amniotic fluid volume regulation (amniotic fluid dynamics)

 

2.1. Amniotic fluid dynamics in the first trimester of pregnancy

 

            During the first trimester, the amniotic fluid composition is similar to that of fetal plasma. There is bi-directional diffusion between the fetus and the amniotic fluid across the skin that is not keratinized yet, and the surface of the amnion, placenta, and umbilical cord being freely permeable to water and solutes. The amniotic fluid serves as a physiologic buffer and an extension of the fetal extracellular compartment [1]. Neither fetal urination nor swallowing contributes significantly to the amniotic fluid volume until 14 weeks of pregnancy.

 

2.2. Amniotic fluid dynamics in the second and third trimester of pregnancy

 

Keratinization of fetal skin begins at 19 to 20 weeks of gestation and is usually complete at 25 weeks after conception. Numerous factors contribute to the formation and removal of amniotic fluid, following keratinization of the fetal skin [1,2]. Production of amniotic fluid is predominately accomplished by the fetal urine and lung fluid production. Fetal breathing movements contribute to the efflux of the lung secretion into the amniotic fluid. Other contributions consist of oral, nasal, and tracheal secretions [1,2,3,4]. Removal of the amniotic fluid is predominately accomplished by fetal swallowing. Additionally an intra-membranous pathway transfers fluid and solutes from the amniotic cavity to the fetal circulation across the amniotic membrane (across the network of blood vessels on the fetal surface of the placenta). Trans-membranous pathway involves direct exchange across fetal membranes between the fetus and maternal blood within the uterus and affects amniotic volume only minimally [2,5,6].

Amniotic fluid volume is dependent on gestational age, maintained within a fixed range, and appears to be highly regulated (although the precise regulation mechanism remains elusive). The volume peaks between the 36 and 38 weeks of gestation [2,7].

Amniotic fluid volume homeostasis is maintained by the delicate balance between inflow (fetal urine and to a lesser extend, lung secretion) and outflow (swallowing and intramembranous absorption) of fluid in the amniotic cavity [3,5,8,9]. Several studies demonstrate that the amount of fluid removed by fetal swallowing is significantly smaller than that produced by fetal urination [2,5,6]. Despite these considerably unequal parameters, amniotic fluid volume remains in relative equilibrium [3]. Several studies suggest that neither lung fluid production nor urination serves as a regulatory role in the control of amniotic fluid volume. Whether fetal swallowing serves a regulatory role remains possible but inconclusive[10,11]. Studies suggest that the intramembranous pathway is responsible for the correction of imbalances and that it appears to play a significant role in establishing of the amniotic fluid volume [2,12].

Intramembranous absorption is known to be a significant pathway for fluid movement from the amniotic cavity to the fetal circulation across the amniotic membrane (across the network of blood vessels on the fetal surface of the placenta). Increase of the intramembranous absorption would serve to limit the increase of the amniotic fluid volume12. Some studies suggest that the amnion is the structure limiting intramembranous water flow. Passive diffusion accounts for only part of the intramembranous fluid absorption. It is likely that much larger shifts of fluid and solutes occur by bulk transfer of amniotic fluid with all of its dissolved solutes into the fetal circulation perhaps via a trans-cellular vesicular transport mechanism [1,13]. Vascular endothelial growth factor (VEGF) in the ovine fetal membranes appears to be a mediator of this process. Other studies suggest that up regulation of VEGF gene expression in the amnion and chorion is associated with increased transfer of amniotic fluid into fetal blood. Vascular endothelial growth factor appears to involve regulation of the intramembranous blood vessel proliferation, influences the permeability of the microvessels and regulation of membrane transport via passive permeation as well as non-passive transcytotic vesicular movement of the fluid [14].

The demonstration of aquaporin proteins in fetal membranes suggests the possibility of water channels as another potential regulator of water flux across both the amnion and the placenta [4,15]. However, further studies are needed to identify the exact regulatory factors of amniotic fluid volume and the underlying mechanisms, which may allow better understanding and management of amniotic fluid abnormalities [4,9].

 

3.    Role of Amniotic fluid

 

The amniotic fluid provides a number of important functions to the developing fetus. It contains nutrients and growth factors that facilitate fetal growth. It provides mechanical cushioning and antimicrobial effectors that protect the fetus.

Normal fluid is also important in the development of the gastrointestinal, pulmonary and musculoskeletal system [1], and a new source for stem cells [16].

 

3.1. The nutritive role of the amniotic fluid

 

Amniotic fluid contains carbohydrates, proteins and peptides, lipids, lactate, pyruvate, electrolytes, enzymes, and hormones [17,18].

Trophic effects of amniotic fluid have been demonstrated on cultured human fetal small intestinal cells [19]. This study suggests that growth factors found in the amniotic fluid, comparable to those in human milk, play a role in fetal growth and development. These trophic mediators include:

 

·        Epidermal growth factor (EGF), which increases significantly during the second trimester, but is reduced in fetal growth restriction. The function of EGF in the human fetus is still largely unknown. In monkeys, in utero treatment with EGF improves lung maturity [20].

·       Transforming growth factor beta-1 (TGF-b1) is found in amniotic fluid only during late stages of gestation. TGF-b1 is believed to induce terminal differentiation of intestinal epithelial cells and to accelerate the rate of healing of intestinal wounds by stimulating cell migration. TGF-b1 may also stimulate IgA production [19].

·        Insulin-like growth factor I (IGF-I), and IGF-II receptors, as well as, insulin receptors, are found throughout the neonatal gut. Several studies in animals have shown that IGF-I in AF improves somatic growth, spleen weight, and bowel wall thickness [21].

·        Granulocyte colony-stimulating factor (G-CSF) is found in amniotic fluid. Enteral administration of the G-CSF enhances intestinal growth of suckling mice [1].

·        Erythropoietin is found in amniotic fluid, colostrum, and mature milk. In the neonatal rat, enteral erythropoietin is absorbed, stimulates erythropoiesis, and is a trophic factor for intestinal growth. The role of swallowed erythropoietin in the human fetus and neonate is not clear [1,22]. Its concentrations in human amniotic fluid have been correlated directly with increased umbilical cord blood erythropoietin concentrations, and so elevated amniotic fluid erythropoietin has been suggested as a marker for chronic fetal hypoxia[23,24].

 

Amniotic fluid plays an important protective role by providing a supportive cushion allowing fetal movement and growth. Amniotic fluid also has a significant defensive role as a part of the innate immune system.

 

3.1.1.   A part of innate immune system

 

The innate immune system is the first line of defense against pathogens and includes anatomic and physiologic barriers, enzymes and antimicrobial peptides, as well as phagocytosis and release of proinflammatory mediators by neutrophils and macrophages [1]. Many of the substances that comprise the innate immune system have been identified in amniotic fluid and vernix and have been shown to have significant antimicrobial properties; these include the human beta defensin that are a major family of vertebrate natural antimicrobials. Human beta defensins1-4 are expressed widely at mucosal surface [25,26]. Sarah J et al have shown in their study that in addition to the antimicrobial activity of human beta defensin, they have chemoattractant properties that suggest they interact between the innate and adaptive immune system. It is also considered an important chemokine that is involved in parturition [25]. Other antimicrobial agents include alpha defensin [HNP1-3] whose concentrations in the amniotic fluid increase with preterm labor, premature rupture of membranes, and chorioamnionitis probably due to release from neutrophils and, lactoferrin, lysozyme, bactericidal/permeability-increasing protein, calprotectin, secretory leukocyte protease inhibitor, psoriasin, and a cathelicidin [1,27,28]. These potent antimicrobial agents show broad-spectrum activity against bacteria, fungi, protozoa, and viruses [25,28]. However more work is required to demonstrate anti-infective properties of these antimicrobial peptides. A better understanding of such mechanisms may identify specific bioactive peptides as adjuncts to correct therapies for chorioamnionitis and neonatal infections. Such treatment modalities would target improved immunocompetency in the early gestational fetus or premature infant and potentially leads to better medical outcom [28].

The activity of the ‘‘cellular’’ innate immune system within amniotic fluid as a protective mechanism for the fetus is less well defined. The numbers of mononuclear phagocytes (i.e. monocytes, macrophages, histiocytes) in amniotic fluid are limited in normal pregnancies, while their numbers are increased in fetuses with neural tube defects. Whether these macrophages are present to prevent infection because of a disruption of the fetal skin or as scavenger cells to clean up neural debris is uncertain. Neutrophils are not normally identified in the amniotic fluid of healthy fetuses, but are useful as a marker of amniotic fluid infection [1]. However, further studies are needed for better understanding of the amniotic fluid protective role.

 

3.1.2.   Effect on fetal lung development

 

Fetal lung development is affected by numerous intrauterine factors including amniotic fluid adequacy, available thoracic spaces and neuromuscular functions [29]. Fetal lung growth, in part, appears to be stimulated by the distending force of lung fluid in the airways and to be inhibited by the absence of this fluid as occurs in oligohydramnios [29]. Lung development is regulated also by several transcription factors, such as thyroid transcription factor 1 family, hepatocyte nuclear family, and peptide growth factors. Growth factors are present in the amniotic fluid and they send signals, which are integrated with environmental influences, such as fluid volume and hyperoxia, to cause cellular proliferation and differentiation [30]. Fetal urine is an important component of amniotic fluid during late gestation and contributes to lung growth. During fetal development, the kidney is an example of major source of proline. Proline aids in the formation of collagen and mesenchyme in the lung, thus explaining the severe pulmonary hypoplasia in renal agenesis and dysplasias [30].

 
3.1.3.   Effect on fetal musculoskeletal system

 

As for fetal musculoskeletal system, amniotic fluid plays an important role in its development [31]. Frost proposed in his study that one of the primary factors in the development of bone strength is the load (force) placed on the bone. This load causes a strain on the bone, which is transmitted as an input signal to a sensor within the bone, Frost called the mechanostat. This mechanostat then directs an appropriate output to the effector cells, osteoblasts and osteoclasts [32]. Bone loading strongly influences bone modeling and during fetal life is determined primarily by fetal movement. Bone loading is far greater in the fetus in the intrauterine environment than in a newborn infant in the extrauterine environment because of the ability of the fetus to kick against the uterine wall in the buoyancy of the amniotic fluid. Fetal activity also promotes muscle growth, which contributes to bone loading [31,32]. Diminshed fetal movement and intrauterine confinement have been put forth as the underlying basis of temporary brittle bone disease [31,33],34].

 
3.1.4.   Effect on fetal gastrointestinal tract

 

Numerous studies have shown that the maturation of the fetal gastrointestinal tract is partially enhanced by swallowed amniotic fluid [35,36]. The micelles in the swallowed amniotic fluid might act as a promoter of fetal intestinal maturation [96].

Mulvihill, et al, have shown in their study that the esophageal ligation of fetal rabbit pups results in marked reductions in gastric and intestinal tissue weight and gastric acidity and these reductions were reversed by fetal intragastric infusion of amniotic fluid [37,38]. In similar studies on ovine fetuses, it has been noticed that the esophageal ligation induces some decrease of small intestine villous height as well as reduction in liver, pancreas, and intestinal weights [39,40]. Although ingestion of amniotic fluid nutrients may be necessary for optimal fetal growth, trophic growth factors as epidermal growth factor within the amniotic fluid also importantly contribute [41]. Other examples of trophic mediators in the amniotic fluid and their effect on the gastrointestinal tract development have been discussed above.

                                                                                                                                   

3.2. A Source of stem cells

Amniotic fluid contains multiple cell types derived from the developing fetus, including some that can give rise to differentiated adipose, muscle, bone, and neuronal cell lines [42]. De Coppi P et al, have identified in their study lines of broadly multipotent amniotic fluid-derived stem (AFS) cells that have the ability to differentiate into a wide range of lineages including those in all embryonic germ layer, thereby meeting the criterion for pluripotent stem cells [43]. Amniotic fluid stem cells have physical characteristics of both embryonic and adult stem cells, which suggest that amniotic fluid stem cells may exist at an intermediate stage between two stem cell types [42,44]. Stem cells isolated from amniotic fluid have several advantages over embryonic and adult stem cells: they are readily accessible, they replicate rapidly in culture (typically doubling every 36 hours), they do not require the support of other “feeder” cells that can cause contamination, and they do not form tumors in vivo [43].

Amniotic fluid stem cells can serve as precursors to a broad range of differentiated cell types that potentially have therapeutic applications [43]. Recently, it has been suggested that amniotic fluid stem cells might be capable of repairing damaged tissues resulting from conditions such as spinal cord injuries, cartilage damage, diabetes, Alzheimer disease, and stroke [43,44,45]. The results of study by Tsai et al, suggest that besides being an easily accessible and expandable source of fetal stem cells, amniotic fluid will provide a promising source of neural progenitor cells that may be used in future cellular therapies for neurodegenerative diseases and nervous system injuries [46,47].

De Coppi J et al, stated that, banking of cells that would otherwise be discarded could provide a convenient source not only for autologous treatment later in life, but for matching of histocompatible donor cells with prospective recipients [43].

 

3.3. Diagnostic amniocentesis and amniotic fluid uses

 

Amniotic fluid contains amniocytes in addition to fetal cells from the skin, genitourinary system, and gut, along with biochemical products that may be removed for analysis [48]. Amniocentesis is the most widely performed invasive prenatal diagnostic procedure, most commonly used for diagnosing genetic and chromosomal abnormalities prenatally [49].

