SMFM Clinical Guideline ajog.orgSociety for Maternal-Fetal Medicine(SMFM) Clinical Guideline #7:nonimmune hydrops fetalis

Society for Maternal-Fetal Medicine (SMFM); Mary E. Norton, MD;Suneet P. Chauhan, MD; and Jodi S. Dashe, MDydrops fetalis is a Greek termOBJECTIVE: Nonimmune hydrops is the presence of 2 abnormal fetal fluid collectionsin the absence of red cell alloimmunization. The most common etiologies include car-diovascular, chromosomal, and hematologic abnormalities, followed by structural fetalanomalies, complications of monochorionic twinning, infection, and placental abnor-malities. We sought to provide evidence-based guidelines for the evaluation and man-agement of nonimmune hydrops fetalis.METHODS: A systematic literature review was performed using MEDLINE, PubMed,EMBASE, and Cochrane Library. The search was restricted to English-language articlespublished from 1966 through June 2014. Priority was given to articles reporting originalresearch, although review articles and commentaries also were consulted. Abstracts ofresearch presented at symposia and scientific conferences were not consideredadequate for inclusion in this document. Evidence reports and guidelines published byorganizations or institutions such as the National Institutes of Health, Agency for HealthResearch and Quality, American Congress of Obstetricians and Gynecologists, andSociety for Maternal-Fetal Medicine were also reviewed, and additional studies werelocated by reviewing bibliographies of identified articles. Grading of RecommendationsAssessment, Development, and Evaluation methodology was employed for definingstrength of recommendations and rating quality of evidence. Consistent with US Pre-ventive Task Force guidelines, references were evaluated for quality based on the highestlevel of evidence.RESULTS AND RECOMMENDATIONS: Evaluation of hydrops begins with an antibodyscreen (indirect Coombs test) to determine if it is nonimmune, detailed sonography of thefetus(es) and placenta, including echocardiography and assessment for fetal arrhythmia,and middle cerebral artery Doppler evaluation for anemia, as well as fetal karyotype and/or chromosomal microarray analysis, regardless of whether a structural fetal anomaly isidentified. Recommended treatment depends on the underlying etiology and gestationalH that describes pathological fluid(dur, Greek for water) accumulationin fetal soft tissues and serous cavities.The features are detected by ultrasound,and are defined as the presence of 2abnormal fluid collections in the fetus.These include ascites, pleural effusions,pericardial effusion, and generalizedskin edema (defined as skin thickness>5 mm).1 Other frequent sonographicfindings include placental thickening(typically defined as a placental thickness4 cm in the second trimester or 6cm in the third trimester)2,3 and poly-hydramnios (Figure 1). Nonimmunehydrops fetalis (NIHF) refers specificallyto cases not caused by red cell alloim-munization. With the developmentand widespread use of Rh(D) immuneglobulin, the prevalence of Rh(D)alloimmunization and associatedhydrops has dramatically decreased. Asa result, NIHF now accounts for almost90% of cases of hydrops,4 with theprevalence in published series reportedas 1 in 1700-3000 pregnancies.5-7From the Society for Maternal-Fetal MedicinePublications Committee, Washington, DC; theDivision of Maternal-Fetal Medicine, University ofCalifornia, San Francisco, San Francisco, CA(Dr Norton); the Department of Obstetrics,Gynecology and Reproductive Sciences, TheUniversity of Texas Health Science Center atHouston, Houston, TX (Dr Chauhan); and theDepartment of Obstetrics and Gynecology,University of Texas Southwestern MedicalCenter, Dallas, TX (Dr Dashe).

Received Nov. 5, 2014; accepted Dec. 12,2014.

The authors report no conflict of interest.

Corresponding author: Society for Maternal-Fetal Medicine: Publications Committee. pubs@smfm.org

0002-9378/free 2015 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.ajog.2014.12.018

age; preterm delivery is recommended only for obstetric indications including devel-opment of mirror syndrome. Candidates for corticosteroids and antepartum surveillanceinclude those with an idiopathic etiology, an etiology amenable to prenatal or postnataltreatment, and those in whom intervention is planned if fetal deterioration occurs. Suchpregnancies should be delivered at a facility with the capability to stabilize and treatcritically ill newborns. The prognosis depends on etiology, response to therapy iftreatable, and the gestational age at detection and delivery. Aneuploidy confers a poorprognosis, and even in the absence of aneuploidy, neonatal survival is often

FIGURE 1Sonographic features of hydrops fetalis

A, Pericardial effusions. B, Pleural effusions; note midline heart anterior to small lungs with bilateral

effusions. C, Placental thickening, with placenta measuring>4 mm in thickness. D, Skin thickening

at level of fetal skull. E, Ascites, sagittal, with free-floating loops of bowel surrounded by ascites.

F, Ascites in upper abdomen, at level of fetal liver and stomach.SMFM. Nonimmune hydrops fetalis. Am J Obstet Gynecol 2015.

