Amniotic fluid dynamic - Goemescam.com.br

and adult stem cells, which suggest that amniotic fluid stem cells may exist at an intermediate stage between twostem cell types [42,44]. Stem cells isolated from amniotic fluid have several advantages over embryonic andadult 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 tumorsin vivo [43].Amniotic fluid stem cells can serve as precursors to a broad range of differentiated cell types thatpotentially have therapeutic applications [43]. Recently, it has been suggested that amniotic fluid stem cells mightbe 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 besidesbeing an easily accessible and expandable source of fetal stem cells, amniotic fluid will provide a promisingsource of neural progenitor cells that may be used in future cellular therapies for neurodegenerative diseasesand nervous system injuries [46,47].De Coppi J et al, stated that, banking of cells that would otherwise be discarded could provide aconvenient source not only for autologous treatment later in life, but for matching of histocompatible donor cellswith prospective recipients [43].3.3. Diagnostic amniocentesis and amniotic fluid usesAmniotic 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 widelyperformed invasive prenatal diagnostic procedure, most commonly used for diagnosing genetic andchromosomal abnormalities prenatally [49].Most amniocenteses are performed to obtain amniotic fluid for karyotyping and the majority isundertaken from 15 completed weeks onwards [50]. Indications for fetal karyotyping include an abnormalscreening test result as for trisomy 21, advanced maternal age, a sonographically detected structuralabnormality, previous aneuploidy, and a known chromosomal translocation in either partner [48]. Amniocentesisto diagnose inborn errors of metabolism and cystic fibrosis by measuring the activity of fetal enzymes and theirbyproducts has been largely replaced by molecular DNA analysis [48]. Likewise, amniocentesis to measurealpha feto protein and acetylcholinestrase to diagnose a neural tube defect is rarely necessary because of thereliability of ultrasonography [48, 51]. Evaluation of amniotic fluid bilirubin level based on optical density hasbeen used to predict the severity of fetal hemolysis in alloimmunized pregnancies. Currently, the combination ofamniocentesis to assess optical density, Doppler flow studies of the intra-hepatic umbilical vein and the middlecerebral artery and fetal blood sampling by cordocentesis are recommended to closely monitor the anemicfetus [52,53,54]. Oepkes D et al, have shown in their study that middle cerebral artery Doppler peak velocitymeasurement shows better test characteristics in the prediction of fetal anemia than the traditional amniotic fluidspectrophotometry in Rh alloimmunized pregnancies [55]. Allele-specific polymerase chain reaction of amnioticfluid fetal cells can also be used to identify fetuses at risk for hemolytic disease of the newborn due to minorblood group incompatibilities [56,57].The rate of miscarriage associated with amniocentesis is approximately 1%. More recent largeuncontrolled series suggest that procedure-related loss rates around 0.5% can be achieved [58,59]. Fetal lossdue 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. Earlyamniocentesis is not a safe alternative to second-trimester amniocentesis or CVS [50]. The CEMAT group (TheCanadian Early and Midtrimester Amniocentesis Trial group), have reported in their randomized trial asignificantly greater fetal loss and a higher incidence of talipes in the early amniocentesis cases compared withthe ‘late’ ones (7.6% versus 5.9%) [62]. A randomized study by Nicolaides et al compared transabdominalchorionic 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 thanTA-CVS and mid-trimester amniocentesis[64,65,66].Amniotic fluid assessment has been studied in patients with preterm labor and/or preterm prematurerupture of membranes (PPROM) to investigate possible intra-amniotic infection (IAI). Amniotic fluid indicatorssuggestive of infection include elevated levels of matrix metalloproteinase (e.g., MMP-9) [67,68,69], andelevated 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 infectioninclude interleukins (e.g., IL-6 and IL-1b) [71], tumor necrosis factor (TNF-a) [72,73], G-CSF, elevated whiteblood cell count, low glucose [71,74], elevated concentration of amniotic fluid S100B [75], and the presence ofbacteria identified by Gram stain or culture [71,76]. However it is unclear whether the information gained inwomen with preterm premature rupture of membranes changes the clinical outcome, additionally no randomizedtrial supports the use of routine amniocentesis to diagnose chorioamnionitis in women with either preterm laboror preterm premature rupture of membranes [1,48].Amniocentesis has also been helpful with the use of polymerase chain reaction in prenatal diagnosis offetal infection as with cytomegalovirus [77,78], toxoplasma [79], and parvovirus B-19 infection [80,81,82].

