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Articles ยป Amniotic fluid
2007-12-19-01 Amniotic fluid dynamic © Moghazy
Amniotic fluid dynamic 

Mona Moghazy, MD.



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      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].      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].      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].      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      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].      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].


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