SMFM Clinical Guideline ajog.orgfluid movement between the vascularand interstitial spaces,8 with an increasein interstitial fluid production or adecrease in lymphatic return. Variousmechanisms thought to lead to NIHFinclude increased right heart pressure,resulting in increased central venouspressure (eg, structural heart defects);obstruction of venous or arterialblood flow (eg, pulmonary masses);inadequate diastolic ventricular filling128 American Journal of Obstetrics & Gynecology(eg, arrhythmias); hepatic venous con-gestion leading to decreased hepaticfunction and hypoalbuminemia; in-creased capillary permeability (eg,congenital infection); anemia leadingto high output cardiac failure andextramedullary hematopoiesis, oftenwith resultant hepatic dysfunction;lymphatic vessel dysplasia and obs-truction (eg, cystic hygroma); andreduced osmotic pressure (eg,FEBRUARY 2015congenital nephrosis). The precisepathogenesis of NIHF depends on theunderlying disorder, and in manycases remains unclear. Pathophysio-logic mechanisms that contribute to thedevelopment of hydrops are describedin Table 1 according to underlying eti-ology or category.What are the causes of NIHF?NIHF can result from a large numberof underlying pathologies (Table 1).The differential diagnosis is extensive,and the success in identifying a causepartially depends on the thoroughnessof efforts to establish a diagnosis.Although older studies considered manycases to be idiopathic,9-11 more recent,larger series and a systematic review re-port that a cause can be found in nearly60% of cases prenatally12 and in 85%when postnatal detection is included.13

A number of series have been pub-lished describing the many disordersassociated with NIHF.8,13-16 Review ofthese indicates that the most commonetiologies ofNIHF include cardiovascularcauses, chromosomal anomalies, andhematologic abnormalities. Other con-ditions associated with NIHF in-clude fetal malformations, particularlythoracic abnormalities, twin-twin tran-sfusion syndrome, congenital infection,placental abnormalities, fetal tumors, andgenetic or metabolic disorders (Table 1).

Overall, cardiovascular abnormalitiesare the most common cause of NIHFin most series, accounting for about20% of cases.13 NIHF can result fromcardiac structural abnormalities, ar-rhythmias, cardiomyopathy, cardiac tu-mors, or vascular abnormalities. Inmost cardiac cases, hydrops is likelycaused by increased central venouspressure due to a structural malforma-tion or from inadequate diastolic ven-tricular filling.8,17 The most commoncongenital heart defects reported in as-sociation with NIHF are right heart de-fects.6,14,18 The prognosis of NIHF dueto cardiac structural abnormalities ispoor, with combined fetal and infantmortality reported as 92%, largely dueto the severity of the heart defects thatcause in utero congestive heart failure.19

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TABLE 1Etiologies of nonimmune hydrops fetalis6,11,12,14,75

Cause Cases Mechanism

Cardiovascular 17-35% Increased central venous pressure

Chromosomal 7-16% Cardiac anomalies, lymphatic dysplasia, abnormalmyelopoiesis

Hematologic 4-12% Anemia, high output cardiac failure; hypoxia (alphathalassemia)

Infectious 5-7% Anemia, anoxia, endothelial cell damage, andincreased capillary permeability

Thoracic 6% Vena caval obstruction or increased intrathoracicpressure with impaired venous return

Twin-twin transfusion 3-10% Hypervolemia and increased central venous pressure

Urinary tract abnormalities 2-3% Urinary ascites; nephrotic syndrome withhypoproteinemia

Gastrointestinal 0.5-4% Obstruction of venous return; gastrointestinalobstruction and infarction with protein loss anddecreased colloid osmotic pressure

Lymphatic dysplasia 5-6% Impaired venous return

Tumors, includingchorioangiomas

2-3% Anemia, high output cardiac failure, hypoproteinemia

Skeletal dysplasias 3-4% Hepatomegaly, hypoproteinemia, impaired venousreturn

Syndromic 3-4% Various

Inborn errors ofmetabolism

1-2% Visceromegaly and obstruction of venous return,decreased erythropoiesis and anemia, and/orhypoproteinemia

Miscellaneous 3-15%

Unknown 15-25%

SMFM. Nonimmune hydrops fetalis. Am J Obstet Gynecol 2015.

ajog.org SMFM Clinical GuidelineBoth tachyarrhythmias and bradyar-rhythmias can lead to NIHF.14,20 Themost common tachyarrhythmias aresupraventricular tachycardia and atrialflutter, and both can often be successfullytreated with transplacental medicaltherapy.14,19,20 We recommend maternaltreatment with antiarrhythmic medica-tions for NIHF secondary to fetaltachyarrhythmia unless the gestationalage is close to term or there is a maternalor obstetrical contraindication. Medica-tion selection and dosing are reviewedelsewhere.21

Fetal bradycardia is most commonlycaused by congenital heart block, whichmay occur secondary to an immuneetiology such as transplacental passageof anti-Sjogrens-syndrome-related an-tigen A, also called anti-Ro, or thecombination anti-Ro/SSA and anti-La/SSB antibodies associated with maternalautoimmune disease. It may also resultfrom structural abnormalities affectingcardiac conduction, as with endocardialcushion defects in the setting of a het-erotaxy syndrome. Once third-degreeatrioventricular block has developed,treatment with corticosteroid therapyhas not been shown to be beneficial, andin the setting of hydrops the prognosis ispoor.22 For this reason, in-utero therapyfor fetal bradyarrhythmia resulting inhydrops is considered investigationaland is not generally recommendedoutside of a research setting.

Chromosomal abnormalities, particu-larly Turner syndrome (45,X) and Downsyndrome (trisomy 21) are also commoncauses of NIHF, accounting for 13% ina large systematic review.13 In prenatalseries, aneuploidy is the most commoncause of NIHF, particularly when iden-tified early in gestation.4,5,12 Turnersyndrome is associated with 50-80%of cases of cystic hygromas, which resultfrom a lack of communication betweenthe lymphatic system and venousdrainage in the neck.23 Lymphaticdysplasia likely leads to the developmentof NIHF in these cases.

