hydrops

DOI: 10.1542/neo.5-1-e52004;5;e5Neoreviews

Janet H. MurphyNonimmune Hydrops Fetalis

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Nonimmune Hydrops FetalisJanet H. Murphy, MB,

ChB*Objectives After completing this article, readers should be able to:

1. Describe the common causes of nonimmune hydrops fetalis (NIHF).2. Characterize the primary steps in antenatal investigation of NIHF.3. Describe the clinical interventions required for in utero management of NIHF.4. Delineate the procedures required for ongoing postnatal management of the neonate

who has NIHF.5. Describe the role of postmortem studies in NIHF.

IntroductionHydrops fetalis has been a well-recognized fetal and neonatal condition throughouthistory. Until the latter half of the 20th century, it was believed to be due to Rhesus bloodgroup isoimmunization of the fetus, although Potter described infants who had nonim-mune causes of fetal hydrops. The advent of Rho (D) immune globulin resulted in adecline in the incidence of isoimmune fetal hydrops and increasing prominence ofnonimmune causes of this severe and highly lethal fetal and neonatal condition.

Diagnostic CriteriaNonimmune hydrops fetalis (NIHF) is as pathologic accumulation of fluid in the skin andone or more other body compartments of the fetus, including the pleural space, peritonealcavity, pericardial sac, or placenta. Some authors define NIHF as edema of the skin plusfluid accumulation in two other compartments of the fetus, but the former definition ismore common.

IncidenceNIHF is estimated to occur in 1 in 2,500 to 1 in 4,000 pregnancies, but the incidencevaries with the ethnic population studied. For example, in Southeast Asia, NIHF is seen in1 in 500 to 1 in 1,500 pregnancies. In this population, homozygous alpha thalassemia iscommon, accounting for 57% to 81% of cases of NIHF in some series, although a morerecent study from Taiwan showed that homozygous alpha thalassemia accounted for only31% of NIHF. Variations in the incidence of NIHF have been documented when aninfectious epidemic occurs, such as with parvovirus B19 (erythema infectiosum).

General PathophysiologyFluid accumulates within fetal tissues or body cavities when the production of interstitialfluid exceeds its rate of reabsorption and removal by the capillary and lymphatic circula-tions. The production of interstitial fluid is a function of the hydrostatic and oncoticpressures within the capillary and interstitial space and of the integrity of the capillaryendothelium. This relationship is expressed in the Starling equation for the balance of fluidacross a membrane as adapted for a capillary:

Filtration of fluid � k [(Pcap – Ptiss) – r ( Oplas – Otiss)]

Where k is the filtration coefficient across the capillary wall, Pcap is the hydrostatic pressurein the capillary, Ptiss is the hydrostatic pressure in the tissue, r is the reflection coefficient

*Associate Professor of Pediatrics, University of Washington, Seattle, WA.

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of a solute, Oplas is the osmotic pressure of plasma, andOtiss is the osmotic pressure of tissue fluid.

If the filtration coefficient k was 1, the capillary wouldbe freely permeable to water, but this does not occurnaturally. Certain factors, such as hypoxia, endotoxins,and inflammatory mediators, may increase capillary per-meability to water, resulting in capillary fluid leak.

Hydrostatic pressure within the capillary (Pcap) riseswhen there is an increase in central venous pressure, anobstruction to venous drainage, or a rise in arterial pres-sure. Hydrostatic pressure in the tissue (Ptiss) rises with adecrease in lymphatic drainage caused by obstruction oflymphatic duct drainage due to high central venouspressure, malformation of the lymphatic drainage chan-nels, or rapid interstitial fluid production that exceeds thecapacity for lymphatic drainage and capillary reabsorp-tion. Given the expansile nature of this compartment,Ptiss rises slowly.

The reflection coefficient r is the degree of permeabil-ity of the capillary to a given solute. When r � 1, thecapillary is impermeable to the solute that would exertmaximum osmotic effect across the capillary wall. Largemolecules, such as albumin, have a high reflection coef-ficient and exert greater osmotic pressure within thecapillary. Conditions such as infection or asphyxia in-crease the permeability of the capillary wall to albumin,thus decreasing its reflection coefficient and, thereby,increasing edema formation.

A decrease in plasma oncotic pressure (Oplas), such asoccurs in hypoproteinemic states, results in an increase intissue fluid production. This can occur when hepaticsynthetic function is impaired, as in hepatic infection orcongestion; when plasma protein is lost in the urine, as innephrotic syndrome; or when a generalized capillary leakof protein occurs due to impaired capillary integrity, as inasphyxia or infection.