Most amniocenteses are performed to obtain amniotic fluid for karyotyping and the majority is undertaken from 15 completed weeks onwards [50]. Indications for fetal karyotyping include an abnormal screening test result as for trisomy 21, advanced maternal age, a sonographically detected structural abnormality, previous aneuploidy, and a known chromosomal translocation in either partner [48]. Amniocentesis to diagnose inborn errors of metabolism and cystic fibrosis by measuring the activity of fetal enzymes and their byproducts has been largely replaced by molecular DNA analysis [48]. Likewise, amniocentesis to measure alpha feto protein and acetylcholinestrase to diagnose a neural tube defect is rarely necessary because of the reliability of ultrasonography [48, 51]. Evaluation of amniotic fluid bilirubin level based on optical density has been used to predict the severity of fetal hemolysis in alloimmunized pregnancies. Currently, the combination of amniocentesis to assess optical density, Doppler flow studies of the intra-hepatic umbilical vein and the middle cerebral artery and fetal blood sampling by cordocentesis are recommended to closely monitor the anemic fetus [52,53,54]. Oepkes D et al, have shown in their study that middle cerebral artery Doppler peak velocity measurement shows better test characteristics in the prediction of fetal anemia than the traditional amniotic fluid spectrophotometry in Rh alloimmunized pregnancies [55]. Allele-specific polymerase chain reaction of amniotic fluid fetal cells can also be used to identify fetuses at risk for hemolytic disease of the newborn due to minor blood group incompatibilities [56,57].

The rate of miscarriage associated with amniocentesis is approximately 1%. More recent large uncontrolled series suggest that procedure-related loss rates around 0.5% can be achieved [58,59]. Fetal loss due to amniocentesis seems to occur within the first 2 to 3 weeks following the procedure [60,61].

Amniocentesis performed before 14 completed weeks of gestation is referred to as early. Early amniocentesis is not a safe alternative to second-trimester amniocentesis or CVS [50]. The CEMAT group (The Canadian Early and Midtrimester Amniocentesis Trial group), have reported in their randomized trial a significantly greater fetal loss and a higher incidence of talipes in the early amniocentesis cases compared with the ‘late’ ones (7.6% versus 5.9%) [62]. A randomized study by Nicolaides et al compared transabdominal chorionic villus sampling to early amniocentesis and suggested that loss rates might be higher in the latter [63]. Several studies showed that early amniocentesis had a significantly higher rate of amniotic fluid leakage than TA-CVS and mid-trimester amniocentesis[64,65,66].

Amniotic fluid assessment has been studied in patients with preterm labor and/or preterm premature rupture of membranes (PPROM) to investigate possible intra-amniotic infection (IAI). Amniotic fluid indicators suggestive of infection include elevated levels of matrix metalloproteinase (e.g., MMP-9) [67,68,69], and elevated midtrimester amniotic fluid levels of A disintegrin and metalloprotease-8 (ADAM-8) and interferon- (gamma)-inducible T cell- (alpha) chemoattractant (ITAC) [70]. Other amniotic fluid indicators of infection include interleukins (e.g., IL-6 and IL-1b) [71], tumor necrosis factor (TNF-a) [72,73], G-CSF, elevated white blood cell count, low glucose [71,74], elevated concentration of amniotic fluid S100B [75], and the presence of bacteria identified by Gram stain or culture [71,76]. However it is unclear whether the information gained in women with preterm premature rupture of membranes changes the clinical outcome, additionally no randomized trial supports the use of routine amniocentesis to diagnose chorioamnionitis in women with either preterm labor or preterm premature rupture of membranes [1,48].

Amniocentesis has also been helpful with the use of polymerase chain reaction in prenatal diagnosis of fetal infection as with cytomegalovirus [77,78], toxoplasma [79], and parvovirus B-19 infection [80,81,82].

Assessment of fetal lung maturity by determination of the lecithin/sphingomyelin ratio and/or the presence of phosphatidyl glycerol in amniotic fluid has been an accepted procedure. The assessment of lamellar body counts in amniotic fluid [83], the surfactant to albumin ratio in amniotic fluid [84], and electrical conductivity of amniotic fluid [85] have more recently been proposed as potentially superior methods for evaluation of fetal lung maturity. Also measurement of the fetal lung volume with magnetic resonance imaging and three-dimensional ultrasonography would be helpful in predicting the outcome in cases with suspected impaired lung growth [86].

Changes in levels of inhibin-related proteins in both maternal serum and amniotic fluid throughout pregnancy have been proposed as indicators of good fetal health. While the studies are contradictory, elevated levels of inhibin-A and activin-A may be useful markers related to fetal well being during preeclampsia, trisomy 21, preterm delivery, and intrauterine growth restriction. However more research in this area is needed [87].

 

4.    Abnormalities of the amniotic fluid

 

4.1. Amniotic Fluid Particulate Matter

 

Particulate matter in the amniotic fluid (AF) is present in about 4% of pregnancies during transvaginal ultrasound in the first and early second trimester [88]. The prevalence of this sonographic finding increases with gestational age, reaching 88% by 35 weeks [89].

 

4.1.1.   Particulate matter in the first and second trimester

 

Particulate matter in the first two trimesters of pregnancy has been associated with intra-amniotic bleeding [90,91]. With subsequent swallowing of the blood by the fetus, gastric pseudomasses are commonly visualized as well as echogenic bowel [92].

Free-floating particles in the amniotic fluid in the first trimester have been associated with acrania [93]. Cafici D et al suggested in their study that in these cases, the fetal brain is exposed to increasing mechanical trauma, resulting in progressive "rubbing off" of the brain tissue. Exfoliating neural tissue and blood in the amniotic cavity, therefore can be identified on sonography as echogenic free-floating particles. This usually starts from about 10 weeks of gestation, when substantial portions of the amnion are fused with the chorion, due to closer contact of the fetus with the uterine wall [93]. Cafici D et al, also suggested that this sign also support the hypothesis of the transition from acrania to anencephaly, with the unprotected brain undergoing progressive destruction from the first trimester, leading to the classic finding of anencephaly in the second trimester. However this hypothesis needs support by further studies [93].

Also particulate matter has been observed in women with high concentrations of maternal serum alpha-fetoprotein [94].

 

4.1.2.   Particulate matter in the third trimester

 

In the last trimester of pregnancy, particulate matter and ‘echogenic amniotic fluid’ have been attributed to the presence of vernix caseosa and/or meconium. Studies using in vitro analysis have shown that the interaction between pulmonary surfactant and vernix caseosa could explain the appearance of amniotic fluid turbidity and, that pulmonary surfactant induces a “roll up” phenomenon that leads to detachment of vernix caseosa from the fetal skin surface [95,96].

Several studies have shown that echogenic amniotic fluid seen on prenatal sonography is not predictive of fetal distress and is not a reliable indicator of meconium or blood in amniotic fluid and should not typically alter antenatal management [97,98,99,100].

 

4.1.3.   Congenital anomalies and particulate matter

 

Congenital anomalies associated with particulate matter in the amniotic fluid include fetal acrania, harlequin ichthyosis [101,102] and epidermolysis bullosa letalis [103,104]. Harlequin ichthyosis is the most severe form of congenital ichthyosis and is characterized by a profound thickening of the keratin layer in fetal skin, flattened ears, and diffuses platelike scales. Prenatal sonographic diagnosis has been described with findings of a persistently open mouth, fixed flexion of the extremities and echogenic amniotic fluid [105,101]. Particulate matter in the amniotic fluid is attributed to sloughed abnormally thickened skin. Microscopic examination of the amniotic fluid revealed masses of aberrantly keratinized cells probably desquamated from the hair canal or other areas of fetal skin [106]. Epidermolysis bullosa is a group of inherited bullous disorders characterized by blister formation in response to mechanical trauma [107]. Particulate matter in the amniotic fluid in these cases, the “snow flake” sign, is due to sloughing of the skin [108,104]. This is one of the ultrasonographic criteria for diagnosis, together with polyhydramnios, gastric outlet obstruction, malformed ears, kidney malformation and, fisted hands, skin thinning at level of nasal bones due to skin denudation, narrow nasal orifices due to skin blistering [104].

 

4.1.4.   Amniotic fluid sludge

 

Aggregates of hyperechogenic particulate matter in the gallbladder of adult patients have been described as biliary’ sludge’, and might be associated with ascending microbial invasion of the gallbladder [109]. Similarly, dense aggregates of particulate matter giving the ultrasound appearance of amniotic fluid ‘sludge’ have been frequently seen, in the proximity of the internal cervical os, in patients with preterm labor and intact membranes. ‘Sludge’ may represent clusters of inflammatory cells and bacterial biofilms. These bacterial biofilms are matrices of polymeric compounds. They are produced by microorganisms, in which they are embedded, to protect them against host defense mechanisms [110]. It is possible also that aggregates of exfoliated cells from the fetal digestive, respiratory and urinary tracts, amniotic membranes, fetal skin and umbilical cord [111,102] may contribute to the presence of amniotic fluid ‘sludge’ and participate in the host response during microbial invasion of amniotic cavity.  Espinoza J, et al discussed in their study the prevalence and clinical significance of the ultrasound finding of amniotic fluid sludge, that patients with preterm labor and intact membranes with ‘sludge’ are more likely to have microbiological and histological evidence of microbial invasion of the amniotic cavity (MIAC) [99]. Espinoza J et al proposed in their study that this sonographic sign may identify patients at risk for microbial invasion of amniotic cavity, who in turn are at risk for preterm delivery and short- and long-term complications such as cerebral palsy and chronic lung disease [99] Kusanovic JP, et al showed in their study that amniotic fluid sludge is an independent risk factor for spontaneous preterm delivery, preterm premature rupture of membranes, MIAC and histologic chorioamnionitis in asymptomatic patients at high risk for spontaneous preterm delivery. Furthermore, they added that the combination of "sludge" and a short cervix confers a higher risk for spontaneous preterm delivery at < 28 weeks and < 32 weeks than a short cervix alone [112].

 

4.2. Amniotic Fluid Volume Abnormality

 

4.2.1.   Quantification Of The Amniotic Fluid

 

Ultrasound visualization of the amniotic fluid permits both subjective and objective estimates of the amniotic fluid. Subjective evaluation of the amniotic fluid is usually performed in pregnancies less than 20 weeks’ gestation [113]. Semi quantitative methods include estimates of the deepest vertical pool and the amniotic fluid index. Amniotic fluid index, which summates the deepest vertical pool in each of four quadrants, might be referred to as a more sensitive estimate of amniotic fluid volume throughout gestation[114,115]. It has been suggested that amniotic fluid index is reasonably reliable in determining normal or increased amniotic fluid but is less accurate in determining oligohydramnios [116]. It is preferred by many to the deepest vertical pool, because the deepest vertical pool does not allow for an asymmetrical fetal position within the uterus and because the regression curve between amniotic fluid index and gestational age is similar in shape to that between amniotic fluid volume and gestational age [7]. Morris JM et al, have shown that amniotic fluid index is superior to a measure of the single deepest pool as an assessment of the fetus at or after 40 weeks [117]. On the other hand, Megann et al, showed in their study that the single deepest pool is more reliable than either amniotic fluid index or two diameter pocket measurements of amniotic fluid because it is least likely to lead to a false positive diagnosis of either oligohydramnios or hydramnios [118]. Chauhan SP et al, suggested in their study that during antepartum fetal surveillance, use of single deepest pocket compared with amniotic fluid index is associated with a significantly lower rate of suspected oligohydramnios and added that the use of single deepest pocket with modified biophysical profile would decrease the rate of induction for suspected oligohydramnios [119].

Several studies have concluded that amniotic fluid index has a poor sensitivity for adverse pregnancy outcome, and that, oligohydramnios is a poor diagnostic test to predict poor outcome [117,120,121,122,123,124,125]. Garmel et al in their study found a higher incidence of premature delivery with oligohydramnios, but no increase in intrauterine growth restriction, perinatal death, or birth asphyxia [122]. Kreiser et al, found no increase in poor perinatal outcome in cases of isolated oligohydramnios [123]. Megann et al reported that oligohydramnios was a poor test to predict poor outcome [121]. A large study by Morris et al found that amniotic fluid index has a poor sensitivity for adverse pregnancy outcome, and was likely to lead to increased obstetric intervention without improving outcome [117].

However, the amniotic fluid index identification of polyhydramnios might be helpful in identifying large for gestational age fetuses and fetuses at risk for congenital anomalies [125].

In a recent study by Lee SM, et al they have suggested that fetal urine production rate UPR can be easily measured by 3D ultrasound assessment of bladder volume. And have added that this modality may be a promising alternative to conventional methods of amniotic fluid volume measurement such as amniotic fluid index and single deepest pocket, and might be an alternative option for predicting fetal hypoxia [126]. However more studies might be needed regarding this aspect.