NIHF has been described in associa-tion with other aneuploidies, includingtrisomies 13 and 18, and triploidy.24-27

In some cases, hydrops occurs dueto cardiovascular malformations inaneuploid fetuses. NIHF has also beenreported in trisomy 21 in the absence ofstructural heart defects.24,25,27,28 Somesuch cases occur due to a transientabnormal myelopoiesis, a leukemiccondition that occurs in about 10%of infants with Down syndrome.25,27

Postnatally, transient abnormal myelo-poiesis is often mild and self-limiting;prenatally, it is less common but typi-cally more severe. For these reasons,we recommend that NIHF is an indica-tion to offer prenatal diagnosis withkaryotype, fluorescence in situ hybridi-zation, and/or chromosomal microarrayanalysis, even when severe anemiais present (Figure 2). Screening withnoninvasive prenatal testing may detectsome chromosomal causes but providesmore limited information aboutFEBRUARY 2015 Ampossible genetic etiologies, and thereforewe recommend diagnostic testing.

Fetal anemia, which can result inimmune hydrops if caused by bloodgroup alloimmunization, can also leadto NIHF. Etiologies include inheritedconditions such as hemoglobinopathies,as well as acquired conditions, such ashemolysis, fetomaternal hemorrhage,parvovirus infection, or red cell aplasia.

Among the hemoglobinopathies, themost common cause of NIHF is alphathalassemia. This autosomal recessivedisorder is common in Southeast Asianpopulations, where it accounts for 28-55% of NIHF.29,30 The incidence in mostother series of NIHF is about 10%.13

Parents can be screened by evaluationof the mean cell volume, which will be

FIGURE 2Workup of nonimmune hydrops fetalis*

AFAFP, amniotic fluid alpha fetoprotein; CBC, complete blood count; CMA, chromosomal microarray; CMV, cytomegalovirus; G6PD,glucose-6-phosphate dehydrogenase deficiency; MCA PSV, middle cerebral artery peak systolic velocity; MCV, mean corpuscularvolumne; MoM, multiple of the median; PCR, polymerase chain reaction; RPR, rapid plasma reagin.

*Assuming negative indirect Coombs test, thereby excluding alloimmunization; **CMV/toxoplasmosis testing if fetal anomalies sug-gestive of infection; ***Either amniocentesis or FBS; ****Available in some laboratories.67,76

SMFM. Nonimmune hydrops fetalis. Am J Obstet Gynecol 2015.

SMFM Clinical Guideline ajog.orgdiagnosis of an affected fetus can bemade by detection of one of the commonDNA deletions or point mutations thataccount for most cases.31 Conversely, afetal blood sample can be evaluated forthe presence of the abnormal Barts he-moglobin seen in this condition. Bartshemoglobin is an ineffective oxygencarrier, thus the fetus with alpha thalas-semia will suffer severe intrauterinehypoxia from an early gestational age.The resultant NIHFwill typically presentin the late second or early third trimester.

Fetal anemia may also occur due tofetal hemorrhage. NIHF occurs only withsignificant fetomaternal bleeding thatis not enough to lead to fetal hypo-volemia and death. Fetomaternal hem-orrhage leading to hydrops may occur130 American Journal of Obstetrics & Gynecologyas either an isolated acute event, or as achronic, ongoing hemorrhage.32,33 Witheither, a Kleihauer-Betke smear willshow the presence of fetal cells in thematernal peripheral blood in most cases.Flow cytometry can also be used to es-timate the volume of fetal bleedinginto the mother. This is an importantdiagnosis to make, because even witha massive fetomaternal hemorrhage,intravascular fetal transfusion can belifesaving.34-36 For this reason, werecommend that NIHF due to anemiafrom fetomaternal hemorrhage betreated with transfusion, unless thepregnancy is at an advanced gestationalage and risks associated with deliveryare considered to be less than thoseassociated with the procedure.FEBRUARY 2015Other, less common causes of fetalanemia and hydrops include G-6-PDdeficiency, erythrocyte enzymopathiessuch as pyruvate kinase deficiency, andmaternal acquired red cell aplasia.37,38

NIHF has been reported in asso-ciation with a number of viral, bacterial,and parasitic infectious diseases, in-cluding parvovirus, cytomegalovirus,syphilis, and toxoplasmosis.39-42 Inmost series, such infections account for5-10% of NIHF.6,13,14,16 Although theassociations are less clear, NIHF hasalso been reported to occur with Cox-sackie virus, trypanosomiasis, varicella,human herpesvirus 6 and 7, herpessimplex type 1, respiratory syncytial vi-rus, congenital lymphocytic choriome-ningitis virus, and leptospirosis.6,43-47

Fetal infection can cause NIHF due toanemia, anoxia, endothelial cell damage,increased capillary permeability, andmyocarditis.