Tissue osmotic pressure (Otiss) is lower than capillaryosmotic pressure, but it does rise when osmotically activesolutes such as plasma proteins leak into the interstitialcompartment, as occurs in asphyxial injury or infection.

In the fetus and neonate, all factors in the Starlingequation may be affected to varying degrees by theunderlying pathophysiologic process causing NIHF. Theedema of NIHF is the final common pathway for amultitude of multifactorial disease processes that influ-ence edema formation in the fetus. Isolated hypopro-teinemic states may be insufficient to cause NIHF, asdemonstrated by the low incidence of NIHF in thehypoalbuminemia of congenital (Finnish) nephrosis or inanalbuminemia. For any specific precipitating cause ofNIHF, one factor in the equation may predominate. For

example, raised central venous pressure resulting in in-creased capillary hydrostatic pressure is a major factor incardiac causes of NIHF, whether they are disorders ofcardiac structure, function, or rhythm.

Etiologic and Diagnostic Categories of NIHFA multitude of fetal diseases can precipitate NIHF, andthe list of causes continues to expand as more geneticconditions associated with NIHF are identified. Causesof NIHF can be divided into six broad categories: 1) car-diac, including arrhythmias and anatomic abnormalities;2) genetic abnormalities; 3) malformations; 4) hemato-logic disorders; 5) infections; and 6) idiopathic. Currenttexts provide comprehensive lists of fetal conditions as-sociated with NIHF.

Depending on the trimester of pregnancy in whichNIHF is diagnosed, one of the diagnostic categories maypredominate in a series of patients. Published series ofNIHF diagnosed in the first trimester show that chromo-somal abnormalities (genetic) predominate; NIHF iden-tified in the latter half of the second trimester and thethird trimester is associated with a high percentage ofcardiac disorders. As previously noted, hematologicproblems predominate in some Southeast Asian studies.In all published series of NIHF, the idiopathic categoryremains appreciable, responsible for 5% to 40% of cases inrecent series. More sophisticated fetal diagnostic tech-niques as well as expanded studies in cytogenetics andmolecular biology are reducing the incidence of theidiopathic NIHF.

Cardiac causes of NIHF can be divided into structuralmalformations, arrhythmias, and myocardiopathies.A composite of these cardiac factors occurs in somepatients. Structural cardiac anomalies of the right heartassociated with NIHF are those lesions that result inright heart congestion, elevation of central venous pres-sure, and right heart failure, such as pulmonary valveatresia or incompetence and abnormalities of the tricus-pid valve (eg, Ebstein anomaly). Abnormalities of the leftheart associated with NIHF include aortic valve stenosisor atresia, hypoplastic left heart, coarctation of the aorta,truncus arteriosus, endocardial fibroelastosis, and non-compacted myocardium. Fetal premature closure of theforamen ovale or ductus arteriosus is associated withNIHF, as are absence of the ductus venosus or obstruc-tion of the superior or inferior vena cava.

Supraventricular tachycardia (SVT) is the predomi-nant tachyarrhythmia causing NIHF. Heart rates of220 to 260 beats/min result in inadequate ventricularfilling in diastole with consequent elevation of centralvenous pressure. Decreased systolic ejection volume is a

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further result of decreased ventricular filling, and there ispoor perfusion and oxygenation of fetal tissues. Hepaticvenous congestion can result in decreased hepatic syn-thetic function and hypoalbuminemia. The myocardiumfails because of the sustained increased work load causedby the tachycardia. These combined factors result inaccumulation of fluid in the fetal tissues and NIHF.

Bradyarrhythmia, as occurs in fetal congenital heartblock (usually with heart rates of �65 beats/min), canresult in fetal hydrops due to venous congestion andelevation of the central venous pressure as well as de-creased cardiac output and poor tissue perfusion andoxygenation. Hepatic congestion and impaired synthesisof albumin can contribute to the NIHF. Fetal bradycar-dia is difficult to treat, and the resulting NIHF is usuallyfatal. When congenital heart block is associated withmaternal collagen diseases, particularly systemic lupuserythematosus or anticardiolipin syndromes, anticardio-lipin can cross the placenta and affect the atrioventricularnode, resulting in impaired conduction or even fibrosis.Attachment of anticardiolipin to myocardial cells also hasbeen documented by some investigators and may con-tribute to cardiomyopathy in the fetus.

Cardiomyopathy associated with NIHF may be pri-mary, as in endocardial fibroelastosis and noncompactedmyocardium, or secondary, as in infection due to herpes-virus, cytomegalovirus, and coxsackievirus infections. Italso may be due to hypoxia and high cardiac output, as insevere fetal anemia.