4.3.1.1. Definition of oligohydramnios and sonographicevaluationOligohydramnios complicates 0.5% to 8% of pregnancies and the prognosis for pregnanciescomplicated by oligohydramnios is gestational age dependent [113]. Oligohydramnios can be diagnosedsubjectively [127]. The visual criteria for oligohydramnios include evidence of fetal crowding and an obviouslack of fluid [128]. Using the single largest pocket of amniotic fluid, oligohydramnios has been variously definedas 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 lessthan or equal to 3 cm [131]. Moore defined oligohydramnios as an amniotic fluid index below the 5 th percentile[115]. This corresponds o amniotic fluid index less than 7 cm near term. However, a common definition ofoligohydramnios is amniotic fluid index less than 5 cm [132]. Criteria of amniotic fluid index less than 5 cm orlargest pocket of fluid less than 2 cm are highly specific for oligohydramnios but not sensitive when compared tothe dye dilution technique [118,133]. A wider interobserver variation in the amniotic fluid index has beenobserved when oligohydramnios is present. Therefore, averaging three amniotic fluid index measurements isrecommended when a low value is obtained [115]. The concurrent use of color Doppler has been reported that itmay lead to over diagnosis of oligohydramnios [134,135].4.3.1.2. Etiology of oligohydramniosOligohydramnios in the second trimester is usually the result of preterm premature rupture of themembranes, uteroplacental insufficiency, and urinary tract malformations (bilateral renal agenesis, multicystic orpolycystic kidneys, or urethral obstruction), and twin to twin transfusion [132]. Oligohydramnios with intactmembranes warrants a comprehensive evaluation to detect possible fetal and placental abnormalities, growthrestriction, or aneuploidy [113]. Demonstration of early symmetric intra uterine growth restriction with markedoligohydramnios 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 channelblockers, nonsteroidal anti inflammatory drug that inhibit renal vascular flow and decrease glomerular filtrationrate [136], and angiotensin converting enzyme inhibitors that reduce fetal blood pressure, decrease renalperfusion, and subsequently result in oligohydramnios [137].The most common etiologies of oligohydramnios includePremature rupture of membranes:It complicates 3% to 17% of pregnancies. Although the clinical diagnosis is obvious in most cases, only5% to 44% have ultrasonic evidence of oligohydramnios [138]. The earlier the gestation, the lower theincidence 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 pregnanciesmore than 50% of neonates die due to pulmonary hypoplasia [127]. Kilbride et al, in their study reported thatsevere oligohydramnios (single pocket less than 1 cm) lasting for 14 days or more after spontaneous prematurerupture of membranes at less than 25 weeks’ gestation is associated with 90% neonatal mortality [139]. On theother hand iatrogenic rupture of membranes after genetic amniocentesis have a much more favorable prognosiswith reported survival rate up to 91% [140].Fetal anomaliesThe 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 Grubersyndrome and, lower urinary tract obstruction as posterior urethral valve [48,132].Bilateral renal agenesis is associated with oligohydramnios after 17 weeks gestation. However prior tothis, the liquor volume may be normal [141] and, therefore, normal liquor prior to 17 weeks ‘ gestation does notexclude renal agenesis [142]. The diagnosis rests on the demonstration of absence of both kidneys and thebladder. 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, makeconfident exclusion of fetal defects sometimes impossible [127]. Transvaginal sonography may be used in thesecond trimester to more accurately assess the renal fossa. The documentation of a lying down adrenal sign (thepsoas muscles are visualized and the adrenal glands flatten to fill in the space left by the absent kidney) confirmsthat the kidney is not appropriately positioned in the renal fossa [143,144]. Color or power Doppler may beused 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 bilaterallysymmetrically enlarged kidneys with increased echogenicity, associated with oligohydramnios. However, thismay not be demonstrable until 24 weeks’ gestation [142,146,147].In multicystic dysplastic kidney disease, the affected kidney appears sonographically as a paraspinalmass 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 thebladder. 