Parvovirus is the most commonly re-ported infectious cause of NIHF. Inthe fetus, the virus has a predilectionfor erythroid progenitor cells, leadingto inhibition of erythropoiesis and sub-sequent anemia.48,49 The risk of a pooroutcome for the fetus is greatest whenthe congenital infection occurs in theearly second trimester (

ajog.org SMFM Clinical GuidelineWith a large lesion or effusion, medias-tinal shift may impair venous returnand cardiac output, and the associatedesophageal compression may result inpolyhydramnios. Hydrops occurs in onlyabout 5% of fetuses with CPAM butconfers a poor prognosis without treat-ment.57 If the lesion is macrocystic,the cyst may be treated with needledrainage or thoracoamniotic shuntplacement.58,59 If predominantly solid(microcystic), both corticosteroid ther-apy and in utero resection have beenadvocated, and corticosteroid treatmentis currently recommended as a first-linetreatment.60 Large bronchopulmonarysequestrations have also been treatedwith a needle procedure involvingneodymium:yttrium-aluminium-garnetlaser of the feeding vessel.57

The most common etiology of anisolated effusion leading to NIHF ischylothorax, caused by lymphaticobstruction. The fluidmay be sampled atthe time of needle drainage or shuntplacement, and the diagnosis is con-firmed by the finding of a fetal pleuralcell count with >80% lymphocytes inthe absence of infection. Reported sur-vival exceeds 50% in hydropic fetusestreated with thoracoamniotic shuntplacement.61

Twin-twin transfusion syndrome resultsfrom an imbalance in blood flow causedby anastomoses in the placentas ofmonochorionic twin pregnancies. In se-vere cases, one or both twinsmay developNIHF, although more commonly therecipient twin is affected, likely due tohypervolemia and increased centralvenous pressure.62 Cases of twin-twintransfusion sequence with hydropshave a very poor prognosis withouttreatment, and laser therapy is consid-ered by most experts to be the bestavailable therapeutic approach toimprove the prognosis.63 Selective ter-mination via umbilical cord coagulationis also an option for pregnancies withtwin-twin transfusion sequence result-ing in NIHF. Another complication ofmonochorionic twinning that mayresult in NIHF is twin-reversed arterialperfusion sequence. Radiofrequencyablation of the acardiac twin has beenadvocated for severe cases, includingthose with hydrops, with reportedoverall survival of 80%.64

Structural urinary and gastrointestinalabnormalities are less common causes ofNIHF. A ruptured bladder or renal col-lecting system may cause urinary ascitesand mimic NIHF. Congenital nephroticsyndromes have been reported to causeNIHF due to hypoproteinemia.19,65,66

Surviving infants may have massiveproteinuria at birth and develop renalfailure in childhood.Few primary abnormalities of the

gastrointestinal tract have been associ-ated with NIHF. Those that have beenreported include diaphragmatic hernia,midgut volvulus, gastrointestinal ob-struction, jejunal atresia, malrotation ofthe intestines, and meconium perito-nitis.6,19 Intraabdominal masses maycause NIHF due to obstruction ofvenous return, while gastrointestinalobstruction and infarction may lead todecreased colloid osmotic pressure dueto protein loss.19 Hepatic disorderssuch as cirrhosis, hepatic necrosis,cholestasis, polycystic disease of the liver,and biliary atresia have been reported inassociation with NIHF, most likely dueto hypoproteinemia.7 Hemangiomaof the liver has also been reported as acause of NIHF, probably due to arterio-venous shunting resulting in cardiacfailure.Neoplastic diseases or fetal tumors can

occur in utero and have been associatedwith NIHF. Relatively common in thiscategory are lymphangiomas, hemangi-omas, sacrococcygeal, mediastinal, andpharyngeal teratomas, and neuroblas-tomas.19,67,68 Many of these are veryvascular and lead to NIHF due to highoutput cardiac failure. Fetal therapy hasbeen offered for cases of solid sacro-coccygeal teratoma resulting in NIHF,and in a recent systematic review, openfetal surgery resulted in survival in 6 of11 cases (55%), and minimally invasivetherapy was associated with survival in6 of 20 (30%).69 Tuberous sclerosis isan autosomal dominant disorder char-acterized by fibroangiomatous tumorsin multiple organs, most typically thecortex of the brain, the skin, and thekidneys. Cardiac rhabdomyomas andliver fibrosis are also sometimes present.FEBRUARY 2015 AmNIHF has been reported in associationwith tuberous sclerosis, probably eitheras a result of cardiac failure due torhabdomyomas (resulting in obstructionto filling or outflow), or hepatic failuredue to fibrosis.70

Placental and cord lesions that havebeen associated with NIHF include cho-rioangiomas, angiomyxoma of the cord,aneurysm of the umbilical artery, cordvein thrombosis, umbilical vein torsion,true knots, and amniotic bands.7,19,68

Placental chorioangiomas are relativelycommon, occurring in about 1% ofpregnancies. While small lesions areusually not clinically significant, thosemeasuring >5 cm can act as highvolume arteriovenous shunts and leadto hydrops due to high output cardiacfailure. Other vascular tumors and arte-riovenous malformations can similarlycause NIHF. Hemangiomas have beenreported to cause NIHF, likely due tosevere anemia, hypoproteinemia, and/orextramedullary erythropoiesis.

A large number of skeletal dysplasiashave been associatedwithNIHF, includingachondroplasia, achondrogenesis, osteo-genesis imperfecta, osteopetrosis, thana-tophoric dysplasia, short-rib polydactylysyndrome, and asphyxiating thoracicdysplasia.14,19,71-73 In all of these, themechanism is unclear, although it hasbeen proposed that hepatic enlargementoccurs secondary to intrahepatic prolifer-ation of blood cell precursors tocompensate for a small bone-marrowvolume. This may cause large vesselcompression and lead to anasarca in thesefetuses.