Inherited DisordersInherited disorders associated with NIHF encompasschromosome abnormalities, inborn errors of metabo-lism, and genetic disorders.

Chromosome abnormalities represent the largest sin-gle category in published series of cases of NIHF diag-nosed in the first trimester. Turner syndrome (45XO)and trisomy 21 are the most common, although trisomyof chromosomes 18, 13, 15, and 16 all have been asso-ciated with NIHF. In most of these syndromes, NIHF isassociated with a congenital cardiac malformation of atype previously described. However, other conditionsassociated with the trisomy may contribute to the NIHF.For example, an atrioventricular septal defect is a com-mon cardiac malformation in trisomy 21, but chylotho-rax and disorders of lymphatic drainage also occur, notnecessarily in association with a cardiac defect. Hypoto-nia and decreased motility associated with this trisomyalso may contribute to the edema, as may polycythemiaand, rarely, congenital leukemia. Congenital cardiac dis-ease is common with Turner syndrome, but disordered

lymphatic drainage and lymphedema also occur in thistrisomy in the absence of a cardiac abnormality.

Genetic syndromes associated with NIHF usually areautosomal recessive. Autosomal dominant disorders in-clude Noonan syndrome, tuberous sclerosis, and myo-tonic dystrophy. Tuberous sclerosis presenting as NIHFfrequently is seen with rhabdomyoma of the heart, con-sequent cardiac compromise, and resulting fetal hydrops;such patients may provide the index case for retrospectivediagnosis within the kindred of the propositus. Amongother associated disorders are certain types of achondro-genesis and chondrodysplasia; in these conditions, ab-normal rib growth and decreased thoracic volume maybe contributing factors to NIHF.

Inborn errors of metabolism associated with NIHFinclude glycogen storage disease type IV, lysosomal stor-age diseases, hyperthyroidism, hypothyroidism, and car-nitine deficiency. New lysosomal storage diseases arebeing identified, and many cases of NIHF previouslyidentified as idiopathic may have been caused by a lyso-somal storage abnormality.

Malformations and TumorsA variety of congenital malformations associated withNIHF have been documented. Among the intrathoraciclesions are congenital diaphragmatic hernia, congenitalcystic adenomatoid malformation of the lung, congenitalpulmonary lymphangiectasia, and bronchopulmonarysequestration. Congenital malformations associated withNIHF are often complex, and some include cardiacmalformations as part of the cause of the hydrops.

Congenital diaphragmatic hernia (CDH) is illustra-tive of a complex malformation in which many factorsmay contribute to the development of fetal hydrops.Abdominal organs displaced through the diaphragmaticdefect cause an intrathoracic mass effect with mediastinalshift that not only contributes to the pulmonary hypopla-sia, but also compresses the heart, impairs cardiac func-tion, and reduces venous return. Displacement of theliver into the chest could result in impaired hepaticvenous drainage by compression of the portal and he-patic veins. In left-sided diaphragmatic hernia, there maybe associated left ventricular hypoplasia or other complexheart disease. Any or all of these factors may contribute toNIHF in a patient who has CDH.

Congenital cystic adenomatoid malformation of thelung (CCAM) has been associated with NIHF. The masseffect of the tumor may raise intrathoracic pressure anddisplace the mediastinum and the heart, leading to im-paired venous return to the heart and an increase in






central venous pressure, with consequent edema, ascites,and pleural effusions.

Fetal tumors are associated with NIHF. Most notableare large cystic hygromas of the neck and chest, arterio-venous malformations, teratomas (especially sacrococcy-geal lesions), and large hemangiomas or lymphangiomas.Polycystic renal disease also can be a cause of NIHF.Sacrococcygeal teratomas may include a vascular malfor-mation, and bleeding into the teratoma has been associ-ated with fetal anemia and hydrops. These malformationsalso may result in high-output cardiac failure and conse-quent fetal hydrops.

Arteriovenous malformations may occur within thefetus, most commonly in the brain and liver, and maycause fetal hydrops due to high-output cardiac failure.Hemorrhage associated with the malformation may leadto anemia and hydrops.