142 The diagnosis is made as early as 12 weeks. When unilateral, the contralateral kidney showsassociated abnormalities in up to 39% of cases. Contralateral anomalies include renal agenesis, renalhypoplasia, pelviureteral junction obstruction and vesico ureteric reflux [148].Posterior urethral valve accounts for half of the cases of antenatally diagnosed lower urinary tractobstruction (LUTO). Ultrasound criteria includes; a thick walled, large bladder with a key hole sign, whichrepresents 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 prognosticfactors on ultrasound include dilatation of the upper tract, increased bladder wall thickness, and evidence of renaldysplasia (echogenic renal cortex and macrocystic renal change), especially before 24 weeks [150].Intrauterine growth restriction intrauterine & post term pregnanciesIntrauterine growth restriction is suspected when the estimated fetal weight falls below the10 th percentile for the expected gestational age[151]. The cause of oligohydramnios might be related todecreased intramembranous flow of the amniotic fluid [132].In post term pregnancies, oligohydramnios is a common complication, and is associated withdiminished placental function [132]. In uteroplacental insufficiency, Doppler blood flow studies will oftendemonstrate high impedance to flow in the placental circulation and redistribution in the fetal circulation [127].4.3.1.3. Oligohydramnios sequelaePulmonary hypoplasia and skeletal deformities are common complications of prolongedoligohydramnios [152]. Severe oligohydramnios from 16 weeks onwards appears to preclude furtherpulmonary development. In contrast, oligohydramnios after the second trimester is unlikely to result in pulmonaryhypoplasia because the crucial canalicular phase of lung development (occurring between 16 and 25 weeks) haslargely been completed by this stage. Thus, the prevalence of pulmonary hypoplasia after oligohydramniosdepends on several factors: the gestation at onset, the severity, and the duration [153,154]. Bilateral renalagenesis, muticystic or polycystic kidneys are lethal abnormalities, usually in the neonatal period due topulmonary hypoplasia [127]. Patients presenting in the second, in contrast to the third, trimester have a higherprevalence of structural malformations (50.7%vs. 22.1%) and a lower survival rate (10.2% vs. 85.3%). Isolatedoligohydramnios 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 markeddeformation of the fetus due to of intrauterine constraint (Potter syndrome). Other obstructive uropathies causesimilar 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, talipesand limb contractures. Thoracic compression also may occur [152]. In a study by Christianson C et al, on limbdeformities in case of oligohydramnios, they concluded that contractures in fetuses with oligohydramnios weremore frequent with earlier onset and longer duration of oligohydramnios [156]. They added that the type ofcontracture varied with the gestational age, club foot the most frequent at all ages but hand contractures such ascamptodactyly were common only in the second trimester, flat hands were almost exclusively in the fetuses inthe third trimester [156].4.3.1.4. Therapeutic options and amnioinfusionThe ultrasonic visualization of fetal anatomy, particularly renal agenesis, is difficult in severeoligohydramnios/anhydramnios. Intra-amniotic instillation of normal saline may help improve ultrasonographicexamination and lead to the diagnosis of fetal abnormalities like renal agenesis [48,127,157,158]. Howeverthe use of amnioinfusion has greatly diminished with the widespread availability of the use of color Doppler toidentify the renal arteries, being an accurate and a noninvasive way to predict the absence of renal function as inrenal 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 thecanalicular phase [160]. Quintero et al described effective resealing in cases of iatrogenic previable prematurerupture of membranes by intra amniotic injection of platelets and cryoprecipitate although this approach has notbeen reported to work after spontaneous membrane rupture [161].Some reports have also shown that in pregnancies with preterm premature rupture of membranes witholigohydramnios 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 testprocedure to try and preselect cases of mid trimester preterm premature rupture of membranes which maybenefit from serial amnioinfusion [164]. A quarter of patients who retained infused fluid went on to subsequentserial 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 andextreme prematurity, so ideally a large series in a prospectively randomized trial would be needed to assess thebenefits [160].Chhabra et al concluded in their study that antepartum amnioinfusion is a useful procedure to reducecomplications 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 cordcompression in cases of rupture of membranes and to dilute meconium when, present in the amniotic fluid andso reduce the risk of meconium aspiration during labour [160]. Two cochrane reviews have been done, showingimprovements in perinatal outcome [166] when it is used to dilute meconium and appears to reduce theoccurrence of variable heart rate decelerations and lower the use of caesarean section due to cord compressionin labor [167]. However, further studies are needed to reach definite conclusions about the efficacy and safetyof amnioinfusion.Other suggested treatments to maintain amniotic fluid volume in oligohydramnios, include maternalhydration by oral or intravenous administration [168,169]. Desmopressin which