 

4.3. Amniotic Fluid Volume Abnormality: Oligohydramnios And Polyhydramnios

 

4.3.1.   Oligohydramnios

 

4.3.1.1.      Definition of oligohydramnios and sonographic evaluation
 

Oligohydramnios complicates 0.5% to 8% of pregnancies and the prognosis for pregnancies complicated by oligohydramnios is gestational age dependent [113]. Oligohydramnios can be diagnosed subjectively [127]. The visual criteria for oligohydramnios include evidence of fetal crowding and an obvious lack of fluid [128]. Using the single largest pocket of amniotic fluid, oligohydramnios has been variously defined as a single pocket with a depth of less than or equal to 0.5 cm [129], less than 1 cm and 2 cm [130], and less than or equal to 3 cm [131]. Moore defined oligohydramnios as an amniotic fluid index below the 5th percentile [115]. This corresponds o amniotic fluid index less than 7 cm near term. However, a common definition of oligohydramnios is amniotic fluid index less than 5 cm [132]. Criteria of amniotic fluid index less than 5 cm or largest pocket of fluid less than 2 cm are highly specific for oligohydramnios but not sensitive when compared to the dye dilution technique [118,133]. A wider interobserver variation in the amniotic fluid index has been observed when oligohydramnios is present. Therefore, averaging three amniotic fluid index measurements is recommended when a low value is obtained [115]. The concurrent use of color Doppler has been reported that it may lead to over diagnosis of oligohydramnios [134,135].

 

4.3.1.2.      Etiology of oligohydramnios

 

Oligohydramnios in the second trimester is usually the result of preterm premature rupture of the membranes, uteroplacental insufficiency, and urinary tract malformations (bilateral renal agenesis, multicystic or polycystic kidneys, or urethral obstruction), and twin to twin transfusion [132]. Oligohydramnios with intact membranes warrants a comprehensive evaluation to detect possible fetal and placental abnormalities, growth restriction, or aneuploidy [113]. Demonstration of early symmetric intra uterine growth restriction with marked oligohydramnios suggest the possibility of an underlying chromosomal disorder, notably trisomy 18 or triploidy [132]. Other causes of oligohydramnios include: maternal dehydration [48], medications as calcium channel blockers, nonsteroidal anti inflammatory drug that inhibit renal vascular flow and decrease glomerular filtration rate [136], and angiotensin converting enzyme inhibitors that reduce fetal blood pressure, decrease renal perfusion, and subsequently result in oligohydramnios [137].

 

The most common etiologies of oligohydramnios include

 

·         Premature rupture of membranes:

 

It complicates 3% to 17% of pregnancies. Although the clinical diagnosis is obvious in most cases, only 5% to 44% have ultrasonic evidence of oligohydramnios [138]. The earlier the gestation, the lower the incidence of premature rupture of membranes as an explanation of oligohydramnios [48].  

Preterm rupture of membranes at 20 weeks or earlier is associated with a poor prognosis; about 40% miscarry within five days of membrane rupture due to chorioamnionitis and in the remaining 60% of pregnancies more than 50% of neonates die due to pulmonary hypoplasia [127]. Kilbride et al, in their study reported that severe oligohydramnios (single pocket less than 1 cm) lasting for 14 days or more after spontaneous premature rupture of membranes at less than 25 weeks’ gestation is associated with 90% neonatal mortality [139]. On the other hand iatrogenic rupture of membranes after genetic amniocentesis have a much more favorable prognosis with reported survival rate up to 91% [140].

 

·         Fetal anomalies

 

The majority of fetal anomalies that result in oligohydramnios involve the urinary tract, including, bilateral renal agenesis, multicystic dysplastic kidneys, and infantile polycystic kidney disease, Meckle Gruber syndrome and, lower urinary tract obstruction as posterior urethral valve  [48,132].

Bilateral renal agenesis is associated with oligohydramnios after 17 weeks gestation. However prior to this, the liquor volume may be normal [141] and, therefore, normal liquor prior to 17 weeks ‘ gestation does not exclude renal agenesis [142]. The diagnosis rests on the demonstration of absence of both kidneys and the bladder. This can be difficult in the setting of severe oligohydramnios as, the absence of the "acoustic window" normally provided by the amniotic fluid, and the "undesirable" postures often adopted by these fetuses, make confident exclusion of fetal defects sometimes impossible [127]. Transvaginal sonography may be used in the second trimester to more accurately assess the renal fossa. The documentation of a lying down adrenal sign (the psoas muscles are visualized and the adrenal glands flatten to fill in the space left by the absent kidney) confirms that the kidney is not appropriately positioned in the renal fossa [143,144]. Color or power Doppler may be used to confirm the presence or absence of the renal arteries & thus is helpful in the diagnosis of renal agenesis [132,145].

Infantile polycystic kidney disease is an autosomal recessive condition. In most cases are bilaterally symmetrically enlarged kidneys with increased echogenicity, associated with oligohydramnios. However, this may not be demonstrable until 24 weeks’ gestation [142,146,147].

In multicystic dysplastic kidney disease, the affected kidney appears sonographically as a paraspinal mass containing multiple cysts of variable size, of dense stroma within the kidney but no normal renal tissue. When the condition is bilateral, there is associated oligohydramnios and absence of urine within the bladder. 142The diagnosis is made as early as 12 weeks. When unilateral, the contralateral kidney shows associated abnormalities in up to 39% of cases. Contralateral anomalies include renal agenesis, renal hypoplasia, pelviureteral junction obstruction and vesico ureteric reflux [148].

Posterior urethral valve accounts for half of the cases of antenatally diagnosed lower urinary tract obstruction (LUTO). Ultrasound criteria includes; a thick walled, large bladder with a key hole sign, which represents the enlarged bladder and dilated proximal urethra, bilateral hydronephrosis and oligohydramnios [48]. Other causes of LUTO are prune belly syndrome and urethral atresia [149]. The prognosis is worse (95% mortality rate) in those diagnosed antenatally when midtrimester oligohydramnios is present.48 Poor prognostic factors on ultrasound include dilatation of the upper tract, increased bladder wall thickness, and evidence of renal dysplasia (echogenic renal cortex and macrocystic renal change), especially before 24 weeks [150].

 

·         Intrauterine growth restriction intrauterine & post term pregnancies

 

Intrauterine growth restriction is suspected when the estimated fetal weight falls below the 10th percentile for the expected gestational age [151]. The cause of oligohydramnios might be related to decreased intramembranous flow of the amniotic fluid [132].

In post term pregnancies, oligohydramnios is a common complication, and is associated with diminished placental function [132]. In uteroplacental insufficiency, Doppler blood flow studies will often demonstrate high impedance to flow in the placental circulation and redistribution in the fetal circulation [127].

 

4.3.1.3.      Oligohydramnios sequelae

 

Pulmonary hypoplasia and skeletal deformities are common complications of prolonged oligohydramnios [152]. Severe oligohydramnios from 16 weeks onwards appears to preclude further pulmonary development. In contrast, oligohydramnios after the second trimester is unlikely to result in pulmonary hypoplasia because the crucial canalicular phase of lung development (occurring between 16 and 25 weeks) has largely been completed by this stage. Thus, the prevalence of pulmonary hypoplasia after oligohydramnios depends on several factors: the gestation at onset, the severity, and the duration [153,154]. Bilateral renal agenesis, muticystic or polycystic kidneys are lethal abnormalities, usually in the neonatal period due to pulmonary hypoplasia [127]. Patients presenting in the second, in contrast to the third, trimester have a higher prevalence of structural malformations (50.7%vs. 22.1%) and a lower survival rate (10.2% vs. 85.3%). Isolated oligohydramnios during the third trimester is not necessarily associated with poor perinatal outcome [122,155]. When the oligohydramnios is associated with renal agenesis or dysgenesis, symptoms include marked deformation of the fetus due to of intrauterine constraint (Potter syndrome). Other obstructive uropathies cause similar deformations, including external compression with a flattened facies and epicanthal folds, hypertelorism, low-set ears, a mongoloid slant of the palpebral fissure, a crease below the lower lip, and micrognathia, talipes and limb contractures. Thoracic compression also may occur [152]. In a study by Christianson C et al, on limb deformities in case of oligohydramnios, they concluded that contractures in fetuses with oligohydramnios were more frequent with earlier onset and longer duration of oligohydramnios [156]. They added that the type of contracture varied with the gestational age, club foot the most frequent at all ages but hand contractures such as camptodactyly were common only in the second trimester, flat hands were almost exclusively in the fetuses in the third trimester [156].

 
4.3.1.4.      Therapeutic options and amnioinfusion

 

The ultrasonic visualization of fetal anatomy, particularly renal agenesis, is difficult in severe oligohydramnios/anhydramnios. Intra-amniotic instillation of normal saline may help improve ultrasonographic examination and lead to the diagnosis of fetal abnormalities like renal agenesis [48,127,157,158]. However the use of amnioinfusion has greatly diminished with the widespread availability of the use of color Doppler to identify the renal arteries, being an accurate and a noninvasive way to predict the absence of renal function as in renal agenesis or muticystic dysplastic renal disease [48,159].

The prognosis and the possibility of management of oligohydramnios depend upon the etiology. Attempts at therapy, focus on restoring the amniotic fluid to allow continued development of the lungs during the canalicular phase [160]. Quintero et al described effective resealing in cases of iatrogenic previable premature rupture of membranes by intra amniotic injection of platelets and cryoprecipitate although this approach has not been reported to work after spontaneous membrane rupture [161].

Some reports have also shown that in pregnancies with preterm premature rupture of membranes with oligohydramnios at < 26 weeks’ of gestation, serial amnioinfusion improve the perinatal outcome when compared to those with persistent oligohydramnios [162,163]. Fisk et al, have recently described an amnioinfusion test procedure to try and preselect cases of mid trimester preterm premature rupture of membranes which may benefit from serial amnioinfusion [164]. A quarter of patients who retained infused fluid went on to subsequent serial amnioinfusion and prolongation of pregnancy with decrease in the risk of pulmonary hypoplasia [164]. However there are risks of procedure related complications as chorioamnionitis, placental abruption and extreme prematurity, so ideally a large series in a prospectively randomized trial would be needed to assess the benefits [160].

Chhabra et al concluded in their study that antepartum amnioinfusion is a useful procedure to reduce complications resulting from decreased intra-amniotic volume. It is especially useful in preterm pregnancies, where the procedure allows for a better perinatal outcome by prolonging the duration of pregnancy [165].

Amnioinfusion has also been used to prevent or relieve variable decelerations from umbilical cord compression in cases of rupture of membranes and to dilute meconium when, present in the amniotic fluid and so reduce the risk of meconium aspiration during labour [160]. Two cochrane reviews have been done, showing improvements in perinatal outcome [166] when it is used to dilute meconium and appears to reduce the occurrence of variable heart rate decelerations and lower the use of caesarean section due to cord compression in labor [167]. However, further studies are needed to reach definite conclusions about the efficacy and safety of amnioinfusion.

Other suggested treatments to maintain amniotic fluid volume in oligohydramnios, include maternal hydration by oral or intravenous administration [168,169]. Desmopressin which is a selective antidiuretic agonist has been suggested to increase amniotic fluid volume [170], cervical canal occlusion with fibrin gel [171] and vesico-amniotic shunting in obstructive uropathies [172].

 

4.3.2.   Polyhydramnios

 

4.3.2.1.      Definition of polyhydramnios and sonographic evaluation

 

Polyhydramnios is generally defined as amniotic fluid volume greater than 2,000 ml [173]. Visual criteria of polyhydramnios include an obvious discrepancy between the size of the fetus and the amount of amniotic fluid. In the latter part of the third trimester the fetal abdomen approximates the anterior and the posterior uterine wall. When there is an ample amount of amniotic fluid between the fetus and the anterior and the posterior uterine walls, significant polyhydramnios is generally present [132].

Polyhydramnios is defined as an amniotic fluid index greater than the 95th percentile for gestational age or a maximum vertical pocket greater than 8 cm [113]. In older studies, hydramnios was reported to complicate 3.5% of pregnancies [174,175], but the study of Thompson et al, found the incidence to be much lower about 0.2% [176].

Ultrasound evaluation of the amniotic fluid allows polyhydramnios to be classified as mild if the maximum pocket is between 8 and 11 cm, moderate if the maximum pocket is 12 to 15 cm, and severe if the maximum pocket is over 16 cm.48 The latter occurs in less than 5% of all cases of polyhydramnios. The degree and prognosis of polyhydramnios is related to the underlying etiology. The definition of polyhydramnios using the amniotic fluid index has been reported to be greater than 20 cm [177], greater than 24 cm [178,179], and greater than 25 cm [180,181]. An amniotic fluid index greater than 25 cm has been associated with a higher incidence of macrosomia and congenital anomaly rate. 181 However several studies showed that, semi quantitative sonographic methods for detecting polyhydramnios are relatively poor and tend to underestimate the degree of polyhydramnios [182,183,184,185].

When the diagnosis of polyhydramnios is made, careful evaluation of the fetal anatomy is warranted [113]. Advances in the maternal fetal medicine have significantly altered not only the overall prevalence but also the types of cases seen with polyhydramnios [132].

As severity of polyhydramnios increases, so does the likelihood of determining an underlying etiology [175].

 

4.3.2.2.      Etiology of polyhydramnios

 

The most common etiologies of polyhydramnios include:

 

·         Congenital malformations

 

Central nervous system malformations were considered the most common anomalies associated with polyhydramnios [186]. However, another study by Ben Chetrit et al, favored gastrointestinal malformations (39%), followed by central nervous system (26%), circulatory (22%), and urinary tract (13%) anomalies [187]

Gastrointestinal malformations:  obstruction of the gastrointestinal tract is often associated with increased amniotic fluid, reflecting the role of fetal swallowing and fluid absorption in the regulation of the amniotic fluid 113. Proximal obstructions as esophageal atresia, duodenal atresia, or jejunal atresia are particularly likely to produce polyhydramnios. However, distal obstructions are associated with less prevalence of polyhydramnios [113,188].