The placenta in a monochorionic twin pregnancy maybe the site of an arteriovenous communication betweenthe two fetal circulations, leading to twin-twin transfu-sion and fetal hydrops. Vascular communications withinthe placenta of twins are common. Venovenous commu-nications or arteriovenous communications with addi-tional vascular communications within the placenta thatpermit equilibration of circulating blood volume be-tween the two fetuses do not pose a severe problem.However, an arteriovenous communication between thetwo fetuses, with the first twin’s circulation feeding thearterial side and its venous drainage entering the circula-tion of the second twin, has severe hemodynamic andhematologic consequences defined as twin-twin transfu-sion syndrome. The recipient twin has an increase incirculating blood volume and increased venous return tothe heart, resulting in high-output cardiac failure withmyocardiopathy and fetal hydrops. The associated poly-cythemia also may contribute to overload of the heart,and renal impairment is common. The donor twin occa-sionally develops hydrops due to severe anemia andcardiac failure. Other lesions of the placenta associatedwith NIHF include severe fetomaternal hemorrhage, inwhich the fetus develops severe anemia and hydrops.Chorioangioma and choriocarcinoma of the placentaalso can lead to NIHF.

Hematologic DisordersAnemia that results in cardiac failure is the usual mecha-nism by which hematologic disorders lead to NIHF. Theanemia is due to hemolysis, hemorrhage, or failure of redblood cell production.

Intrinsic red blood cell abnormalities due to hemo-globinopathy or red blood cell enzyme or membrane

abnormality result in hemolysis and anemia. Homozy-gous alpha thalassemia is a common cause of NIHF inSoutheast Asia and the Eastern Mediterranean. Redblood cell enzyme abnormalities associated with NIHFinclude glucose-6-phosphate dehydrogenase (G-6-PD),pyruvate kinase, and glucosephosphate isomerase defi-ciencies. Hemolysis also is associated with fetal heman-giomas in Kasabach-Merritt syndrome. Anemia andNIHF occur in severe acute fetomaternal hemorrhage,twin-twin transfusion syndrome, or hemorrhage intoarteriovenous malformations or other fetal tumors.

The production of red blood cells is reduced in clinicalsyndromes in which abnormal material is deposited in thebone marrow. Transient myeloproliferative disorders orcongenital leukemia result in anemia and fetal hydrops.A few cases of transient myeloproliferative disorder havebeen reported in association with trisomy 21, with reso-lution of the disorder within months of birth. This dis-order must be differentiated from a leukemoid reactionassociated with congenital infection and severe hemoly-sis. Parvovirus B19 is tropic for erythroid progenitorsthat are lysed, and infection with this virus has beenassociated with a transient severe anemia and NIHF.

InfectionsA number of infectious diseases have been associatedwith NIHF, including those caused by viral, bacterial,spirochetal, and parasitic agents (Table 1). The most

Table 1. Common InfectiousCauses of NonimmuneHydrops FetalisViruses

● Human parvovirus B19● Cytomegalovirus● Other herpesviruses (Type I)● Coxsackievirus● Rubella

Parasites

● Toxoplasma gondii● Trypanosoma

Spirochetes

● Treponema pallidum● Leptospira

Bacteria

● Listeria monocytogenes






common infectious causes of NIHF are cytomegalovirusinfection, toxoplasmosis, syphilis, and parvovirus B19infection.

Human parvovirus B19 initially was reported as acause of NIHF in 1984. Fully 50% of the adult popula-tion has antibodies to this parvovirus, making the re-maining 50% of pregnant women vulnerable to infection.However, there is seasonal variation in parvovirus infec-tions in the community, and the infection rate in thesusceptible adult is 25% to 50%. The virus is not alwaystransmitted to the fetus, which may not develop anemiaor hydrops. The net result is that few fetuses exposed toparvoviral infection develop NIHF.

Syphilis always should be a concern in the differentialdiagnosis of NIHF, particularly with the resurgence incongenital syphilis in recent decades. Serology may befalse-negative due to the prozone phenomenon in whicha high antibody level in the tested sera prevents theflocculation of the positive rapid plasma reagin (RPR)test. Serum dilutions should be a routine procedurewhen the initial RPR is negative in a patient who hasNIHF.

Antenatal Investigation of NIHFNIHF frequently presents based on ultrasonography fora rapid increase in fundal height due to polyhydramniosor as an incidental finding on routine ultrasonography.Currently, increasing attention is turning to the occur-rence of nuchal edema in the fetus because it may be theearly herald sign of fetal abnormalities, including thoseassociated with NIHF. Techniques for early identifica-tion of a prodromal stage of NIHF are needed to permitearly, disease-specific therapeutic intervention beforecatastrophic fetal hydrops occurs. The finding of a fetusthat has evidence of edema requires a comprehensiveevaluation of mother and fetus to determine the under-lying cause and the appropriate clinical management.

The evaluation of NIHF requires a well-coordinatedobstetric, genetic, and laboratory investigation. The eval-uation usually is conducted in a tertiary obstetric facilitywhere the expertise of a perinatologist, geneticist, pedi-atric cardiologist, neonatologist, pathologist, and socialworker may be needed for evaluation of the fetus andcounseling of the family.

