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 bidirectional 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 intramembranousabsorption 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 thefetus 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 alphafetoprotein [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.
Pulmonary

Oligohydramnios sequelae
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. 181However 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].

age

Macrosomia and large for gestational age fetuses

The most common condition associated with polyhydramnios is macrosomia and large for gestational
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, thoracoamniotic 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

[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
proximal tubular resorption of water and sodium

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 inutero [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,
341348, 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: 748753, 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: 280289, 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: R236R242, 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: 352365, 1997.
[11] Faber JJ and Anderson DF. Absorption of amniotic fluid by amniochorion in sheep. Am J Physiol
Heart Circ Physiol 282: H850H854, 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 191:83746, 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: 6374, 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: 12261231, 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;35:28797.
[18] Kwon H, Wu G, Bazer FW, Spencer TE. Developmental changes in polyamine levels and synthesis in
the ovine conceptus. Biol Reprod2003;69:162634.
[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;34:5248.
[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;35:306.
[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;162:22735.
[22] Juul SE, Christensen RD. Absorption of enteral recombinant human erythropoietin by neonates. Ann
Pharmacother 2003;37:7826.
[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: 139147.
[33] Miller ME, Hangartner TN. Temporary brittle bone disease: association with decreased fetal
movement and osteopenia. Calcif Tissue Int1999 64: 137143.
[34] Miller ME. Temporary brittle bone disease: a real entity? Semin Perinatol 1999 23: 174182.
[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 fluidderived 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;375378.
[54] Whitecar, Paul W , MAJ, MC Moise, Kenneth J. Jr. Sonographic Methods to Detect Fetal Anemia in
Red Blood Cell AlloimmunizationObstet 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;19:415.

[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 physicians experience with four thousand six hundred
genetic amniocenteses. Am J Obstet Gynecol 2001;185:27988.
[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;42:558.
[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;351:2427.
[63] Nicolaides K, Brizot M de L,Patel F, Snijders R.Comparison of chorionic villus sampling and
amniocentesis for fetal karyotyping at 1013 weeks gestation. Lancet 1994;344:4359.
[64] Brambati, Bruno; Tului, Lucia Chorionic villus sampling and amniocentesis[Prenatal diagnosis] current
opinion in obstetrics and gynecologyLippincott 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; 350:697703.
[66] Philip J, Silver RK, Wilson RD, et al. Late first-trimester invasive prenatal diagnosis: results of an
international randomized trial. Obstet Gynecol 2004; 103:11641173.
[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 Creactive 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 intraamniotic 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;97:3059.
[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;326:618.
[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;16:904.
[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 Endocrinol2001;180:12330.
[88] Zimmer EZ, Bronshtein M. Ultrasonic features of intraamniotic unidentified debris at 1416 weeks
gestation. Ultrasound Obstet Gynecol1996; 7: 178181.
[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: 462464.
[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: 839842.
[92] McNamara A, Levine D, Intra abdominal fetal echogenic masses: a practical guide to diagnosis and
management RadioGraphics 2005; 25:633645 ? 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:
402406.
[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 48:120124,2000.
[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 Med2003; 22: 737739.
[102] Espinoza J, Calves L. F. Gon , Romero R. , Nien J. K. , Stitles S. , Kim Y. M.The prevalence and
clinical significance of amniotic fluidsludge in patients with preterm labor and intact
membranes. Ultrasound Obstet Gynecol 2005; 25: 346352.
[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 weeks 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 Med9:607-609.
[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: 240245.
[110] Leid JG, Shirtliff ME, Costerton JW, Stoodley AP. Human leukocytes adhere to, penetrate, and
respond to Staphylococcus aureus biofilms.Infect Immun 2002; 70: 63396345.
[111] Tyden O, Bergstrom S, Nilsson BA. Origin of amniotic fluid cells in mid-trimester pregnancies. Br
J Obstet Gynaecol 1981;88: 278286.