Inborn errors of metabolism and othergenetic conditions are historically asso-ciated with 1-2% of cases of NIHF, whichmay be transient or manifest as isolatedascites. Inherited metabolic disordersthat have been implicated as a cause ofNIHF are most typically lysosomalstorage diseases such as various muco-polysaccharidoses, Gaucher disease, andNiemann-Pick disease.74,75 In a recentreview of the literature including 678cases of NIHF, lysosomal storage diseasesoccurred in 5.2% of all NIHF cases, andin 29.6% of idiopathic NIHF cases ifa comprehensive workup for these con-ditions is done.76 Proposed mechanismserican Journal of Obstetrics & Gynecology 131

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SMFM Clinical Guideline ajog.orginvolve visceromegaly and obstructionof venous return, decreased erythropoi-esis and anemia, and/or hypopro-teinemia. Although such disorders are arelatively uncommon cause of NIHF,they are important because of the highrecurrence risk of these mainly auto-somal recessive disorders. Careful his-tology of the placenta, liver, spleen,and bone marrow will often provide aclue that a metabolic storage disorderwas present. For many such disorders,testing is available to determine a diag-nosis and for prenatal diagnosis in asubsequent pregnancy. Panels of causa-tive storage disorders can be tested forin some laboratories, and this shouldbe considered for cases of NIHF ina structurally normal fetus in whichanother cause has not been identified,or with cases of recurrence within afamily.76,77

A number of other syndromes havebeen associated with NIHF. Many ofthese are disorders associated withlymphatic dysfunction, such as Noonanand multiple pterygium syndrome, bothof which frequently present with cystichygroma; idiopathic chylothorax, inwhich a local pleuromediastinal lymphvessel disturbance occurs as the possiblepathogenic mechanism; yellow nail syn-drome, a dominantly inherited congen-ital lymphedema syndrome; andcongenital pulmonary lymphangiectasia.Familial recurrence in some of thesecases suggests a hereditary maldevelop-ment of lymphatic vessels.6,14,19,78

What is the appropriate evaluationwhen fetal hydrops is detected?Sonographic identification of thehydropic fetus is not difficult. The diag-nostic challenge is to establish the etiol-ogy and determine the appropriatetherapy (if available) and timing of de-livery. It has been reported that the causeof hydrops can be determined in about60-85% of cases, although this includespostnatal evaluation.13

Figure 2 outlines the various steps inthe evaluation of the hydropic fetus. It isespecially important to rule out poten-tially treatable conditions, as well as ge-netic disorders with a risk of recurrencein future pregnancies. Often, the etiology132 American Journal of Obstetrics & Gynecologyof the hydrops can be determined at thetime of diagnosis, since several etiologiesare confirmed or excluded based uponultrasound findings (eg, twin-to-twintransfusion, cardiac arrhythmias, andstructural anomalies associated withNIHF).Management is guided by the pres-

ence or absence of additional anomalies.Sonographic evaluation should includea detailed survey for anomalies of thefetus, umbilical cord, and placenta, andestimation of amniotic fluid volume. Afetal echocardiogram should be in-cluded, as fetal cardiac anomalies areamong the most common causes ofNIHF.In a structurally normal fetus, the first

step is to rule out alloimmunization as acause. The maternal blood type andRh(D) antigen status are assessed as partof routine prenatal care, along with anindirect Coombs test (an antibodyscreen) to evaluate for circulating redblood cell antibodies. These resultsshould be reviewed, and if the indirectCoombs test was previously normal, itshould be repeated. Maternal bloodstudies should also include a completeblood cell count with differentialand indices, Kleihauer-Betke stain forfetal hemoglobin, and parvovirus B19serology. Serologic test results for syph-ilis should be reviewed or repeated, andconsideration should be given to acutephase titers for cytomegalovirus andtoxoplasmosis.It is particularly important to perform

middle cerebral artery Doppler studiesto assess for the presence of fetal anemia,which may be treatable with intravas-cular transfusion. The fetus with NIHFdue to severe anemia will have increasedvelocity through the middle cerebralartery.79

A fetal karyotype, fluorescence in situhybridization studies, and/or chromo-somal microarray analysis should beoffered with or without identified so-nographic anomalies.80 This can beperformed by amniocentesis or fetalblood sampling; the latter allows directanalysis of fetal hematocrit and hemo-globin if anemia is suspected. Invasivetesting also allows testing for lysosomalstorage disorders, and polymerase chainFEBRUARY 2015reaction studies for parvovirus, toxo-plasmosis, and cytomegalovirus infec-tion. Such testing should be performedin a structurally normal fetus in whichno other cause has been identified.

An important step in the evalua-tion of NIHF is to exclude a geneticabnormality. Genetically transmitteddisorders account for about onethird of cases of NIHF, and includechromosomal abnormalities, hemo-globinopathies, skeletal dysplasias,metabolic storage disorders, and eryth-rocyte enzymopathies. A complete fam-ily history is thus imperative to rule out aknown inherited disorder in the familyand to assess for consanguinity, whichwill increase the likelihood of a recessivedisorder. Although idiopathic NIHFhas a low recurrence risk, the risk forsome cases of NIHF may be as highas 25%, making genetic counseling anintegral part of the management of anypatient with NIHF.