Partial bowel obstruction as in intestinal volvulus, meconium ileus, and abdominal wall defects, and meconium peritonitis [189], as well as, non-obstructive bowel disorders as congenital chloridorrhea [190] and megacystis microcolon intestinal hyperplastic syndrome [191], are associated with polyhydramnios.

Central nervous system: central nervous system abnormalities as anencephaly, hydrocephalus, microcephaly, encephalocele, spina bifida, Dandy Walker malformation, cerebral arteriovenous malformation, are associated with polyhydramnios. Polyhydramnios is probably due to depression of the fetal swallowing [132].

In anencephaly, although impairment of fetal swallowing is implicated, only 65% develop hydramnios. Although this association may reflect variation in the amount of brain tissue present, alternative mechanisms include fluid transudation from the exposed meninges and lack of antidiuretic effect because of impaired arginin vasopressin secretion resulting in fetal polyuria [48,113,192].

Head and neck:  facial clefts, facial tumors, and neck masses, such as goiter and teratomas have been associated with polyhydramnios. Polyhydramnios is due to reduced fetal swallowing [127] either due to mechanical obstruction in neck masses or ineffective swallowing in facial clefting [132].

Respiratory, Thoracic abnormalities, and Cardiovascular anomalies: compressive pulmonary disorders as pleural effusions, diaphragmatic hernia or cystic adenomatoid malformation of the lungs are associated with polyhydramnios [127]. In upper airway obstruction and cystic adenomatoid malformation, polyhydramnios may be due to either esophageal or cardiac compression [193,194]. In diaphragmatic hernia, polyhydramnios is often due to partial obstruction of the gastrointestinal tract [132].

Genitourinary anomalies unilateral renal anomalies (ureteropelvic obstruction, muticystic dysplasia, and renal tumors), as well as bilateral malformations have been associated with polyhydramnios [186,195,196]. Polyhydramnios also develops in 10% of cases of ovarian cysts, presumably from compression on the adjacent bowel [132].

Skeletal dysplasias: Thanatophoric dysplasia and achondroplasia most frequently associated with polyhydramnios [197]. This combination is associated with a poor prognosis and a high probability of pulmonary hypoplasia [132].

Chromosomal abnormalities (as trisomy 18, 13, 21):  Alteration in the amniotic fluid has been associated with an increased prevalence of karyotypic abnormalities [198]. Polyhydramnios together with growth retardation are common findings in fetuses with chromosomal disease [142,199]. Generalized hydrops with or without the presence of cystic hygroma can be seen in up to 24% of fetuses with trisomy 13 [200] and should always prompt a karyotype examination [142]. In trisomy 18, the presence of associated polyhydramnios is an ominous sign and can be seen in up to 21% of fetuses with trisomy 18 [201].

Fetal and placental tumors:  As sacrococcygeal teratoma, intracranial tumors, cervical teratoma, cavernous hemangioma, congenital mesoblastic nephroma, adrenal neuroblastoma, epignathus, mediastinal teratoma, placental chorioangioma and metastatic neuroblastoma. The etiology of polyhydramnios varies with type of tumor [132].

 

·         Fetal hydrops, Rh alloimmunization, and non-hydropic red blood cell alloimmunization

 

Approximately 30% of fetuses with non immune hydrops have polyhydramnios [202]. Increased cardiac output may underlie hydramnios in some cases of fetal hydrops and Rh alloimmunization, although investigations in a gravid sheep suggest this may be oversimplification [48,203]. Hydramnios in non hydropic red blood cell alloimmunization may in part be explained by a hypoxia induced hyperlecithinemia [204] as animal data reveal powerful osmotic effects as an elevated fetal plasma lactate draws fluid from the maternal into the fetal compartement [203].

 

·         Twin oligohydramnios polyhydramnios sequence

 

This sequence [205] is a heterogenous group of disorders associated with discrepancy in the amniotic fluid with polyhydramnios of one sac and oligohydramnios of the other. Etiologies may include fetal anomalies, intra uterine growth retardation affecting one fetus, or twin-to-twin transfusion [206].  Twin-to-twin transfusion syndrome affects 10 to 15 % of monozygous twin pregnancies with monochorionic placentation [207,208]. The donor is small, hypoperfused, anemic and has poor urinary output with oligohydramnios or anhydramnios and the amniotic membrane may be totally invisible to the ultrasound assessment, the donor may be plastered to the uterine wall by its membranes, a so called, stuck twin. The recipient, however, is hyperperfused, plethoric, discrepantly larger and found in polyhydramnionic sac [142]. Fetal polyuria is documented in recipient fetus of twin-to-twin transfusion syndrome in association with increased atrial naturetic peptide level [209]. When twin-to-twin transfusion begins in the second trimester, it produces some of the most severe cases of polyhydramnios [132].

Acute hydramnios, which refers to a sudden accumulation of amniotic fluid and which is associated with maternal symptoms, is almost exclusively a manifestation of twin to twin transfusion before 26 weeks’ gestation when there is a rapid accumulation in the sac of the recipient [210]. However, congenital anomalies may also be responsible [211]. For idiopathic acute polyhydramnios, it may be due to a functional deficit in the chorionic receptors for prolactin [212]. As prolactin has been shown to stimulate fluid transport out of the amniotic cavity [213]. However still the etiology in some cases of idiopathic acute hydramnios is not determined [132].

 

·         Maternal diabetes

 

The incidence of hydramnios secondary to maternal diabetes has declined from 26% to 22% in older series [214] to 13% to 5% [175] presumably as a result of tighter glucose control. Polyhydramnios secondary to maternal diabetes is not well understood [113]. Although fetal polyuria secondary to osmotic diuresis might seem an obvious mechanism in diabetes mellitus, Van Otterlo and associates found normal fetal urine production rates in most diabetic pregnancies with mild polyhydramnios [215]. However, Yasui et al observed increased fetal urine output during maternal fasting [48,216].

                                                                       

·         Macrosomia and large for gestational age fetuses

 

The most common condition associated with polyhydramnios is macrosomia and large for gestational age fetuses. Some studies have found a 27% to 37 % prevalence of macrosomia with polyhydramnios [217,218].

Lazebnik et al, found in their study that polyhydramnios increased the risk of macrosomia by 2.7 fold [218,219]. Lazebnik et al, reported in their study that polyhydramnios is present in equivalent number of diabetic and non-diabetic women with macrosomic fetuses [218]. The cause of polyhydramnios with large for gestational age fetuses is unknown. It has been suggested that polyhydramnios may be due to increased renal vascular flow, a reversal of intramembranous flow (from the fetal circulation to the amniotic fluid), or an increase in the volume of fluid excreted by the fetal lungs [132].

 

·         Congenital infections

 

Cytomegalovirus, toxoplasmosis, varicella, parvovirus, and syphilis may all give rise to no immune hydrops and polyhydramnios [220,221].

 

·         Idiopathic polyhydramnios

 

Idiopathic polyhydramnios has been suggested when there is no identifiable cause [222]. The incidence of idiopathic polyhydramnios is related to severity, with a cause identified in 75% to 91% when the deepest pocket is greater than 12 cm, compared to 17% to 29 % with deepest pool of 8 to 12 cm [175,186]. If the sonographic evaluation is normal, the risk of a major anomaly, approximates1% with mild hydramnios, 2% with moderate hydramnios, and 11% with severe hydramnios [223].

 

·         Rare causes of polyhydramnios

 

Rare causes include substance abuse [224], maternal lithium therapy [225], and Bartter syndrome which is an autosomal recessive condition characterized by hypokalemic alkalosis, hypercalcemia and, may present with polyhydramnios [226]. Also fetal cerebral dysfunction associated with nonketotic hyperglycinemia [227] and the abnormal renal concentrating ability in pseudohypoaldosteronism explains the polyhydramnios in these conditions [228]. Fetal akinesia deformation sequence [127] and fetuses with arthrogryposis. Other causes include Beckwith- Weidman syndrome [229], intrahepatic arteriovenous shunt [230], and retroperitoneal fibrosis [231] and DiGeorge syndrome [232].

Maternal complications are mostly attributed to uterine distension, and include abdominal discomfort, uterine irritability, post partum hemorrhage, and compromised respiratory function [233]. The incidence of cesarean section is also increased as a result of unstable lie and placental abruption, which may occur with the rapid decrease in intrauterine pressure that accompanies membrane rupture [234]. The higher incidence of preeclampsia may be a manifestation of the mirror syndrome in association with fetal hydrops [235]. Ureteric obstruction occurs very rarely with gross uterine distension [236,237].

                               

5.    Fetal risks

 

             Perinatal mortality rate (<5% in a study by Dashe et al, 2002 and Biggio et al, 1999 [180,223]) associated with polyhydramnios is largely due to the presence of congenital malformations, preterm premature rupture of membranes, or preterm labor and delivery [48]. Six to 14% of perinatal deaths occur antepartum in normally formed singletons [175,238]. One explanation may be an increased risk of hypoxemia and academia and raised intra-amniotic pressure observed in fetuses with hydramnios [233]. Based on the increased pressure, it is suggested that uteroplacental perfusion can be impaired by extreme hydramnios. This hypothesis is supported by the observation that the uterine blood flow increases substantially after amnioreduction in pregnancies complicated by severe hydramnios [239].

 

6.    Treatment of polyhydramnios

 

The aim is to reduce the risk of very premature delivery and the maternal discomfort that often accompanies severe polyhydramnios. Treatment will obviously depend on the diagnosis as, better glycemic control of maternal diabetes mellitus, antiarrhythmic medication for fetal hydrops due to dysrhythmias, thoraco-amniotic shunting for fetal pulmonary cysts or pleural effusions [48,132].

 

7.    Amniotic fluid management

 

7.1. Amniotic fluid reduction

 

Amniotic fluid reduction can relieve maternal symptoms with severe polyhydramnios and prolong the gestation in both singleton and multiple pregnancies and improves perinatal survival.48 It is one of the possible treatments for twin-to-twin transfusion syndrome [240,241]. Common criteria for amniotic fluid drainage are amniotic fluid index>40 cm or the deepest pool of >12 cm but many prefer to make the decision mostly on maternal discomfort [242]. Removal of a small volume can rapidly reduce amniotic fluid pressure but it usually re-accumulates quickly [243]. The procedure often has to be repeated in order to prolong gestational age until maturity allows delivery [160]. Instead of using syringes to aspirate amniotic fluid at amniodrainage, Leung et al, have suggested in their study using vacuum wound drainage system for rapid amniodrainage (with rate of 178 ml/min) and have concluded that it is a safe and efficient method to treat severe polyhydramnios [244]. Abruption, premature rupture of membranes, and fetal bradycardia can be a complication of removal of large volumes of amniotic fluid but this risk has been estimated at about 3.1% [244]. Large volume amniodrainage in twin-to-twin transfusion syndrome may have a profound impact on the distribution of fetoplacental blood volume with consequent dramatic alterations in cardiac loading conditions.[245] When pregnancy advances and the fetoplacental blood volume increases radical amniodrainge leads to reduction in amniotic pressure and placental decompression, which may cause massive volume shifts from the recipient twin to its placenta and to the co-twin when there are venovenous anastomoses [244]. Such an effect can be compared to that observed in the surviving twin after the death of the co-twin [246]. So amniodrainage for twin-to-twin transfusion syndrome should be less radical as pregnancy advances to minimize the effect of this placental steal phenomenon [244]. Fetoscopic laser ablation of the vascular anastomosis is associated according to the recently published Eurofetus study with improved perinatal outcome compared with amnioreduction in women presenting with twin-to-twin transfusion syndrome [160,247].

                                                              

7.2. Medical treatment

 

Prostaglandin synthase inhibitors as, indomethacin affects amniotic fluid volume by impairing lung liquid production, or enhancing the resorption of lung liquid and decreasing fetal urinary output by enhancing proximal tubular resorption of water and sodium [248,249]. Indomethacin is effective in reducing amniotic fluid volume as early as 21 weeks’ gestation [250]. The dose of indomethacin varies between 50 and 200 mg/day, depending on the amniotic fluid volume response assessed ultrasonically [251]. By 32 to 35 weeks treatment is discontinued because of reports of neonatal morbidity resulting from indomethacin use in late gestation [252]. The maternal side effects are usually mild, however the potential fetal effects of indomethacin are more significant, as premature closure of the ductus, cerebral vasoconstriction in the fetus [253]. The development of fetal pleural effusions and frank hydrops has been attributed to persistent ductal constriction from continued indomethacin use [253]. Vermillion et al, showed in their study that ductal constriction was reversible with early identification and timely discontinuation of therapy and they advised caution in use over 31 weeks’ gestation [254]. Oligohydramnios is an additional complication associated with indomethacin therapy. When indomethacin is discontinued, the amniotic fluid volume gradually reaccumulates [36,250] renal failures and irreversible renal damage have been observed in neonates with prolonged exposure to indomethacin in-utero [255]. It is contraindicated in twin –twin transfusion syndrome because of the adverse effects on the oliguric donor twin [48]. Some studies suggest the increased risk for intracranial hemorrhage and necrotizing enterocolitis with indomethacin therapy [256]. The true safety of prenatally administered indomethacin requires more studies especially prospective randomized controlled trials. Until one is performed, the evidence indicates long-term indomethacin should be avoided, but that cautious short-term use of indomethacin before 32 weeks of gestation will add minimal risks for neonatal complications [48].