Presentations in the first trimester or early in thesecond trimester often have chromosomal or other ge-netic causes of fetal hydrops. Prompt identification of thecause of the NIHF before fetal viability is reached isnecessary to permit the family the option of pregnancytermination where appropriate.

Table 2 outlines a protocol for evaluation of mother

and fetus. Amniotic fluid testing is common, but evalu-ation by chorionic villus sampling may be undertakeninstead early in gestation. Because the quantity of fetal

Table 2. Antenatal Investigationof Nonimmune Hydrops FetalisHistory

1. Maternal past medical and obstetric history2. Details of current pregnancy and reason for referral3. Results of previous ultrasonography and laboratory

studies4. Family history of metabolic or genetic disorders,

consanguinity, ethnic origins5. History of recent infection or exposure risk to same

Maternal

1. Complete blood count2. Maternal blood group and antibody testing3. Infection screening tests: hepatitis, syphilis,

cytomegalovirus, herpesvirus, Toxoplasma, humanimmunodeficiency virus, group B Streptococcus,rubella, parvovirus B19, coxsackievirus

4. Autoantibody screen for systemic lupuserythematosus, antiRo La

5. Evaluation for diabetes mellitus6. Hemoglobin electrophoresis of both parents if

possible alpha thalassemia carriers7. Kleihauer-Betke test for fetomaternal hemorrhage

Fetal

1. Detailed level III fetal ultrasonography of all fetalstructures, especially the brain, heart, lungs, liver,intestine, kidneys, and skeleton. Doppler flow studiesof the umbilical vessels and middle cerebral arteries

2. Fetal echocardiography, including M-mode withheart rate and rhythm and cardiac dimensions

3. Placental thickness and morphology4. Amniotic fluid index

Amniotic Fluid

1. Amniotic fluid cells for karyotype and fluorescent insitu hybridization (FISH) for specific chromosomedefects

2. Amniotic fluid for cell count and viral polymerasechain reaction

3. Optical density

Percutaneous Umbilical Blood Sampling(where clinically indicated)

1. Fetal complete blood count, including reticulocytes2. Fetal blood group and Coombs antibody testing3. Hemoglobin electrophoresis (if indicated)4. Glucose-6-phosphate deficiency screen (males in

“at-risk” ethnic group)5. Fetal karyotype and FISH studies if not already

obtained on amniotic fluid






blood obtained by percutaneous umbilical blood sam-pling (cordocentesis) is limited to a few milliliters, thepriority of planned tests must be established. In cases ofsuspected fetal anemia, blood group O-negative bloodshould be available for umbilical transfusion.

In Utero ManagementNIHF presenting in the first trimester of pregnancy isassociated with a high incidence of chromosome or othergenetic anomalies. Rapid, definitive diagnosis of thecause is essential, and the family requires extensive ob-stetric, genetic, and social work counseling regarding thecurrent and future pregnancies. If the pregnancy is con-tinued, fetal mortality is extremely high.

Presentation of NIHF in the second or third trimesteroffers some hope for effective therapeutic intervention ifa treatable cause is found. Often intervention is directedtoward palliation and maintenance of the fetus untilviability and lung maturity are achieved, but deliverybefore 34 weeks’ gestation remains associated with ahigh neonatal mortality rate. Spontaneous preterm laborand delivery is common and usually related to polyhy-dramnios. Accordingly, repeated amnioreduction canhelp to maintain the pregnancy until fetal viability isachieved. Following are a few specific examples of clinicalinterventions.

Fetal tachycardia requires fetal echocardiography toevaluate fetal cardiac anatomy and function. Fetal heartrates of 200 beats/min or greater in SVT can be man-aged with digoxin or other agents. A return to sustainednormal fetal cardiac rates usually results in resolution ofthe NIHF. Administration of digoxin to the mother tothe threshold of toxicity has been effective, but fetalvenous congestion and associated placental edema mayinterfere with transfer of digoxin to the fetus. In somecases, direct infusion of a loading dose of digoxin into thefetal umbilical vein has converted the SVT, and adminis-tration of subsequent doses to the mother has main-tained control. If digoxin alone is insufficient, otheragents such as propanolol or flecainide have been usedwith success, but pediatric cardiology consultation isnecessary before these drugs are used.

NIHF due to anemia has been treated effectively withdirect transfusion of packed red blood cells into the fetalumbilical vein. The presence of fetal hydrops and asinusoidal fetal heart rate pattern indicates fetal anemia.Diagnostic PUBS usually is combined with transfusion ofblood group O-negative red blood cells if anemia isconfirmed.