[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):762767.
[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):2816.
[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 Gynecol1984:149:355-361.
[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 Med1996:15:395-399.
[137] Piper JM, Ray WA, Rosa FW. Pregnancy outcome following exposure to angiotensin converting
enzyme inhibitors. Obstet Gynecol1992:80:429-432.
[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 Gynecol1990:75:491-493.
[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 Gynecol1984:148(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 ofoligohydramnios 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 weeks 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 Gynecol1987:69:21-25.
[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 Med1987:32:601-604.
[178] Smith CV, Plambeck RD, Rayburn WF, Albugh KJ. Relation of mild idiopathic polyhydramnios to
perinatal outcome. Obstet Gynecol1992:79:387-389
[179] Panting Kemp A, Nquyen T, Chang E, Quillen E, Castro L. Idiopathic polyhydramnios and perinatal
outcome. Am J Obstet Gynecol1999:181:1079-82
[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- microcolonintestinal 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 Gynecol1970:108(8):1251-1256.
[193] De Hullu JA, Kornman LH, Beekhuis JR, Nikkels PGJ. The hyperechogenic lungs of laryngotracheal
obstruction. Ultrasound Obstet Gynecol1995:5:271-274.
[194] Thorpe Beeston JG, Nicolaides KH. Cystic adenomatoid malformation of the lung: prenatal diagnosis
and outcome. Prenat Diagn1994:14:677-688.
[195] Mahony BS, Filly RA, Callen PW, Chinn DH, Golbus MS. Severe non immune hydrops fetalis:
sonographic evaluation. Radiology1984:151:757-761.
[196] Kleiner B, Callen PW, Filly RA. Sonographic analysis of the fetus with ureteropelvic junction
obstruction. AJR Am J Roentgenol1987:148:359-363.
[197] Thomas RL, Hess LW, Johnson TRB. Prepartum diagnosis of limb shortening defects with
associated hydramnios. Am J Perinatol1987:4;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. Radiology1995:194:217-222.

[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 Diagn2000:20:347-348.
[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 Perinatol1990:7:340-2.
[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 Batters syndrome. Bartters 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):201202.
[236] Seeds JW, Cefalo RC, Herbert WN, Bowes WJ. Hydramnios and maternal renal failure: Relief with
fetal therapy. Obstet Gynecol1984:64(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 Gynecol1990:75(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 Gynecol1995:173:502-507.
[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. Mechanism of action of indomethacin in tubular
defects. Pediatrics 1985:75(3):501-507.
[250] Goldenberg RL, Davis RO, Baker RC. Indomethacin induced oligohydramnios. Am J Obstet
Gynecol 1989:160:1196-1197.
[251] Moise K, Ou CN, Kirshon B, et al. Placental transfer of indomethacin in the human pregnancy. Am J
Obstet gynecol 1990:162(2):199-201.
[252] Cabrol D, Landesman R, Muller J, et al. Treatment of polyhydramnios with prostaglandin synthetase
inhibitor(indomethacin). Am J Obstet Gynecol 1987:157(2):422-426.
[253] Kramer WB, Van Der Veyver I, Kirshon B. Treatment of polyhydramnios with indomethacin. Clin
Perinatol 1994:21:615-630.
[254] Vermillion ST, Scardo JA, Lashus AG, Wiles HB. The effect of indomethacin tocolysis on fetal ductus
arteriosus constriction with advancing gestational age. Am J Obstet Gynecol 1997:177(2):256-259.
[255] Van Der Heijden BJ, Carlus C, Narcy F, et al. Persistant anuria, neonatal death, and renal
microcystic lesions after prenatal exposure to indomethacin. Am J Obstet Gynecol 1994:171(3):617-623.
[256] Norton ME, Merrill J, Cooper BA, et al. Neonatal complications after the adminstration of
indomethacin for preterm labor. N Engl J Med1993:329(22):1602-1607.
[257] Carlan SJ, O Brien WF, O Leary TD. Randomized comparative trial of indomethacin and sulindac
for the treatment of refractory preterm labor. Obstet Gynecol 1992:79(2):223-228.
[258] Peek MJ, McCarthy A, Kyle P, et al. Medical amnioreduction with sulindac to reduce cord
complications in monoamniotic twins. Am J Obstet Gynecol 1997:176(2):334-336.