What maternal risks are associatedwith NIHF?Women with NIHF may develop mirrorsyndrome, an uncommon complicationin which the mother develops edemathat mirrors that of her hydropic fetus.Mirror syndrome may represent a formof preeclampsia, and is characterized byedema in approximately 90%, hyper-tension in 60%, and proteinuria in 40%of cases.81 As it is uncommon and likelyunderdiagnosed, the incidence is un-clear. Additional associated findings withthe syndrome include headache, visualdisturbances, oliguria, elevated uric acid,liver function tests, or creatinine levels,low platelets, anemia, and hemodilu-tion.82 A review of the literature (1956through 2009) by Braun et al81 notedthat among 56 cases ofmirror syndrome,the major maternal morbidity was pul-monary edema, which occurred in 21%.Resolution occurs with either the treat-ment of the hydrops or with delivery.81,82

There have been case reports inwhich pregnancies with mirror syn-drome and various treatable causes ofhydropsesecondary to fetal arrhythmia,hydrothorax, parvovirus, and bladderobstructionehave experienced resolu-tion of both hydrops and mirror

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ajog.org SMFM Clinical Guidelinesyndrome following treatment.83-86 Thesame imbalance of angiogenic and anti-angiogenic factors described with severepreeclampsia has also been observed incases of mirror syndrome, with correc-tion following treatment and resolutionof the NIHF.83,84 However, there areno data regarding the likelihood of res-olution or long-term benefits. Givenrisks of expectant management ofsevere preeclampsia, it is recommendedthat this approach be taken only withcaution, and that delivery not be delayedif the maternal condition deteriorates.Thus for most cases of NIHF, includingall cases without a treatable etiology,development of mirror syndrome ne-cessitates delivery.

What obstetric complications areassociated with NIHF?Polyhydramnios and preterm birthoccur frequently with NIHF, withTABLE 2Therapy for selected etiologies of noEtiology Thera

Cardiac tachyarrhythmia,supraventricular tachycardia,atrial flutter, or atrial fibrillation

Materof ant

Fetal anemia secondary toparvovirus infection orfetomaternal hemorrhage

Fetalintrau

Fetal hydrothorax, chylothorax,or large pleural effusion associatedwith bronchopulmonary sequestration

Fetalor plashunt;needleselect

Fetal CPAM Macroof effushunt;adminbetamh 26.25 m

TTTS or TAPS Laseror sel

Twin-reversed arterialperfusion sequence

Percu

For each of these etiologies, it is recommended that treatment

CPAM, congenital pulmonary airway malformation; IM, intramus

SMFM. Nonimmune hydrops fetalis. Am J Obstet Gynecolreported incidences as high as 29%71 and66%,87 respectively. If the poly-hydramnios is associated with maternalrespiratory symptoms, reported man-agement options have included a shortcourse of a prostaglandin inhibitor orserial amnioreduction. Since both treat-ment modalities lack evidence of bene-fit and have potential complications,including in utero constriction of theductus arteriosus, abruption, prematurerupture of the membranes, and neo-natal complications such as necrotizingenterocolitis and patent ductus arterio-sus, they should be used judiciously.88,89

Tocolytic agents are a consideration

SMFM Clinical Guideline ajog.orgreported to be as high as 60%.91 Withchylothorax as the underlying etiology,the mortality may be as low as 6%;however, when the infant has associatedanomalies, almost two-thirds do notsurvive.14 Treatable causes of hydrops,such as fetal arrhythmia or infectionwith parvovirus B19,92 have a betterprognosis. In a large series of newbornsadmitted to the neonatal intensive careunit, the independent risk factors fordeath in logistic regression analyses wereyounger gestational age, low 5-minuteApgar score, and need for high levels ofsupport during the first day after birth(higher levels of inspired oxygen supportand greater need for high-frequencyventilation).14

Temporal trends suggest that amongcases of liveborn infants with NIHF, theassociated mortality has not improvedover 2 decades. Comparing the mortalityamong hydropic newborns delivered in1993 through 2003 vs 2003 through2009, there was no significant differencein mortality in the 2 time periods, 47%vs 67%, respectively.91 In addition to thesmall sample size, an explanation for thelack of improvement in survival overtime may be that the more severe casesare now more frequently diagnosedTABLE 3Society for Maternal-Fetal MedicineRecommendations

We recommend that initial evaluation of hydroCoombs test) to verify that it is nonimmune,ography to evaluate for fetal and placental abnanemia, and fetal karyotype or chromosomawhether structural fetal anomalies are identi

We recommend that fetal therapy decisionsparticular whether there is a treatable causewhich NIHF develops or is first identified

As prematurity is likely to worsen prognosis,be undertaken only for obstetric indications

We recommend that pregnancies with NIHF detiologies be considered candidates for cortisurveillance, and that they be delivered at aand treat critically ill neonates

We recommend that in most cases, developmfor delivery

MCA, middle cerebral artery; NIHF, nonimmune hydrops fetalis.