Human parvovirus B19 infection with anemia can betreated successfully with intrauterine transfusion. Not all

infected fetuses become anemic, but when anemia doesoccur, it is usually within 8 weeks of infection, althoughmany authorities recommend monitoring the fetus for12 weeks after documented maternal parvovirus infec-tion during pregnancy. One to three transfusions of redblood cells may be required before the fetal bone marrowrecovers erythropoietic function. Cases that present inthe third trimester may require only a single transfusionto correct the fetal hydrops, followed by elective deliveryonce lung maturity is assured by amniocentesis and thepossible use of antenatal betamethasone.

Fetal persistent pleural effusions occurring before26 weeks’ gestation are associated with restriction of fetallung growth and result in pulmonary hypoplasia. This, inturn, is associated with a high neonatal morbidity andmortality. Intrauterine centesis of fetal pleural effusionshas been attempted, but often pleural fluid reaccumu-lates within 24 hours of the procedure. Placement ofpigtail pleuroamniotic drains has met with some thera-peutic success in reducing pleural effusions and allowingimproved fetal lung growth.

Fetal surgery for resection of fetal tumors, such assacrococcygeal teratomas or congenital cystic adenoma-toid malformation (CCAM) of the lung, has been under-taken in specialized fetal surgery centers with some doc-umented successes. Spontaneous arrest of tumor growthor even remission has occurred in some patients whohave CCAM. However, it is intriguing to note thatHarrison’s group in San Francisco documented threeinstances of prompt resolution of CCAM when antenatalsteroids were administered to fetuses awaiting plannedsurgical resection. This lesion is considered a disorder ofpulmonary differentiation, which suggests that the re-sponse to antenatal steroid therapy may be more thancoincidence.

Interventions for twin-twin transfusion have includedamnioreduction for polyhydramnios and fetal transfu-sion if the donor twin has anemia, but these procedureshave met variable success. Identification of feto-fetalvascular communications within the placenta and abla-tion of the abnormal vascular channels has been success-ful in correcting twin-twin transfusion in some reports.

Neonatal DiagnosisNeonatal diagnostic testing is a continuum of the inves-tigation that begins during pregnancy. In most instances,the neonatal intensive care team has time to prepare fordelivery of a fetus that has NIHF. An important aspect ofpreparation is to outline resuscitative measures and neo-natal diagnostic studies. Frequently it is necessary toremove ascitic fluid from the abdomen or pleural fluid to






improve ventilation during resuscitation. This ascitic orpleural fluid should be obtained in a sterile procedureand placed in sterile containers; if fetal infection is aconcern, the fluid is sent for culture and viral PCRstudies. The fluid should be analyzed for total proteinand albumin. Chylothorax is characterized by a cell countof 80% to 90% lymphocytes, underlining the importanceof differential analysis of cells in pleural or ascitic fluid.

The presence of profound anemia may necessitateimmediate packed red blood cell transfusion with washedO-negative cells, but it is essential to obtain samples ofthe infant’s blood prior to transfusion. A complete bloodcount and reticulocyte count, blood typing, measure-ment of serum albumin and total protein, immunoglob-ulin (Ig) M and IgG studies, fetal chromosome studies, asample for G-6-PD studies or hemoglobin electrophore-sis, and routine newborn metabolic screening are impor-tant to obtain prior to transfusion of donor cells in thedelivery room or neonatal intensive care unit. During theresuscitation or immediately thereafter, it is important tobegin monitoring fetal blood gases and correct any met-abolic or respiratory acidosis.

Detailed macroscopic, microscopic, and electron mi-croscopic evaluation of the placenta can provide impor-tant diagnostic information and review of placental pa-thology such as chorioangioma or vascular abnormalitiesthat may be the primary causes of NIHF.

Once resuscitation is complete, a comprehensivephysical examination is conducted for evidence of fetalanomalies, but edema may obscure many physical fea-tures in the infant who has profound hydrops.

M-mode echocardiography is obtained to evaluatecardiac structure and function, including chamber sizeand myocardial contractility. Small pericardial effusionsare common in NIHF, but an effusion may be of suffi-cient magnitude to impair myocardial function andprompt ultrasonographically guided pericardiocentesis.Electrocardiography is important to evaluate disorders ofrate and rhythm.

Radiographic evaluation of the chest for evidence ofpleural effusions and pulmonary hypoplasia is an impor-tant initial step. Ultrasonography of the lung is helpful inevaluating CCAM of the lung, if computed tomographycannot be obtained immediately. A radiographic skeletalsurvey is obtained to look for anomalies associated withgenetic or chromosomal syndromes. Cranial ultrasonog-raphy for structural abnormalities should include Dopp-ler flow studies for possible arteriovenous malformations,as should abdominal ultrasonography of the liver. Ab-dominal ultrasonography identifies the presence of ascitic

fluid as well as anomalies of the kidneys and urinary tract,liver, and other abdominal organs or masses.