Sulindac is an alternative prostaglandin synthase inhibitor with similar structure to indomethacin [257]. It appears to have a lesser effect on fetal urine output and the ductus arteriosus [257]. At a recommended dose of 200 mg every 12 hours, it can reduce amniotic fluid volume without evidence of ductal constriction during prolonged therapy in the second and third trimester [258]. Any mild effect on the fetal ductus is transient, which is advantageous in the long-term management of hydramnios or threatened preterm labor [48].

 



[1] Underwood MA, Gilbert WM. Amniotic fluid: Not just fetal urine anymore. Journal of Perinatology  25, 341–348, 2005.

[2] Sherer D. A review of mniotic fluid dynamics and the enigma of oligohydramnios. Am J Perinatol 19(5):253-66, 2002.

[3] Gilbert W and Brace R. The missing link in amniotic fluid volume regulation: intramembranous absorption. Obstet Gynecol 74: 748–753, 1989.

[4] Beall MH, Van Den Wijngaard JP, Van Gemert MJ, Ross MG. Amniotic fluid Water Dynamics. Placenta 2007 Jan 22.

[5] Brace RA. Physiology of amniotic fluid regulation. Clin Obstet Gynecol 40: 280–289, 1997.

[6] Gilbert W and Brace R. Amniotic fluid volume and normal flows to and from the amniotic cavity. Semin Perinatol 17:150-157, 1993.

[7] Brace RA, Wolf EJ. Normal amniotic fluid volume changes throughout pregnancy. Am J Obst Gynecol 161:382-388, 1989.

[8] Faber JJ and Anderson DF. Regulatory response of intramembranous absorption of amniotic fluid to infusion of exogenous fluid in sheep. Am J Physiol Regul Integr Comp Physiol 277: R236–R242, 1999.

[9] Yang Q,  Davis L,  Hohimer A, Faber J, Regulatory response to washout of amniotic fluid in sheep.  Am J Physiol Heart Circ Physiol 288: H1339-H1343, 2005.

[10] Ross MG and Nijland MJM. Fetal swallowing: relation to amniotic fluid regulation. Clin Obstet Gynecol 40: 352–365, 1997.

[11] Faber JJ and Anderson DF. Absorption of amniotic fluid by amniochorion in sheep. Am J Physiol Heart Circ Physiol 282: H850–H854, 2002.    

[12] Anderson D, Yang Q,  Hohimer A,  Intramembranous absorption rate is unaffected by changes in amniotic fluid composition.  Am J Physiol Renal Physiol 288: F964-F968, 2005.

[13] Brace RA, Vermin ML, Huijssoon E. Regulation of amniotic fluid volume: intramembranous solute and volume fluxes in late gestation fetal sheep. Am J Obstet Gynecol 191:837–46, 2004

[14] Cheung C. Vascular endothelial growth factor activation of intramembranous absorption: a critical pathway for amniotic fluid volume regulation. J Soc Gynecol Invest 11: 63–74, 2004.

[15] Wang S, Kallichanda N, Song W, Ramirez B, and Ross M. Expression of aquaporin- in human placenta and chorioamniotic membranes: evidence of molecular mechanism for intramembranous amniotic fluid resorption. Am J Obstet Gynecol 185: 1226–1231, 2001.

[16] Holden C. Stem cells. Stem cell candidates proliferate. Science. 2007 Feb 9;315(5813):761.

[17] Bloomfield FH, van Zijl PL, Bauer MK, Harding JE. Effects of intrauterine growth restriction and intraamniotic insulin-like growth factor I treatment on blood and amniotic fluid concentrations and on fetal gut uptake of amino acid in late gestation ovine fetuses. J Pediatr Gastroenterol Nutr 2002;35:287–97.

[18] Kwon H, Wu G, Bazer FW, Spencer TE. Developmental changes in polyamine levels and synthesis in the ovine conceptus. Biol Reprod 2003;69:1626–34.

[19] Hirai C, Ichiba H, Saito M, Shintaku H, Yamano T, Kusuda S. Trophic effect of multiple growth factors in amniotic fluid or human milk on cultured human fetal small intestinal cells. J Pediatr Gastroenterol Nutr 2002;34:524–8.

[20] Goetzman BW, Read LC, Plopper CG, et al. Prenatal exposure to epidermal growth factor attenuates respiratory distress syndrome in rhesus infants. Pediatr Res 1994;35:30–6.

[21] Kimble RM, Breier BH, Gluckman PD, Harding JE. Enteral IGF-I enhances fetal growth and gastrointestinal development in oesophageal ligated fetal sheep. J Endocrinol 1999;162:227–35.

[22] Juul SE, Christensen RD. Absorption of enteral recombinant human erythropoietin by neonates. Ann Pharmacother 2003;37:782–6.

[23] Doi S, Osada H, Seki K, Sekiya S. Relationship of amniotic fluid index and cord blood erythropoietin levels in small for and appropriate for gestational age fetuses. Obstet Gynecol 1999;94:768.

[24] Teramo KA, Widness JA, Clemons GK, Voutilainen P, McKinlay S, Schwartz R. Amniotic fluid erythropoietin correlates with umbilical plasma erythropoietin in normal and abnormal pregnancy. Obstet Gynecol 1987;69:710-716.

[25] Stock SJ, Kelly RW, Riley SC Calder AA. Natural antimicrobial production by the amnion. Am J Obstet Gynecol. 2007 Mar;196(3):255.e1-6.

[26] Soto E, Espinoza J, Nien JK, Kusanovic JP, Erez O, Richani K, Santolaya-Forgas J, Romero R.  Human beta-defensin-2: a natural antimicrobial peptide present in amniotic fluid participates in the host response to microbial invasion of the amniotic cavity.J Matern Fetal Neonatal Med. 2007 Jan;20(1):15-22.

[27] Espinoza J, Chaiworapongsa T, Romero R, Edwin S, Rathnasabapathy C, Gomez R, Bujold E, Camacho N, Kim YM, Hassan S, Blackwell S, Whitty J, Berman S, Redman M, Yoon BH, Sorokin Y.  Antimicrobial peptides in amniotic fluid: defensins, calprotectin and bacterial/permeability-increasing protein in patients with microbial invasion of the amniotic cavity, intra-amniotic inflammation, preterm labor and premature rupture of membranes. : J Matern Fetal Neonatal Med. 2003 Jan;13(1):2-21.

[28] Akinbi HT, Narendran V, Pass AK, Markart P, Hoath SB. Host defense proteins in vernix caseosa and amniotic fluid. Am J Obstet Gynecol. 2004 Dec;191(6):2090-6.

[29] McMillan, Julia A., Feigin, Ralph D., DeAngelis, Catherine, Jones, M. Douglas Oski"s Pediatrics (4th Edition) Chronic Diffuse Interstitial Lung Disease in Childhood Lippincott Williams & Wilkins, 2006.

[30] Chin T, Said Y Ibrahim Abdulhamid Girija Natarajan.  Pulmonary hypoplaia, 2006. www.emedicine.com.

[31] MILLER, MARVIN E. The Bone Disease of Preterm Birth: A Biomechanical Perspective.

 International Pediatrics Research Volume 53(1), January 2003, pp 10-15.

[32] Frost HM. Perspectives: a proposed general model of the “mechanostat” (suggestions from a new paradigm). Anat Rec 1996 244: 139–147.

[33] Miller ME, Hangartner TN. Temporary brittle bone disease: association with decreased fetal movement and osteopenia. Calcif Tissue Int 1999 64: 137–143.

[34] Miller ME. Temporary brittle bone disease: a real entity? Semin Perinatol  1999 23: 174–182.

[35] Trahair JF, Wing SJ, Quinn KJ, Owens PC. Regulation of gastrointestinal growth in fetal sheep by luminally administered insulin-like growth factor-I. J Endocrinol 1997 Jan:152(!):29-38.

[36] Avery GB, Fletcher MA, MacDonald MG: Pathophysiology and Management of the Newborn. 1999 Neonatology  5th Ed. Lippincott Williams & Wilkins, Philadelphia.

[37] Mulvihill, S. J., M. D. Stone, H. T. Debas, and E. W. Fonkal. The role of amniotic fluid in fetal nutrition. J. Pediatr. Surg. 20: 668-672, 1985.

[38] Michael G. Ross and Mark J. M. Nijland.  Development of ingestive behavior. Am J Physiol Regul Integr Comp Physiol Vol. 274, Issue 4, R879-R893, April 1998.

[39] Trahair, J., R. Harding, A. Bocking, M. Silver, and P. Robinson. The role of ingestion in the development of the small intestine in fetal sheep. Q. J. Exp. Physiol. 71: 99-104, 1986.

[40] Avila, C., R. Harding, and P. Robinson. The effects of preventing ingestion on the development of the digestive system in the sheep fetus. Q. J. Exp. Physiol. 71: 99-104, 1986.

[41] Falconer, J. Oral epidermal growth factor is trophic for the stomach in the neonatal rat. Biol. Neonate 52: 347-350, 1987.

[42] Kim J, Lee Y, Kim H, Hwang KJ, Kwon HC, Kim SK, Cho DJ, Kang SG, You J. Human amniotic fluid-derived stem cells have characteristics of multipotent stem cells. Cell Prolif. 2007 Feb;40(1):75-90.

[43] De Coppi, Paolo; Bartsch, Georg Jr; Siddiqui, M Minhaj;  Xu, Tao; Santos, Cesar C.; Perin, Laura; Mostoslavsky, Gustavo; Serre, Angeline C.; Snyder, Evan Y.; Yoo, James J.; Furth, Mark E.; Soker, Shay; Atala, Anthony. Isolation of Amniotic Stem Cell Lines With Potential for Therapy. Obstetrical & Gynecological Survey. 62(5):316-317, May 2007.

[44] Hampton, Tracy.  Stem Cells Obtained From Amniotic Fluid. JAMA. 297(8):795, February 28, 2007.

[45] Kolamber YM, Preister A, Socker S, Atala A, Guldberg RE. Chondrogenic differentiation of amniotic fluid derived stem cells. J Mol Histol. 2007 August 1.

[46] Tsai  Ms, Lee Jl, Chang YJ, Hwang SM .Isolation of human multipotent mesenchymal stem cells from second-trimester amniotic fluid using a novel two-stage culture protocol. Hum Reprod. 2004 Jun;19(6):1450-6. Epub 2004 Apr 22.

[47] Cipriani S, Bonini D, Marchina E, Balgkouranidou I, Caimi L, Grassi Zucconi G, Barlati S. Mesenchymal cells from human amniotic fluid survive and migrate after transplantation into adult rat brain Cell Biol Int. 2007 Aug;31(8):845-50. Epub 2007 Feb 9.

[48] James DK, Steer PJ, Weiner CP, Gonik B. High risk pregnancy Management options. Volume 1 third edition, 2006.  Taylor MJO, Fisk NM, Hydramnios and oligohydramnios.

[49] Keith A. Eddleman, Fergal D. Malone, Lisa Sullivan, Kim Dukes, Richard L. Berkowitz, Yara Kharbutli, MS, T. Flint Porter, David A. Luthy, Christine H. Comstock, George R. Saade, Susan Klugman,

Lorraine Dugoff, Sabrina D. Craigo, Ilan E. Timor-Tritsch, Stephen R. Carr. Pregnancy Loss Rates After Midtrimester Amniocentesis The American College of Obstetricians and Gynecologists.  VOL. 108, NO. 5, NOVEMBER 2006.      

[50] Royal College of Obstetricians and gynaecologists. Amniocentesis and Chorionic villous sampling. Guideline No. 8 (revised). London: RCOG Press; 2005.

[51] Sepulveda W, Donaldson A, Johnson RD, et al. Are routine alpha fetoprotein and acetylcholinestrase determinations still necessary at second trimester amniocentesis? Impact of high resolution ultrasoundy. Obstst Gynecol 1995:85:107-112.

[52] Moise Jr KJ. Management of Rhesus alloimmunization in pregnancy. Obstet Gynecol 2002;100:600–11.

[53] Warren PS, Gill RW, Fisher CC. Doppler flow studies in Rhesus isoimmunization. Semin Perinatol 1987;375–378.

[54] Whitecar, Paul W , MAJ, MC Moise, Kenneth J. Jr.  Sonographic Methods to Detect Fetal Anemia in Red Blood Cell Alloimmunization Obstet Gynecol Surv Volume 55(4), April 2000, pp 240-250.

[55] Oepkes D, Seaward G, Vandenbussche F, Kingdom J, Windrim R, Beyene J, Kanhai H, Ohlsson A, Ryan G. Minimally invasive management of RH alloimmunization: Can amniotic fluid deltaOD450 be replaced by Doppler studies? A prospective multicenter trial.Am J Obstet Gynecol american journal of obstetrics and gynecology December 2004, Supplement • Volume 191 • Number 6.

[56] Hessner MJ, Pircon RA, Johnson ST, Luhm RA. Prenatal genotyping of the Duffy group system by allele-specific polymerase chain reaction. Prenat Diagn 1999;19:41–5.

[57] Hessner MJ, Pircon RA, Johnson ST, Luhm RA Prenatal genotyping of Jk(a) and Jk(b) of the human Kidd blood group system by allele-specific polymerase chain reaction. Prenat Diagn. 1998 Dec;18(12):1225-31.

[58] Horger EO, Finch H, Vincent VA. A single physician’s experience with four thousand six hundred genetic amniocenteses. Am J Obstet Gynecol 2001;185:279–88.

[59] Scott F, Peters H, Boogert T, Robertson R, Anderson J, McLennan A, et al. The loss rates for invasive prenatal testing in specialised obstetric ultrasound practice.Aust N Z J Obstet Gynaecol 2002;42:55–8.