is a selective antidiureticagonist has been suggested to increase amniotic fluid volume [170], cervical canal occlusion with fibringel [171] and vesico-amniotic shunting in obstructive uropathies [172].4.3.2. Polyhydramnios4.3.2.1. Definition of polyhydramnios and sonographicevaluationPolyhydramnios is generally defined as amniotic fluid volume greater than 2,000 ml [173]. Visualcriteria of polyhydramnios include an obvious discrepancy between the size of the fetus and the amount ofamniotic fluid. In the latter part of the third trimester the fetal abdomen approximates the anterior and theposterior uterine wall. When there is an ample amount of amniotic fluid between the fetus and the anterior andthe posterior uterine walls, significant polyhydramnios is generally present [132].Polyhydramnios is defined as an amniotic fluid index greater than the 95 th percentile for gestational ageor a maximum vertical pocket greater than 8 cm [113]. In older studies, hydramnios was reported to complicate3.5% of pregnancies [174,175], but the study of Thompson et al, found the incidence to be much lower about0.2% [176].Ultrasound evaluation of the amniotic fluid allows polyhydramnios to be classified as mild if themaximum pocket is between 8 and 11 cm, moderate if the maximum pocket is 12 to 15 cm, and severe if themaximum pocket is over 16 cm. 48 The latter occurs in less than 5% of all cases of polyhydramnios. The degreeand prognosis of polyhydramnios is related to the underlying etiology. The definition of polyhydramnios using theamniotic fluid index has been reported to be greater than 20 cm [177], greater than 24 cm [178,179], andgreater than 25 cm [180,181]. An amniotic fluid index greater than 25 cm has been associated with a higherincidence of macrosomia and congenital anomaly rate. 181 However several studies showed that, semiquantitative sonographic methods for detecting polyhydramnios are relatively poor and tend to underestimate thedegree 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 alsothe 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 polyhydramniosThe most common etiologies of polyhydramnios include:Congenital malformationsCentral nervous system malformations were considered the most common anomalies associated withpolyhydramnios [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 withincreased amniotic fluid, reflecting the role of fetal swallowing and fluid absorption in the regulation of theamniotic 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 ofpolyhydramnios [113,188].Partial bowel obstruction as in intestinal volvulus, meconium ileus, and abdominal wall defects, andmeconium peritonitis [189], as well as, non-obstructive bowel disorders as congenital chloridorrhea [190] andmegacystis 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, areassociated 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 mechanismsinclude fluid transudation from the exposed meninges and lack of antidiuretic effect because of impaired argininvasopressin secretion resulting in fetal polyuria [48,113,192].Head and neck: facial clefts, facial tumors, and neck masses, such as goiter and teratomas have beenassociated with polyhydramnios. Polyhydramnios is due to reduced fetal swallowing [127] either due tomechanical obstruction in neck masses or ineffective swallowing in facial clefting [132].Respiratory, Thoracic abnormalities, and Cardiovascular anomalies: compressive pulmonary disordersas pleural effusions, diaphragmatic hernia or cystic adenomatoid malformation of the lungs are associated withpolyhydramnios [127]. In upper airway obstruction and cystic adenomatoid malformation, polyhydramnios maybe due to either esophageal or cardiac compression [193,194]. In diaphragmatic hernia, polyhydramnios isoften due to partial obstruction of the gastrointestinal tract [132].Genitourinary anomalies unilateral renal anomalies (ureteropelvic obstruction, muticystic dysplasia, andrenal 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 adjacentbowel [132].Skeletal dysplasias: Thanatophoric dysplasia and achondroplasia most frequently associated withpolyhydramnios [197]. This combination is associated with a poor prognosis and a high probability ofpulmonary hypoplasia [132].Chromosomal abnormalities (as trisomy 18, 13, 21): Alteration in the amniotic fluid has beenassociated with an increased prevalence of karyotypic abnormalities [198]. Polyhydramnios together withgrowth retardation are common findings in fetuses with chromosomal disease [142,199]. Generalized hydropswith or without the presence of cystic hygroma can be seen in up to 24% of fetuses with trisomy 13 [200] andshould always prompt a karyotype examination [142]. In trisomy 18, the presence of associated polyhydramniosis 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, mediastinalteratoma, placental chorioangioma and metastatic neuroblastoma. The etiology of polyhydramnios varies withtype of tumor [132].Fetal hydrops, Rh alloimmunization, and non-hydropic red blood cell alloimmunizationApproximately 30% of