Finally, genetic consultation is important in the plan-ning of the neonatal diagnostic evaluation.

Neonatal ManagementDelivery Room Resuscitation

In preparing for delivery of an infant who has knownNIHF, the obstetric staff alerts the neonatologist of theimpending delivery. In most instances, the neonatologistwill have been involved in antenatal counseling of thefamily and will have reviewed with the family potentialproblems for the infant and the planned delivery roommanagement.

A skilled neonatal resuscitation team is essential, andpersonnel should be assigned tasks prior to the delivery.Fluid sample tubes and equipment for planned diagnos-tic studies of blood and pleural or ascitic fluid are assem-bled, and umbilical catheters are prepared for emergencyinsertion. Establishment of ventilation is a priority, andprompt intubation and ventilation often are necessary.Other team members are responsible for paracentesisabdominis for removal of ascitic fluid and bilateral tho-racentesis for removal of pleural fluid to permit adequatelung expansion. Placement of an umbilical venous linemay be necessary for administration of sodium bicarbon-ate or blood transfusion after blood is drawn for planneddiagnostic studies. Anemia may be corrected by simplepacked red blood cell transfusion or partial exchangetransfusion.

Ongoing ManagementOnce an airway is established and the infant is stabilized,arterial and central venous access via the umbilical vesselsor peripheral vessels is obtained for blood sampling andfluid administration. Placement of a double-lumen um-bilical venous line permits both fluid administration andmonitoring of central venous pressure. Therapeutic in-tervention includes both respiratory and cardiac supportin addition to treatment specific to the precise diagnosisof the cause of hydrops.

SURFACTANTMany infants who have NIHF are delivered pretermbecause of fetal distress or premature labor due to poly-hydramnios. Once the intubated preterm infant is stabi-lized, surfactant administration is appropriate. Adminis-tration of surfactant to the term infant is controversial,but it should be considered in the presence of severe lungdisease.






MECHANICAL VENTILATIONMechanical ventilation usually is required in infants whohave hydrops, but published studies comparing conven-tional and high-frequency ventilation have not docu-mented any difference in outcome or survival with use ofeither mode of ventilation. Because pleural effusionsoccurring prior to 26 weeks’ gestation frequently areassociated with pulmonary hypoplasia, low peak pres-sures are used for mechanical ventilation, thereby reduc-ing the risk for pneumothorax.

CHEST TUBE PLACEMENTRecurrent pleural effusions require placement of pleuralcatheters for continuous drainage. It can be difficult toplace a catheter in the face of massive chest wall edema,but a coiled pigtail catheter may be retained better than aconventional Argyll catheter.

FLUID AND ELECTROLYTE MANAGEMENTThe infant who has hydrops is in sodium and free waterexcess and represents a challenge in fluid and electrolytemanagement. Sodium and fluid restriction and frequentmonitoring of serum and urine electrolytes and totaloutput are necessary. Diuretic therapy with furosemideshould be used with caution, but it may be effective incombination with inotropic drugs in cardiac failure.A combination of furosemide and albumin or intrave-nous immunoglobulin may help mobilize fluid from thetissues, but 5% albumin approximates a sodium loadequivalent to an equal volume of normal saline. Becausefluid losses from pleural drainage can reach 300 to400 mL/d, careful fluid replacement is important. Thehigh protein and lymphocyte content of pleural fluidnecessitates frequent monitoring of serum albumin, Iglevels, and white blood cell counts. Ongoing replace-ment of pleural or ascitic fluid drainage may be necessaryif these volumes are large and lead to intravascular deple-tion. Fluid losses may be replaced with 0.5 to 1.0 mL ofnormal saline or 5% albumin for each milliliter of fluiddrained. Profound hypoalbuminemia may be managedwith 0.5 to 1 g/kg infusions of 25% albumin to attemptto correct the hypoalbuminemia and optimize renal per-fusion and function.

INFECTIONBecause primary infection may be the cause of NIHF,bacterial and viral studies should be obtained if notincluded in the fetal evaluation. It may be necessary tocontinue antenatal antiviral or antibacterial treatment.Acquired infection is a common problem for the infantwho has hydrops. Broad-spectrum antibiotic therapy

usually is initiated at birth following blood culture, andthe duration of therapy is based on culture results. In-dwelling arterial and central venous catheters and pleuralcatheters increase the risk for infection. Continuinglosses of lymphocytes and gamma globulin in pleuraldrainage also increase the risk of infection; Wy andassociates found a 44% infection risk with the presence ofpleural effusion and a case fatality rate of 64%. Closemonitoring of gamma globulin levels and infusion ofintravenous gamma globulin are important consider-ations for the infant who experiences continuing pleuralor peritoneal drainage.