[60] Kuller J, Chescheir N, Cefalo R. Prenatal Diagnosis and Reproductive Genetics. Chapter 18. Mosby edit. 1996.

[61] Alfirevic Z, Sundberg K, Brigham S. Amniocentesis and chorionic villus sampling for prenatal diagnosis (Cochrane Review). In: The Cochrane Library, Issue 2, 2005.

[62] The Canadian Early and Midtrimester Amniocentesis Trial (CEMAT) Group.Randomised trial to assess safety and fetal outcome of early and midtrimester amniocentesis. Lancet 1998;351:242–7.

[63] Nicolaides K, Brizot M de L,Patel F, Snijders R.Comparison of chorionic villus sampling and amniocentesis for fetal karyotyping at 10–13 weeks’ gestation. Lancet 1994;344:435–9.

[64] Brambati, Bruno; Tului, Lucia Chorionic villus sampling and amniocentesis[Prenatal diagnosis] current opinion in obstetrics and gynecology Lippincott Williams & Wilkins, Inc. Volume 17(2), April 2005, p 197–201.

[65] Sundberg K, Bang J, Smidt-Jensen S, et al. Randomised study of risk of fetal loss related to early amniocentesis versus chorionic villus sampling. Lancet 1997; 350:697–703.

[66] Philip J, Silver RK, Wilson RD, et al. Late first-trimester invasive prenatal diagnosis: results of an international randomized trial. Obstet Gynecol 2004; 103:1164–1173.

[67] Maymon E, Romero R, Pacora P, Gomez R, Athayde N, Edwin S, Yoon BH. Human neutrophil collagenase (matrix metalloproteinase 8) in parturition, premature rupture of the membranes, and intrauterine infection. Am J Obstet Gynecol. 2000 Jul;183(1):94-9.

[68] Yoon BH, Romero R, Kim CJ et al. Amniotic fluid interleukin-6: a sensitive test for antenatal diagnosis of acute inflammatory lesions of preterm placenta and prediction of perinatal morbidity. Am J Obstet Gynecol 1995; 172: 960-970.

[69] Nein JK, Yoon BH, Espinoza J, Kusanovic JP, Erez O et al. A rapid MMP-8 bedside test for the detection of intra-amniotic inflammation identifies patients at risk for imminent preterm delivery.
Am J Obstet Gynecol. 2006 Oct;195(4):1025-30.

[70] Malamitsi-Puchner A, Vrachnis N, Samoli E, Baka S, Iliodromiti Z, Puchner KP, Malligianis P, Hassiakos D. Possible early prediction of preterm birth by determination of novel proinflammatory factors in midtrimester amniotic fluid. Ann N Y Acad Sci. 2006 Dec;1092:440-9.

[71] Romero RR, Yoon BH, Mazor M, Gomez R, Diamond MP, Kenny JS. The diagnostic and prognostic value of amniotic fluid white blood cell count, glucose, interleukin-6, and Gram stain in patients with preterm labor and intact membranes. Am J Obstet Gynecol 1993;169:805-816.

[72] Hitti J, Tarczy-Hornoch P, Murphy J, Hillier SL, Aura J, Eschenbach DA. Amniotic fluid infection, cytokines, and adverse outcome among infants at 34 weeks" gestation or less. Obstet Gynecol 2001;98:1080-1088.

[73] Park KH, Yoon BH, Shim SS, Jun JK, Syn HC.Amniotic fluid tumor necrosis factor-alpha is a marker for the prediction of early-onset neonatal sepsis in preterm labor: Gynecol Obstet Invest. 2004;58(2):84-90.

[74] Tarim, Ebru ; Bais, Tayfun ; Kilicda, Esra Bulan ; Sezgin, Nurzen ; Yanik, Filiz  Are amniotic fluid C-reactive protein and glucose levels, and white blood cell counts at the time of genetic amniocentesis related with preterm delivery?. Journal of Perinatal Medicine. 33(6):524-529, December 2005.

[75] Friel LA, Romero R, Edwin S, Kae Nien J, Gomez R, Chaiworapongsa T, Pedro Kusanovic J, Tolosa JE, Hassan SS, Espinoza J. The calcium binding protein, S100B, is increased in the amniotic fluid of women with intra-amniotic infection/inflammation and preterm labor with intact or ruptured membranes. J Perinat Med. 2007;35(5):385-93.

[76] Hussey MJ, Levy ES, Pombar X, Meyer P, Strassner HT. Evaluating rapid diagnostic tests of intra-amniotic infection: Gram stain, amniotic fluid glucose level, and amniotic fluid to serum glucose level ratio. Am J Obstet Gynecol. 1998 Sep;179(3 Pt 1):650-6.

[77] Reddy UM, Baschat AA, Zlatnik MG, Towbin JA, Harman CR, Weiner CP. Detection of viral deoxyribonucleic acid in amniotic fluid: association with fetal malformation and pregnancy abnormalities. Fetal Diagn Ther. 2005 May-Jun;20(3):203-7.

[78] Van den Veyver IB, Ni J, Bowles N, Carpenter RJ Jr, Weiner CP, Yankowitz J, Moise KJ Jr, Henderson J, Towbin JA. Detection of intrauterine viral infection using the polymerase chain reaction. Mol Genet Metab. 1998 Feb;63(2):85-95.

[79] Antsaklis a, Daskalakis G, Papantoniou N et al: Prenatal diagnosis of congenital toxoplasmosis. Prenat Diagn 2002:22:1107-1011.

[80] Baschat AA, Towbin J, Bowles NE, Harman CR, Weiner CP. Prevalence of viral DNA in amniotic fluid of low-risk pregnancies in the second trimester .J Matern Fetal Neonatal Med. 2003 Jun;13(6):381-4.

[81] McLean LK, Chehab FF, Goldberg JD. Detection of viral deoxyribonucleic acid in the amniotic fluid of low-risk pregnancies by polymerase chain reaction. Am J Obstet Gynecol. 1995 Oct;173(4):1282-6.

[82] Petrikovsky BM, Lipson SM, Kaplan MH. Viral studies on amniotic fluid from fetuses with and without abnormalities detected by prenatal sonography. J Reprod Med. 2003 Apr;48(4):230-2.

[83] Neerhof MG, Haney EI, Silver RK, Ashwood ER, Lee IS, Piazze JJ. Lamellar body counts compared with traditional phospholipid analysis as an assay for evaluating fetal lung maturity. Obstet Gynecol 2001;97:305–9.

[84] Kaplan LA, Chapman JF, Bock JL, et al. Prediction of respiratory distress syndrome using the Abbott FLM-II amniotic fluid assay. Clin Chim Acta 2002;326:61–8.

[85] Pachi A, De Luca F, Cametti C, Barresi S, Berta S. Use of electrical conductivity of amniotic fluid in the evaluation of fetal lung maturation .Fetal Diagn Ther 2001;16:90–4.

[86] Gerards FA, Twisk JW, Bakker M, Barkhof F, Van Vugt JM.  Fetal lung volume: three-dimensional ultrasonography compared with magnetic resonance imaging. Ultrasound Obstet Gynecol. 2007 May;29(5):533-6.

[87] Florio P, Cobellis L, Luisi S, et al. Changes in inhibins and activin secretion in healthy and pathological pregnancies. Mol Cell Endocrinol 2001;180:123–30.

[88] Zimmer EZ, Bronshtein M. Ultrasonic features of intraamniotic ‘unidentified debris’ at 14–16 weeks’ gestation. Ultrasound Obstet Gynecol 1996; 7: 178–181.

[89] Parulekar SG. Ultrasonographic demonstration of floating particles in amniotic fluid. J Ultrasound Med 1983;2:107-110.

[90] Vengalil S, Santolaya-Forgas J, Meyer W, Myles T. Ultrasonically dense amniotic fluid in early pregnancy in asymptomatic women without vaginal bleeding. A report of two cases. J Reprod Med 1998; 43: 462–464.

[91] Sepulveda W, Reid R, Nicolaidis P, Prendiville O, Chapman RS, Fisk NM. Second-trimester echogenic bowel and intraamniotic bleeding: association between fetal bowel echogenicity and amniotic fluid spectrophotometry at 410 nm. Am J Obstet Gynecol 1996; 174: 839–842.

[92] McNamara A, Levine D, Intra abdominal fetal echogenic masses: a practical guide to diagnosis and management RadioGraphics 2005; 25:633–645 ? Published online.

[93] Cafici D, and Sepulveda W,  First-Trimester Echogenic Amniotic Fluid in the Acrania-Anencephaly Sequence J Ultrasound Med 22:1075-1079, 2003

[94] Hallak M, Zador IE, Garcia EM, Pryde PG, Cotton DB,Evans MI. Ultrasound-detected free-floating particles in amniotic fluid: correlation with maternal serum alpha-fetoprotein. Fetal Diagn Ther 1993; 8: 402–406.

[95] Narendran V, Wickett RR, Pickens WL, Hoath SB. Interaction between pulmonary surfactant and vernix: a potential mechanism for induction of amniotic fluid turbidity. Pediatr Res 48:120–124,2000.

[96] Nishijima K, Shukunami K, Tsukahara H, Orisaka M, Miura J, Kotsuji F. Micelles of pulmonary surfactant in human amniotic fluid at term. Pediatr Res. 2006 Aug;60(2):196-9.

[97] Sherer DM, Abramowicz JS, Smith SA, Woods JR. Sonographically homogeneous echogenic amniotic fluid in detecting meconium-stained amniotic fluid. Obstet Gynecol,  1991 Nov;78(5 Pt 1):819-22.

[98] Malinowski W. Clinical significance of echogenic amniotic fluid at term pregnancy Ginekol Pol 2002 Feb:73(2);120-3.

[99] Petrikovsky B, Schneider EP, Gross B. Clinical significance of echogenic amniotic fluid J Cli Ultrasound 1998 May 26(4):191-3.

[100] Brown DL, Polger M, Clark PK, Bromley BS, Doubilet BM. Very echogenic amniotic fluid;ulrasonography amniocentesis correlation. J Ultrasound Med, 1994 Feb;13(2);95-7

[101] Vohra N, Rochelson B, Smith-Levitin M. Three-dimensional sonographic findings in congenital (harlequin) ichthyosis. JUltrasound Med 2003; 22: 737–739.

[102] Espinoza J,  Calves L. F. Gon ,  Romero R.  ,  Nien J. K.  ,  Stitles S.  , Kim Y. M.The prevalence and clinical significance of amniotic fluid‘sludge’ in patients with preterm labor and intact membranes. Ultrasound Obstet Gynecol 2005; 25: 346–352.

[103] Dolan CR, Smith LT, Sybert VP. Prenatal detection of epidermolysis bullosa letalis with pyloric atresia in a fetus by abnormal ultrasound and elevated alpha-fetoprotein. Am J Med Genet 1993; 47: 395–400.

[104] Catherine Lepinard,Philippe Descamps, Guerrino Meneguzzi.  Prenatal diagnosis of pyloric atresia junctional epidermolysis bullosa syndrome in a fetus not known to be at risk.. Prenatal diagnosis prenat Diagn 2000: 20: 70-75.

[105] Shelia AU, Julliette S Prendiville. Ichthyosis fetalis an article 2006 emedicine  www.emedicine.com/derm/topic192 htm.

[106] Akiyama M, Suzumori K, Shimizu H.Prenatal diagnosis of Harlequin Ichthyosis by the examination of keratinized hair canals and amniotic fluid cells at 19 week’s estimated gestational age. Prenat Diagn 1999 19:167-171.

[107] Marinkovich MP. Epidermolysis Bullosa. 2006 www.emedicine.com.

[108] Meizner I, Carmi R.1990. The snow flake sign. A sonographic marker for prenatal detection of fetal skin denudation. J Ultrasound Med 9:607-609.

[109] Sung JY, Leung JW, Shaffer EA, Lam K, Olson ME, Costerton JW. Ascending infection of the biliary tract after surgical sphincterotomy and biliary stenting. J Gastroenterol Hepatol 1992; 7: 240–245.

[110] Leid JG, Shirtliff ME, Costerton JW, Stoodley AP. Human leukocytes adhere to, penetrate, and respond to Staphylococcus aureus biofilms. Infect Immun 2002; 70: 6339–6345.

[111] Tyden O, Bergstrom S, Nilsson BA. Origin of amniotic fluid cells in mid-trimester pregnancies. Br J Obstet Gynaecol 1981;88: 278–286.

[112] Kusanovic JP, Espinoza J, Romero R, Goncalves LF, Nien JK, Soto E, Khalek N, Camacho N, Hendler I, Mittal P, Friel LA, Gotsch F, Erez O, Than NG, Mazaki-Tovi S, Schoen ML, Hassan SS. Clinical significance of the presence of amniotic fluid "sludge" in asymptomatic patients at high risk for spontaneous preterm delivery. Ultrasound Obstet Gynecol. 2007 Aug 22.

[113] Marino T. Ultrasound abnprmalities of the amniotic fluid, membranes, umbilical cord, and placenta Obstet Gynecol Clin N Am 31, 2004:177-200.

[114] Moore TR. Superiority of the four quadrant sum over the single deepest pocket technique in ultrasonographic identification of abnormal amniotic fluid volumes. Am J Obstet Gynecol 1990:163(3):762-767.

[115] Moore TR, Cayle JE. The amniotic fluid index in normal  human pregnancy. Am J Obstet Gynecol 1990:162(5):1168-1173.