fetuses with non immune hydrops have polyhydramnios [202]. Increasedcardiac output may underlie hydramnios in some cases of fetal hydrops and Rh alloimmunization, althoughinvestigations in a gravid sheep suggest this may be oversimplification [48,203]. Hydramnios in non hydropicred blood cell alloimmunization may in part be explained by a hypoxia induced hyperlecithinemia [204] asanimal data reveal powerful osmotic effects as an elevated fetal plasma lactate draws fluid from the maternal intothe fetal compartement [203].Twin oligohydramnios polyhydramnios sequenceThis sequence [205] is a heterogenous group of disorders associated with discrepancy in theamniotic fluid with polyhydramnios of one sac and oligohydramnios of the other. Etiologies may include fetalanomalies, intra uterine growth retardation affecting one fetus, or twin-to-twin transfusion [206]. Twin-to-twintransfusion syndrome affects 10 to 15 % of monozygous twin pregnancies with monochorionicplacentation[207,208]. The donor is small, hypoperfused, anemic and has poor urinary output witholigohydramnios or anhydramnios and the amniotic membrane may be totally invisible to the ultrasoundassessment, the donor may be plastered to the uterine wall by its membranes, a so called, stuck twin. Therecipient, 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 withincreased atrial naturetic peptide level [209]. When twin-to-twin transfusion begins in the second trimester, itproduces some of the most severe cases of polyhydramnios [132].Acute hydramnios, which refers to a sudden accumulation of amniotic fluid and which is associated withmaternal symptoms, is almost exclusively a manifestation of twin to twin transfusion before 26 weeks’ gestationwhen there is a rapid accumulation in the sac of the recipient[210]. However, congenital anomalies may also

e responsible [211]. For idiopathic acute polyhydramnios, it may be due to a functional deficit in the chorionicreceptors for prolactin [212]. As prolactin has been shown to stimulate fluid transport out of the amnioticcavity [213]. However still the etiology in some cases of idiopathic acute hydramnios is not determined [132].Maternal diabetesThe incidence of hydramnios secondary to maternal diabetes has declined from 26% to 22% in olderseries [214] to 13% to 5% [175]presumably as a result of tighter glucose control. Polyhydramnios secondary tomaternal diabetes is not well understood [113]. Although fetal polyuria secondary to osmotic diuresis might seeman obvious mechanism in diabetes mellitus, Van Otterlo and associates found normal fetal urine production ratesin most diabetic pregnancies with mild polyhydramnios [215]. However, Yasui et al observed increased fetalurine output during maternal fasting [48,216].Macrosomia and large for gestational age fetusesThe most common condition associated with polyhydramnios is macrosomia and large for gestationalage fetuses. Some studies have found a 27% to 37 % prevalence of macrosomia withpolyhydramnios [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 ofdiabetic and non-diabetic women with macrosomic fetuses [218]. The cause of polyhydramnios with large forgestational age fetuses is unknown. It has been suggested that polyhydramnios may be due to increased renalvascular flow, a reversal of intramembranous flow (from the fetal circulation to the amniotic fluid), or an increasein the volume of fluid excreted by the fetal lungs [132].Congenital infectionsCytomegalovirus, toxoplasmosis, varicella, parvovirus, and syphilis may all give rise to no immunehydrops and polyhydramnios[220,221].Idiopathic polyhydramniosIdiopathic polyhydramnios has been suggested when there is no identifiable cause [222]. Theincidence of idiopathic polyhydramnios is related to severity, with a cause identified in 75% to 91% when thedeepest pocket is greater than 12 cm, compared to 17% to 29 % with deepest pool of 8 to 12 cm [175,186]. If thesonographic evaluation is normal, the risk of a major anomaly, approximates1% with mild hydramnios, 2% withmoderate hydramnios, and 11% with severe hydramnios [223].Rare causes of polyhydramniosRare causes include substance abuse [224], maternal lithium therapy [225], and Bartter syndromewhich is an autosomal recessive condition characterized by hypokalemic alkalosis, hypercalcemia and, maypresent with polyhydramnios [226]. Also fetal cerebral dysfunction associated with nonketotichyperglycinemia [227] and the abnormal renal concentrating ability in pseudohypoaldosteronism explains thepolyhydramnios in these conditions [228]. Fetal akinesia deformation sequence [127] and fetuses witharthrogryposis. Other causes include Beckwith- Weidman syndrome [229], intrahepatic arteriovenousshunt [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 ofcesarean section is also increased as a result of unstable lie and placental abruption, which may occur with therapid decrease in intrauterine pressure that accompanies membrane rupture [234]. The higher incidence ofpreeclampsia may be a manifestation of the mirror syndrome in association with fetal hydrops [235]. Uretericobstruction occurs very rarely with gross uterine distension [236,237].5. Fetal risksPerinatal mortality rate (