SMFM. Nonimmune hydrops fetalis. Am J Obstet Gynecol

134 American Journal of Obstetrics & Gynecologyprenatally and referred to tertiary cen-ters, which are more likely to contributeto large series in the literature.The long-term prognosis for survivors

of NIHF also depends upon the under-lying etiology. After intrauterine trans-fusion for hydrops secondary toinfection with parvovirus B19, there ispotential for delayed psychomotordevelopment and abnormal neurologicaloutcomes.93 It is unclear if this isbecause of the hydrops, a direct conse-quence of the parvovirus infection,from severe anemia, or associatedwith the transfusion. Finally, fetuseswith supraventricular tachycardia maydevelop Wolff-Parkinson-White syn-drome later in life.94

Management of NIHFThe cornerstone of counseling andmanagement for this condition is athorough evaluation for the underlyingetiology of the hydrops (Figure 2).Pregnancy management decisions willdepend on the etiology, in particularwhether there is a treatable cause andthe gestational age that NIHF developsor is first identified. Cases generally fallinto 1 of 3 categories: those amenable tofetal therapyewhich often requirerecommendations for nonimmune hydroG

ps include an antibody screen (indirecttargeted sonography with echocardi-ormalities, MCA Doppler evaluation forl microarray analysis, regardless offied (Figure 2)

1CSt

be based on underlying etiology, in(Table 2) and the gestational age at

1CSt

we recommend that preterm delivery 1CSt

ue to nonlethal or potentially treatablecosteroid therapy and antepartumcenter that has capability to stabilize

1CSt

ent of mirror syndrome is an indication 1CSt

2015.

FEBRUARY 2015urgent treatment or referral to aspecialized center; those with a lethalprognosis, for whom pregnancy termi-nation or comfort care are the only op-tions realistic to offer; and cases in whichthe etiology is idiopathic and the prog-nosis is likely poor but uncertain. Giventhe poor overall prognosis, pregnancytermination should be offered if NIHF isidentified prior to viability. It is impor-tant in counseling that the potential formaternal complications with expectantmanagement be anticipated, includingmirror syndrome. Serial evaluation ofmaternal blood pressure is thereforerecommended.

What are the fetal therapy optionsavailable for NIHF?Selected etiologies of NIHF for whichfetal therapy should be considered arelisted in Table 2. Therapy options mayinclude intrauterine transfusion(s)for fetal anemia, medications such asantiarrhythmic agents, drainage of largepleural effusions, corticosteroids forCPAMs, or specialized procedures suchas laser coagulation of placental anasto-moses for twin-twin transfusion syn-drome. The list is not intended tobe comprehensive but rather to serve as apsrading of recommendations (Table 4)

rong recommendation, low-quality evidence

rong recommendation, low-quality evidence

rong recommendation, low-quality evidence

rong recommendation, low-quality evidence

rong recommendation, low-quality evidence

http://www.AJOG.org

TABLE 4Grading of Recommendations Assessment, Development, and Evaluation recommendationsGrade of recommendation Clarity of risk/benefit Quality of supporting evidence Implications

1AStrong recommendation,high-quality evidence

Benefits clearly outweigh riskand burdens, or vice versa

Consistent evidence from well-performedrandomized, controlled trials or overwhelmingevidence of some other form; further researchis unlikely to change our confidence in estimateof benefit and risk

Strong recommendations, can apply to mostpatients in most circumstances withoutreservation; clinicians should follow strongrecommendation unless clear and compellingrationale for an alternative approach is present

1BStrong recommendation,moderate-quality evidence

Benefits clearly outweigh riskand burdens, or vice versa

Evidence from randomized, controlled trials withimportant limitations (inconsistent results,methodologic flaws, indirect or imprecise), or verystrong evidence of some other research design;further research (if performed) is likely to have animpact on our confidence in estimate of benefitand risk and may change estimate

Strong recommendation and applies to mostpatients; clinicians should follow strongrecommendation unless clear and compellingrationale for an alternative approach is present

1CStrong recommendation,low-quality evidence

Benefits appear to outweigh riskand burdens, or vice versa

Evidence from observational studies, unsystematicclinical experience, or from randomized, controlledtrials with serious flaws; any estimate of effect isuncertain

Strong recommendation, and applies to mostpatients; some of evidence base supportingrecommendation is, however, of low quality

2AWeak recommendation,high-quality evidence

Benefits closely balanced withrisks and burdens

Consistent evidence from well-performedrandomized, controlled trials or overwhelmingevidence of some other form; further researchis unlikely to change our confidence in estimateof benefit and risk

Weak recommendation, best action maydiffer depending on circumstances orpatients or societal values

2BWeak recommendation,moderate-quality evidence

Benefits closely balanced withrisks and burdens, some uncertainlyin estimates of benefits, risks,and burdens

Evidence from randomized, controlled trials withimportant limitations (inconsistent results,methodologic flaws, indirect or imprecise), orvery strong evidence of some other researchdesign; further research (if performed) is likelyto have an impact on our confidence in estimateof benefit and risk and may change estimate

Weak recommendation, alternative approacheslikely to be better for some patients under somecircumstances

2CWeak recommendation,low-quality evidence

Uncertainty in estimates of benefits,risks, and burdens; benefits may beclosely balanced with risks and burdens

Evidence from observational studies, unsystematicclinical experience, or from randomized, controlledtrials with serious flaws; any estimate of effectis uncertain

Very weak recommendation; other alternativesmay be equally reasonable

Best practice A recommendation in which either:(i) there is an enormous amount of indirectevidence that clearly justifies strongrecommendation; direct evidence would bechallenging, and an inefficient use of timeand resources, to bring together andcarefully summarize; or (ii) recommendationto contrary would be unethical

SMFM. Nonimmune hydrops fetalis. Am J Obstet Gynecol 2015.

ajog.o

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FM

Clin

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JournalofObstetrics

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SMFM Clinical Guideline ajog.orgguideline. With the exception of openfetal surgery, therapy is sometimesoffered to pregnancies identified asbeing at risk for NIHF, with the under-standing that the prognosis worsens ifhydrops develops.