[116] Chauhan SP, Sanderson M, Hendrix NW, Magann EF, Devoe LD. Perinatal outcome and amniotic fluid index in the antepartum and intrapartum periods: a meta analysis. Am J Obstet Gynecol 1999:181:1473-1478.

[117] Morris JM, Thompson K, Smithey J, Gaffney G, Cooke I, Chamberlain P, Hope P, Altman D, MacKenzie IZ The usefulness of ultrasound assessment of amniotic fluid in predicting adverse outcome in prolonged pregnancy: a prospective blinded observational study.   BJOG2003 Nov;110(11):989-94.

[118] Megann EF, Sanderson M, Martin JN, Chauhan S. the amniotic fluid index, single deepest pocket, and two diameter pocket in normal human pregnancy. Am J Obstet Gynecol 2000:182(6):1581-1588.

[119] Chauhan SP, Doherty DD, Magann EF, et al. amniotic fluid index vs single deepest pocket technique during modified biophysical profile: A randomized clinical trial. Am J Obstet Gynecol 2004:191:661-8.

[120] Lam H, Leung WC, Lee CP, Lao TT. Amniotic fluid volume at 41 weeks and infant outcome. J Reprod Med 2006 Jun;51(6):484-8.

[121] Magann EF, Chauhan SP, Doherty DA, Barrilleaux PS, Martin JN, Morrison JC. Predictability of intrapartum and neonatal outcomes with the amniotic fluid volume distribution: a reassessment using the amniotic fluid index, single deepest pocket, and a dye-determined amniotic fluid volume. Am J Obstet Gynecol 2003;188:1523-1528.

[122] Garmel SH, Chelmow D, Sha SJ, Roan JT, D"Alton ME. Oligohydramnios and appropriately grown fetus. Am J Perinatology 1997;14:359-363.

[123] Kreiser D, el-Sayed YY, Sorem KA, Chitkara UI, Holbrook RH, Druzin ML. Decreased amniotic fluid index in low-risk pregnancy. J Reprod Med 2001;46:743-746.

[124] Magann EF, Kinsella MJ, Chauhan SP, McNamara MF, Gehring BW, Morrison JC. Does an amniotic fluid index of <5 cm necessitate delivery in high-risk pregnancies? A case-control study. Am J Obstet Gynecol 1999;180:1354-1359.

[125] William J. Ott Reevaluation of the relationship between amniotic fluid volume and perinatal outcome Transactions of the 71st Annual Meeting of the Central Association of Obstetricians and Gynecologists Am J Obstet Gynecol June 2005 • Volume 192 • Number 6.

[126] Lee SM, Park SK, Shim SS, Jun JK, Park JS, Syn HC. Measurement of fetal urine production by three dimensional ultrasonography in normal pregnancy. Ultrasound Obstet Gynecol. 2007 Sep;30(3):281-6.

[127] Pilu G, Nicolaides K, Ximenes R & Jeanty P. Abnormalities of the amniotic fluid volume. Diagnosis of fetal abnormalities. The 18-23 weeks scan. Diploma in fetal medicine and ISUOG educational series, 2000. http://www.centrus.com/.

[128] Philipson EH, Sokol RJ, Williams T. oligohydramnios clinical associations and predictive value for intrauterine growth retardation. Am J Obstet Gynecol 1983:146:271-278.

[129] Mercer LJ, Brown LG, Petres RE, Messer RH. A survey of pregnancies complicated by decreased amniotic fluid .Am J Obstet Gynecol 1984:149:355-361.

[130] Manning FA, Harman CR, Morrison I, Menticoglous SM, Lange IR, et al. Fetal assessment based on fetal biophysical profile scoring IV. An analysis of perinatal morbidity and mortality. Am J Obstet Gynecol 1990:162:703-709.

[131] Halpern ME, Fong KW, Zalev AH, et al. reliability of amniotic fluid volume estimation from ultrasonograms: intraobserver and interobserver variation before and after the establishment of criteria. Am J Obstet Gynecol 1985:153:264-267.

[132] Nyberg  DA, McGahan JP, Pretorius DH, Pilu G. Diagnostic imaging of fetal anomalies. Lippincott Williams &Wilkins, Philadelphia, 2002.

[133] Horsager R, Nathan L, Leveno KJ. Correlation of measured amniotic fluid volume and sonographic predictions of oligohydramnios. Obstet Gynecol 1994:83:955-958.

[134] Bianco A, Rosen T, Kuczynski E, Tetrokalashvili M, Lockwood CJ. Measurement  of the amniotic fluid index with and without color Doppler. J Perinat Med 1999:27:245-249.

[135] Megann EF, Chauhan SP, Barrilleaux PS, et al. Ultrasound estimate of amniotic fluid volume: Color Doppler overdiagnosis of oligohydramnios. Obstet Gynecol 2001:98(1):71-74.

[136] Hill LM, Lazebnik N, Mny A. effect of indomethacin on individual amniotic fluid indicies in multiple gestations. J Ultrasound Med 1996:15:395-399.

[137] Piper JM, Ray WA, Rosa FW. Pregnancy outcome following exposure to angiotensin converting enzyme inhibitors. Obstet Gynecol 1992:80:429-432.

[138] Robson MS, Turner MJ, Stronge JM, O’ Herlihy C: Is amniotic fluid quantitation of value in the diagnosis and conservative management of prelabor  membrane rupture.

[139] Kilbride HW, Yeast J, Thibeault DW. Defining limits of survival : Lethal pulmonary hypoplasia after midtrimester premature rupture of membranes. Am J Obstet Gynecol 1996:175(3):675-681.

[140] Borgida AF, Mills A, Feldman DM, Rodis JF, Egan JFX. Outcome of pregnancies complicated by ruptured membranes after genetic amniocentesis. Am J Obstet Gynecol 2000:183:937-939.

[141] Bronshtein M, Amil A, Achiron R, Noy I, Blumenfeld Z. The early prenatal diagnosis of renal agenesis: techniques and possible pitfalls. Prenat Diagn 1994:14:291-297.

[142] Twining P, Mchugo JM, Pilling DW. Textbook of fetal abnormalities. 2000.

[143] Benacerraf BR. Examination of the second trimester fetus with severe oligohydramnios using transvaginal scanning. Obstet Gynecol 1990:75:491-493.

[144] Hoffman CIT, Filly RA, Callen PW. The lying down adrenal sign : a sonographic indicator of renal agenesis or ectopia in fetuses and neonates. J Ultrasound Med 1992:11:533-536.

[145] DeVore GR. The value of color Doppler sonography in the diagnosis of renal agenesis. J Ultrasound Med 1995:14:443-449.

[146] Romero R, Cullen M, Jeanty P, et al. The diagnosis of congenital renal anomalies with ultrasound II. Infantile polycystic kidney disease. Am J Obstet Gynecol 1984:150:259-262.

[147] Wisser J, Hebisch G, Froster U, et al. Prenatal sonographic diagnosis of autosomal recessive polycystic kidney disease during  the early second trimester. Prenat Diagn 1995:15:868-871.

[148] Atiyeh B, Husmann D, Baum M. Contralateral renal abnormalities in multicystic dysplastic kidney disease. J Pediatr 1992:121:65-67.

[149] Agarwal SK, Fisk NM. In utero therapy for lower urinary tract obstruction. Prenat Diagn 2001:21(11):970-976.

[150] Thomas DF. Prenatal diagnosis: does it alter outcome? Prenat Diagn 2001:21(11):1004-1011.

[151] Harkness UF, Mari G. Diagnosis and management of intrauterine growth restriction. Clin Perinatol 2004:31:743-64.

[152] RolandL Boyd. Polyhydramnios and oligohydramnios. 2006.  http://www.emedicine.com/ped/topic1854.

[153] Nimrod C, Varela Gittings F, Machin G, et al. The effect of very prolonged membrane rupture on fetal development. Am J Obstet Gynecol 1984:148(5):540-543.

[154] Rotschild A, Ling EW, Puterman ML,Farquharson D. Neonatal outcome after prolonged preterm rupture of membranes . Am J Obstet Gynecol 1990:162(1):46-52.

[155] Magann EF, Morton ML, Nolan TE, Martin JN. Comparative efficacy of two sonographic measurements for the detection of aberrations in the amniotic fluid volume and the effect of amniotic fluid volume on pregnancy outcome. Obstet Gynecol 1994:83:959-962.

[156] Christianson, C. Huff, D. McPherson, E Limb deformations in oligohydramnios sequence: effects of gestational age and duration of oligohydramnios American Journal of Medical Genetics. 86(5):430-3, 1999 Oct 29.

[157] Fisk NM, Ronderos-Dumit D, Soliani A, et al. diagnostic and therapeutic transabdominal amnioinfusion in oligohydramnios. Obstet Gynecol 1991:78(2):270-278.

[158] Gembruch U, Hansmann M. artificial instillation of amniotic fluid as a new technique for the diagnostic evaluation of cases of oligohydramnios. Prenat Diagn 1988:8(1):33-45.

[159] Sepulveda W, Stagiannis KD, Flack NJ, Fisk NM. Accuracy of prenatal diagnosis of renal agenesis with color flow imaging in severe second trimester oligohydramnios. Am J Obstet Gynecol 1995:173(6):1788-1792.

[160] Studd J, Lin Tan S, Chervenak FA. Progress in obstetrics and gynecology. Illans S, Soothill P. Fetal therapy. 2006.

[161] Quintero RA, Morales WJ, Allen M, Bornick PW, et al. Treatment of iatrogenic previable premature rupture of membranes with intra amniotic injection of platelets and cryoprecipitate (amniopatch) :preliminary experience. Am J Obstet Gynecol.1999:181:744-749.

[162] Locatelli A, Vergani P, Di Pirro G, Doria V, Biffi A, Ghidini a. role of amnioinfusion in the management of premature rupture of membranes at <26 week’s gestation. Am J Obstet Gynecol 2000:183:878-882.

[163] De Santis M, Scavo M, Noia G et al. Trans abdominal amnioinfusion treatment of severe oligohydramnios in preterm premature rupture of membranes at less than 26 gestational weeks. Diagn Ther 2003:18:412-417.

[164] Tan LK, Kumar S, Jolly M, Gleeson C, Johnson P, Fisk NM. Test amnioinfusion to determine suitability for serial therapeutic amnioinfusion in midtrimester premature rupture of membranes. Fetal Diagn  2003:18:183-189.

[165] Chhabra S, Dargan R, Nasare M. Antepartum transabdominal amnioinfusion. Int J Gynaecol Obstet. 2007 May;97(2):95-9. Epub 2007 Mar 26.

[166] Hofmeyr GJ. Amnioinfusion for preterm rupture of membranes(Cochrane Review):In:The Cochrane Library, Issue 1, 2004.Chichester.

[167] Hofmeyr GJ. Amnioinfusion for meconium stained liquor in labour (Cochrane Review):In:The Cochrane Library, Issue 1, 2004.Chichester.

[168] Fait G, Pauzner D, Gull I, et al. Effect of 1 week of oral hydration on amniotic fluid index. J Reprod Med 2003:48(3):187-190.

[169] Hofmeyr GJ, Gulmezoglu AM. Maternal hydration for increasing amniotic fluid volume in oligohydramnios and normal amniotic fluid volume. Cochrane Database Syst Rev 2002(1):CD000134.

[170] Ross MG, Cedars L, Nijland MJ, Ogundipe A. Tretment of oligohydramnios with maternal 1-deamnio-(8-D-arginine)vasopressin induced plasma hypoosmolality. Am J Obstet Gynecol 1996:174(5):1608-1613.

[171] Scicione AC, Manley JS, Pollock M, et al. Intracervical fibrin sealants. A potential treatment for early preterm premature rupture of the membranes. Am J Obstet Gynecol 2001 :184(3):368-373.

[172] Manning FA, Harrison MR, Rodeck C. Catheter shunts for fetal hydronephrosis and hydrocephalus. Report of the international Fetal Surgery Registry. N Engl J Med 1986:315(5):336-340.

[173] Queenan JT,Thompson W, Whitfield CR, Shah SI. Amniotic fluid volumes in normal pregnancy. Am J Obstet Gynecol 1972:114:34-38.

[174] Chamberlain PF, Manning FA, Morrison I, Harmon CR, Lange IR. Ultrasound evaluation of amniotic fluid volume II. The relationship of increased amniotic fluid volume to perinatal outcome. Am J Obstet Gynecol 1984:150:250-254.

[175] Hill LM, Breckle R, Thomas ML, Fries JK. Polyhydramnios: ultrasonically detected prevalence and neonatal outcome. Obstet Gynecol 1987:69:21-25.

[176] Thompson O, Brown R, Gunnarson G, Harrington K. prevalence of poyhydramnios in the third trimester in a population screened by first and second trimester ultrasonography. J Perinat Med 1998:26:371-377.

[177] Phelan JP, Ahn MO, Smith CV, Rutherford SE, Anderson E. amniotic fluid index measurements during pregnancy. J Reprod Med 1987:32:601-604.

[178] Smith CV, Plambeck RD, Rayburn WF, Albugh KJ. Relation of mild idiopathic polyhydramnios to perinatal outcome. Obstet Gynecol 1992:79:387-389

[179] Panting Kemp A, Nquyen T, Chang E, Quillen E, Castro L. Idiopathic polyhydramnios and perinatal outcome. Am J Obstet Gynecol 1999:181:1079-82

[180] Biggio JR, Wenstrom KD, Dubard MB, Cliver SP. Hydramnios prediction of adverse perinatal outcome. Obstet Gynecol 1999:94:773-777.