it is suggested that uteroplacental perfusion can be impaired by extreme hydramnios. This hypothesis issupported by the observation that the uterine blood flow increases substantially after amnioreduction inpregnancies complicated by severe hydramnios [239].6. Treatment of polyhydramniosThe aim is to reduce the risk of very premature delivery and the maternal discomfort that oftenaccompanies severe polyhydramnios. Treatment will obviously depend on the diagnosis as, better glycemiccontrol of maternal diabetes mellitus, antiarrhythmic medication for fetal hydrops due to dysrhythmias, thoracoamnioticshunting for fetal pulmonary cysts or pleural effusions [48,132].7. Amniotic fluid management7.1. Amniotic fluid reductionAmniotic fluid reduction can relieve maternal symptoms with severe polyhydramnios and prolong thegestation in both singleton and multiple pregnancies and improves perinatal survival. 48 It is one of the possibletreatments for twin-to-twin transfusion syndrome [240,241]. Common criteria for amniotic fluid drainage areamniotic fluid index>40 cm or the deepest pool of >12 cm but many prefer to make the decision mostly onmaternal discomfort [242]. Removal of a small volume can rapidly reduce amniotic fluid pressure but it usuallyre-accumulates quickly[243]. The procedure often has to be repeated in order to prolong gestational age untilmaturity 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 178ml/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 largevolumes of amniotic fluid but this risk has been estimated at about 3.1% [244]. Large volume amniodrainage intwin-to-twin transfusion syndrome may have a profound impact on the distribution of fetoplacental blood volumewith consequent dramatic alterations in cardiac loading conditions.[245] When pregnancy advances and thefetoplacental blood volume increases radical amniodrainge leads to reduction in amniotic pressure and placentaldecompression, which may cause massive volume shifts from the recipient twin to its placenta and to the co-twinwhen there are venovenous anastomoses [244]. Such an effect can be compared to that observed in thesurviving twin after the death of the co-twin [246]. So amniodrainage for twin-to-twin transfusion syndromeshould be less radical as pregnancy advances to minimize the effect of this placental stealphenomenon[244]. Fetoscopic laser ablation of the vascular anastomosis is associated according to the recentlypublished Eurofetus study with improved perinatal outcome compared with amnioreduction in women presentingwith twin-to-twin transfusion syndrome [160,247].7.2. Medical treatmentProstaglandin synthase inhibitors as, indomethacin affects amniotic fluid volume by impairing lungliquid production, or enhancing the resorption of lung liquid and decreasing fetal urinary output by enhancingproximal tubular resorption of water and sodium [248,249]. Indomethacin is effective in reducing amnioticfluid volume as early as 21 weeks’ gestation [250]. The dose of indomethacin varies between 50 and 200mg/day, depending on the amniotic fluid volume response assessed ultrasonically [251]. By 32 to 35 weekstreatment is discontinued because of reports of neonatal morbidity resulting from indomethacin use in lategestation [252]. The maternal side effects are usually mild, however the potential fetal effects of indomethacinare more significant, as premature closure of the ductus, cerebral vasoconstriction in the fetus[253]. Thedevelopment of fetal pleural effusions and frank hydrops has been attributed to persistent ductal constriction fromcontinued indomethacin use [253]. Vermillion et al, showed in their study that ductal constriction was reversiblewith 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. Whenindomethacin is discontinued, the amniotic fluid volume gradually reaccumulates [36,250] renal failures andirreversible 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 theoliguric donor twin [48]. Some studies suggest the increased risk for intracranial hemorrhage and necrotizingenterocolitis with indomethacin therapy [256]. The true safety of prenatally administered indomethacin requiresmore studies especially prospective randomized controlled trials. Until one is performed, the evidence indicateslong-term indomethacin should be avoided, but that cautious short-term use of indomethacin before 32 weeks ofgestation will add minimal risks for neonatal complications [48].Sulindac is an alternative prostaglandin synthase inhibitor with similar structure toindomethacin [257]. It appears to have a lesser effect on fetal urine output and the ductus arteriosus [257]. At arecommended dose of 200 mg every 12 hours, it can reduce amniotic fluid volume without evidence of ductalconstriction during prolonged therapy in the second and third trimester [258]. Any mild effect on the fetal ductus

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