Counseling for pregnancies withNIHF amenable to fetal therapy shouldinclude a discussion of potential risks,benefits, and alternatives that takes intoconsideration the severity of the under-lying condition and the anticipatedresponse to the intervention. If the pa-tient declines therapy or is unable toreceive therapy, the prognosis is poor.Given the specialized nature of fetaltherapy, patients should receive carefrom physicians with expertise providingthe treatment offered, which in somecases may require evaluation at aspecialized center.

When is antepartum fetal surveillanceappropriate in NIHF?Antepartum surveillance is generallyused in the setting of maternal orpregnancy complications associatedwith an increased risk for fetal demise,and when findings from surveillancewill assist with delivery decisions. ForNIHF, antepartum testing has not beendefinitively shown to improve perinataloutcomes, and all indications fortesting are considered relative.95 Thereare no management trials or observa-tional series of the utility of ante-partum surveillance in the setting ofNIHF upon which to base recommen-dations. Whether an individual preg-nancy with NIHF may benefit fromsurveillance depends on the etiology ofthe hydrops, the underlying patho-physiology, and the potential for pre-natal or postnatal treatment.

Fetuses with NIH may be candidatesfor antepartum surveillance if: (1)the underlying etiology of the hydropsis not considered lethal, (2) the preg-nancy has reached a viable gestationalage, and (3) the findings from surveil-lance would be used to assist with timingof delivery. In such cases, deteriorationof testing results or worsening of thesonographic findings of hydrops mightprompt delivery.136 American Journal of Obstetrics & GynecologyMost fetuses with NIHF secondaryto an etiology listed in Table 2 are can-didates for antepartum surveillance. Iffetal therapy is attempted but does notameliorate the hydrops, the prognosis issignificantly worse.20,61 If the NIHFis idiopathic, counseling about theguarded prognosis should include limi-tations in available treatment options,but in the absence of a contraindication,antepartum testing may be considered. Ifthere are questions about the postnatalprognosis, consultation with a neonatol-ogist or other pediatric subspecialist maybe helpful.

When is the optimal timing of delivery?There are no management trials ofdelivery timing in the setting of NIHFupon which to base recommendations.Many hydropic fetuses succumb priorto viability. There is no evidence thatelective preterm delivery will improvethe outcome. In one retrospective series,preterm birth

ajog.org SMFM Clinical GuidelineRECOMMENDATIONS

Recommendations regarding NIHF arepresented in Table 3. The gradingscheme classifies recommendations aseither strong (grade 1) or weak (grade 2),and classifies the quality of evidence ashigh (grade A), moderate (grade B), orlow (grade C). Thus, the recommenda-tions can fall into 1 of the following6 categories: 1A, 1B, 1C, 2A, 2B, 2C(Table 4).Quality of evidenceThe quality of evidence for each articlewas evaluated according to the methodoutlined by the US Preventative ServicesTask Force:

I Properly powered and conductedrandomized controlled trial (RCT);well-conducted systematic review ormetaanalysis of homogeneous RCTs.

II-1 Well-designed controlled trial withoutrandomization.

II-2 Well-designed cohort or case-controlanalytic study.

II-3 Multiple time series with or withoutthe intervention; dramatic resultsfrom uncontrolled experiment.

III Opinions of respected authorities,based on clinical experience;descriptive studies or case reports;reports of expert committees.This opinion was developed by thePublications Committee of the Societyfor MaternaleFetal Medicine (SMFM)with the assistance of Mary E. Norton,MD, Suneet P. Chauhan, MD, and Jodi S.Dashe, MD and was approved by theexecutive committee of the society onSept. 29, 2014. Each member of thepublications committee (Sean Blackwell,MD [Chair], Mary Norton, MD [ViceChair], Vincenzo Berghella, MD, JosephBiggio,MD, AaronCaughey,MD, SuneetChauhan, MD, Sabrina Craigo, MD, JodiDashe, MD, Brenna Hughes, MD, JamieLo, MD, Tracy Manuck, MD, BrianMercer, MD, Eva Pressman, MD, An-thony Sciscione, DO, Neil Silverman,MD, Alan Tita, MD, and GeorgeWendel,MD) has submitted a conflict of interestdisclosure delineating personal, profes-sional, and/or business interests thatmight be perceived as a real or potentialconflict of interest in relation to thispublication. -

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The practice of medicine continues toevolve, and individual circumstanceswill vary. This opinion reflects informa-tion available at the time of its submis-sion for publication and is neitherdesigned nor intended to establish anexclusive standard of perinatal care.This publication is not expected to reflectthe opinions of all members of theSociety for MaternaleFetal Medicine.

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Society for Maternal-Fetal Medicine (SMFM) Clinical Guideline #7: nonimmune hydrops fetalisWhat is the underlying pathogenesis of NIHF?What are the causes of NIHF?What is the appropriate evaluation when fetal hydrops is detected?What maternal risks are associated with NIHF?What obstetric complications are associated with NIHF?What is the prognosis of NIHF?Management of NIHFWhat are the fetal therapy options available for NIHF?When is antepartum fetal surveillance appropriate in NIHF?When is the optimal timing of delivery?Should corticosteroids be given?What is the optimal mode of delivery?Where should delivery occur?

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