[181] Phelan JP,Park YW, Ahn MO, Rutherford SE. Polyhydramnios and perinatal outcome . J Perinatol 1990:10:347-350.

[182] Megann EF, Martin JN. Amniotic fluid assessment in singelton and twin pregnancies. Obstet Gynecol Clin North Am 1999:26:579-593.

[183] Megann EF, Chauhan SP, Martin JN, Whitworth NS, Morrison JC. Ultrasonic assessment of the amniotic fluid volume in diamniotic twin. J Soc Gynecol Investig 1995:2:609-613.

[184] Megann EF, Chauhan SP, Whitworth NS, Klausen JH, Saltzman AK, et al. Do multiple measurements employing different ultrasonic techniques improve the accuracy of amniotic fluid volume assessment? Aust N Z J Obstet Gynecol 1998:38:172-175.

[185] Chauhan SP, Magann EF, Morrison JC, et al. Ultrasonographic assessment of amniotic fluid does not reflect actual amniotic fluid volume. Am J Obstet Gynecol 1997:177:291-297.

[186] Barkin SZ, Pretorius DH, Beckett MK, Manchester DK, Nelson TR, et al. Severe polyhydramnios: incidence of anomalies. AJR Am J Roentgenol 1987:148:155-159.

[187] Ben Chetrit A, Hochner Celnikier D, Ron M, et al. Hydramnios in the third trimester of pregnancy: a change in the distribution of accompanying fetal anomalies as a result of early ultrasonographic prenatal diagnosis. Am J Obstet Gynecol 1990:162;1344-1345.

[188] Kimble RM, Harding JE, Kolbe A. Does gut atresia cause polyhydramnios? Pediatr Surg Int 1998:13:115-117.

[189] Foster MA, Nyberg DA, Mahony BS, Mack LA, Marks WM, et al. Meconium peritonitis: prenatal sonographic findings and clinical significance. Radiology 1987:165:661-665.

[190] Langer JC, Winthrop AL, Burrows RF, Issenman RM, Caco CC. False diagnosis of intestinal obstruction in fetus with congenital chloride diarrhea. J Pediatr Surg 1991:26:1282-1284.

[191] Chen CP, Wang TY, Chuang CY. Sonographic findings in a fetus with megacystis- microcolon-intestinal hypoperistalsis syndrome. J Clin Ultrasound 1998:26:217-220.

[192] Naeye RL, Milic AM, Blanc W. Fetal endocrine and renal disorders: Clues to the origin of hydramnios. Am J Obstet Gynecol 1970:108(8):1251-1256.

[193] De Hullu JA, Kornman LH, Beekhuis JR, Nikkels PGJ. The hyperechogenic lungs of laryngotracheal obstruction. Ultrasound Obstet Gynecol 1995:5:271-274.

[194] Thorpe Beeston JG, Nicolaides KH. Cystic adenomatoid malformation of the lung: prenatal diagnosis and outcome. Prenat Diagn 1994:14:677-688.

[195] Mahony BS, Filly RA, Callen PW, Chinn DH, Golbus MS. Severe non immune hydrops fetalis: sonographic evaluation. Radiology 1984:151:757-761.

[196] Kleiner B, Callen PW, Filly RA. Sonographic analysis of the fetus with ureteropelvic junction obstruction. AJR Am J Roentgenol 1987:148:359-363.

[197] Thomas RL, Hess LW, Johnson TRB. Prepartum diagnosis of limb shortening defects with associated hydramnios. Am J Perinatol 1987:4;295-299.

[198] Stoll CG, Alembik Y, Dott B. Study of 156 cases of polyhydramnios and congenital malformations in a series of 118,265 consecutive births. Am J Obstet Gynecol 1991:165:586-590.

[199] Nicolaides KH, Shawa L, Brizot M, Snijders R. Ultrasonographically detectable markers of fetal chromosomal defects. Ultrasound Obstet Gynecol 1993:3:56-69.

[200] Lehman CD, Nyberg DA, Winter TC, et al. Trisomy 13 syndrome:perinatal ultrasound findings in a review of 33 cases. Radiology 1995:194:217-222.

[201] Nyberg DA, Kramer D, Resta RG, Kapur R. Prenatal sonographic findings of trisomy 18. J Ultrasound Med 1993: 2:103-113.

[202] McCoy MC, Katz VL, Gould N, Kuller JA. Non immune hydrops after 20 weeks’ gestation:review of 10 years’ experience with suggestions for management. Obstet Gynecol 1995;85:578-582.

[203] Powell TL, Brace RA. Elevated fetal plasma lactate produces polyhydramnios in the sheep. Am J Obstet Gynecol 1991:165(6):1595-1607.

[204] Soothil PW, Nicolaides KH, Rodeck CH, et al. Relationship of fetal hemoglobin and oxygen content to lactate concentration in Rh isoimmunized pregnancies. Obstet Gynecol 1987:69(2):268-271.

[205] Bruner JP, Anderson TL, Rosemond RL. Placental pathophysiology of the twin oligohydramnios polyhydramnios sequence and the twin- twin transfusion syndrome. Placenta 1998:19:81-86.

[206] Bajoria R, Wigglesworth J, Fisk NM. Angioarchitecture of monochorionic placentas in relation to the twin- twin transfusion syndrome. Am J Obstet Gynecol 1995:172:856-863.

[207] Sebire NJ, Snijders RJ, Hughes K, Sepulveda W, Nicolaides KH. The hidden mortality of monochorionic twin pregnancies. Br J Obstet Gynaecol 1997;104:1203-1207.

[208] Carroll SG, Soothill PW, Abdel Fattah SA, Porter H, Montague I, Kyle PM. Prediction of chorionicity in twin pregnancies at 10-14 weeks of gestation. Br J Obstet Gynaecol 2002:109:182-6.

[209] Baoria R, Ward S, Sooranna SR. Atrial natriuretic peptide medicated polyuria. Pathogenesis of polyhydramnios in the recipient twin of twin- twin transfusion syndrome. Placenta 2001:22(8-9):716-724.

[210] Duncan KR, Denbow M, Fisk NM. The aetiology and management of twin- twin transfusion syndrome. Prenatal Diagn 1997:17:1227-1236.

[211] Broecker BH, Redwire FO, Petres RE. Reversal of acute polyhydramnios after fetal renal decompression. Urology 1998:31:60-62.

[212] DeSantis M, Cavaliere AF, Noia G, Masini L, Menini E, et al. Acute recurrent polyhydramnios and amniotic prolactin. Prenat Diagn 2000:20:347-348.

[213] Josimovich JB, Mensko K, Bucella L. Amniotic prolactin control over amniotic and fetal extracellular fluid water and electrolytes in rhesus monkey. Endocrinology 1977:100:564-570.

[214] Queenan JT, Gadow EC. Polyhydramnios, chronic versus acute. Am J Obstet Gynecol 1970;108(3):349-355.

[215] Van Otterlo LC, Wlandimiroff JW, Wallenburg HC. Relationship between fetal urine production and amniotic fluid volume in normal pregnancy and pregnancy complicated by diabetes. Br J Obstet Gynecol 1977:84(3):205-209.

[216] Yasuhi I, Ishimaru T, Hirari M, Yamabe T. Hourly fetal urine production rate in the fasting and the postprandial state of normal and diabetic pregnant women. Obstet Gynecol 1994:84(1):64-68.

[217] Rochelson B, Coury A, Schulman H, Dery C, et al. Doppler umbilical artery velocimetry in fetuses with polyhydramnios. Am J Perinatol 1990:7:340-2.

[218] Lazebnik N, Hill LM, Guzick D, Martin JG, Many A. Severity of polyhydramnios does not affect the prevalence of large for gestational age newborn infants. J Ultrasound Med 1996:15:385-388.

[219] Benson CB, Coughlin BF, Doubliet PM. Amniotic fluid volume in large for gestational age fetuses of non diabetic mothers. J Ultrasound Med 1991:10:149-151.

[220] Drose JA, Dennis MA, Thickman D. Infection in-utero: ultrasound findings in 19 cases. Radiology 1991:178:369-374.

[221] Hohlfeld P, MacAleese J, Capella-Pavlovski M, et al. Fetal toxoplasmosis: ultrasonographic signs. Ultrasound Obstet Gynecol 1991:1:241-244.

[222] Sohaey R, Nyberg D, Sickler GK, Williams MA. Idiopathic polyhydramnios, association with fetal macrosomia. Radiology 1994:190:393-396.

[223] Dashe JS, Mcintire DD, Ramus RM, et al. Hydramnios;Anomaly prevalence and sonographic detection. Obstet Gynecol 202:100(1):134-139.

[224] Panting Kemp A, Nguyen T, Castro L. Substance abuse and polyhydramnios. Am J Obstet Gynecol 2002:187(3):602-605.

[225] Krause S, Ebbesen F, Lange AP. Polyhydramnios with maternal lithium treatment. Obstet Gynecol. 1990:75(3):504-506.

[226] Ohlsson A, Sieck U, Cumming W, et al. A variant  of Batter’s syndrome. Bartter’s syndrome associated with hydramnios, prematurity, hypercalciuria and nephrocalcinosis. Acta Paediatr Scand 1984:73(6):868-874.

[227] Serniste w, Urban G, Stukler ipsiroglu S, Mick R, Sacher M. Polyhydramnios as a first prenatal sympyom of non ketotic hyperglycemia. Prenatal Diag 1998:18;863-864.

[228] Narchi H, Santos M, Kulaylat N. Polyhydramnios as a sign of fetal pseudohypoaldosteronism. Int J Gynecol Obstet 2000:69:53-54.

[229] Ranzini AC, Day Salvatore D, Turner T, Smulian JC, Vintzileos AM. Intra-uterine growth and ultrasound findings in fetuses with Beckwith Wiedemann syndrome. Obstet Gynecol 1997:89;538-542.

[230] Tseng JJ, Chou MM, Lee YH, Ho ESC. Prenatal diagnosis of intrahepatic arteriovenous shunts. Ultrasound Obstet Gynecol 2000:15:441-444.

[231] Duffy SL. Fetal retroperitoneal fibrosis associated with hydramnios. JAMA. 1966:198:993-996.

[232] Devriendt K, Van Schoubroeck D et al. Polyhydramnios as a prenatal symptom of the DiGeorge/ Velo-cardio-facial syndrome. Prenat Diagn 1998:18:68-72.

[233] Fisk NM, Vaughan J, Talbert D. Impaired fetal blood gas status in polyhydramnios and its relation to raised amniotic pressure. Fetal Diagn Ther 1994:9:7-13.

[234] Panting Kemp A, Nguyen T, Chang E, et al. Idiopathic polyhydramnios and perinatal outcome. Am J Obstet Gynecol 1999:181(5):1079-1082.

[235] Midgley DY, Harding K. The Mirror syndrome. Eur J Obstet Gynecol Reprod Biol 2000:88(2):201-202.

[236] Seeds JW, Cefalo RC, Herbert WN, Bowes WJ. Hydramnios and maternal renal failure: Relief with fetal therapy. Obstet Gynecol 1984:64(3):26s-29s.

[237] Vintzileos AM, Turner GW, Campbell WA, et al. Polyhydramnios and obstructive renal failure. A case report and review of the literature. Am J Obstet Gynecol 1985:152(7):883-885.

[238] Carlson DE, Platt LD, Medearis AL, Horenstein J. Quantifiable polyhydramnios. Diagnosis and management. Obstet Gynecol 1990:75(6):989-993.

[239] Bower SJ, Flack NJ, Sepulveda W, et al. Uterine artery blood flow response to correction of amniotic fluid volume. Am J Obstet Gynecol 1995:173:502-507.

[240] Kyle PM, Fisk NM. Oligohydramnios and polyhydramnios. In: Fisk NM, Moise Jr KJ.(eds). Fetal therapy, invasive and transplacental. Cambridge:Cambridge University Press, 1997, 203-217

[241] Wee LY, Fisk NM. The twin- twin transfusion syndrome. Semin Neonatol 2002:7:187-202.

[242] Thein AT, Soothill P. Antenatal invasive therapy. Eur J Pediatr 1998:157(Suppl 1):s2-s6.

[243] Abdel-Fattah SA, Carroll SG, Kyle PM, Soothill PW. Amnioreduction: how much to drain? Fetal Diagn Ther 1999:14:279-282.

[244] Leung WC, Jouannic JM, Hyett J, Rodeck C, Jauniaux E. Procedure related complications of rapid amniodrainage in the treatment of polyhydramnios. Obstet Gynecol 2004:23:154-158.

[245] Jauniaux E, Holmes A, Hyett J, Yates R, Rodeck C. Rapid and radical amniodrainage in the treatment of severe twin-twin transfusion syndrome. Prenat Diagn 2001:21:471-476.

[246] Machin GA, Keith LJ. An atlas of Muliple Pregnancy: Biology and Pathology. Parthenon Publishing Group: New York, 1999.

[247] Senat MV, Deprest J, Boulvain M, Paupe A, Winer N, Ville Y. Endoscopic Lasser surgery versus serial amnioreduction for severe twin to twin transfusion syndrome. N Engl J Med 2004:351:136-144.

[248] Mamopoulos M, Assimakopoulos E, Reece EA, et al. Maternal indomethacin therapy in the treatment of polyhydramnios. Am J Obstet Gynecol 1990:162(5):1225-1229.

[249] Usberti M, Pecoraro C, Federico S, et al.