CARDIAC EVALUATION AND SUPPORTComplete cardiac evaluation and diagnosis-specific treat-ment are vital components of medical management, anda cardiology consultation is essential to the ongoingmanagement of any infant who has hydrops. A primarycardiac malformation may be the cause of the NIHF, andprostaglandin E1 is required for duct-dependent lesions.Interventional cardiology may be necessary for a stenoticor atretic valve or vessel. Inotropic and pressor supportoften is required for the infant who has hydrops, anddopamine and dobutamine are used frequently. Digoxinmay be used for inotropic support in the well-oxygenatedinfant or in conjunction with other agents for ongoingmanagement where fetal tachycardia is the cause of thehydrops. There are complex interactions between manyof the cardiotonic agents and other drugs used in thisclinical setting. Therefore, it is vital for a pediatric cardi-ologist and a pediatric pharmacist to collaborate in themanagement of these patients. Elevated central venouspressure is a feature of NIHF in many infants that re-quires monitoring of central venous pressure and carefulfluid and electrolyte management, as noted previously.

CARNITINECarnitine deficiency has been documented as a cause ofNIHF. Accordingly, following measurement of theblood carnitine level, empiric carnitine therapy should beconsidered for infants who have myocardiopathy andinfants requiring long-term total parenteral nutritionsupport.

USE OF STEROIDSIntravenous hydrocortisone may be effective in correct-ing intractable hypotension unresponsive to pressorssuch as dopamine and dobutamine. Adrenocortical in-sufficiency due fetal and neonatal distress requires corti-costeroid replacement therapy. The use of dexametha-sone for severe lung disease and prevention of potential






bronchopulmonary dysplasia in preterm infants is verycontroversial, as it is in infants who have hydrops.

OCTREOTIDEOctreotide is long-acting synthetic octapeptide analog ofsomatostatin that binds to G-protein receptors and in-hibits adenylate cyclase activity, thereby decreasingcyclic-AMP production. Octreotide has been used suc-cessfully to treat persistent chylothorax and chylous as-cites in adults, and there are anecdotal reports of its use ininfants. It is administered either subcutaneously or byintravenous infusion. Subcutaneous administration of20 mcg/kg of body weight per day divided every 8 hoursor intravenous administration of 1 mcg/kg per minutehas been effective. If chylous drainage persists, the dosemay be increased to a maximum of 40 mcg/kg per day.Octreotide decreases splanchnic blood flow, gastrointes-tinal motility, and gastric emptying as well as gallbladdercontraction. It decreases production of gastrointestinalpeptides and pancreatic enzymes and reduces insulinsecretion. The latter effect is the basis for its use in thetreatment of nesidioblastosis. Described adverse effectsare hypoglycemia, delayed gastric emptying, and intesti-nal ileus. Elevation of liver enzymes has been docu-mented, and prolonged use is associated with cholestasisand cholelithiasis. Thrombocytopenia has been docu-mented with the use of octreotide, and there has been asingle case report of induced pulmonary hypertension.Persistent chylous drainage has been associated with anincrease in morbidity and mortality. Therefore, oct-reotide has been reserved for infants who have severepersistent pleural or peritoneal chylous drainage wherethe benefits of success outweigh the risk of adverseeffects.

PathologyDetailed postmortem study of fetal and neonatal deathsdue to NIHF remains extremely important, particularlyfor those cases described as idiopathic, and parentalconsent for autopsy always should be requested. Anyplanned laboratory investigation listed in Table 2 shouldbe completed. A complete radiographic survey of theskeleton is obtained to look for skeletal anomalies andthoracic dysplasia. Detailed macroscopic, microscopic,and electron microscopic studies are required of theplacenta and the infant organs, including brain, heart,lungs, liver, kidneys, and any masses or tumors. Anyconcerns for underlying genetic disease, such as lysoso-mal storage disease, should prompt harvesting of DNAfor analysis and for comparison with fetal DNA in themother’s future pregnancies. Preservation of DNA for

further study is especially important in those cases classedas idiopathic; fetal cells can be grown to confluence,harvested, and frozen for future reference.

Mortality and OutcomeDespite advances in fetal diagnosis and fetal and neonataltherapy, the mortality for NIHF remains extremely highin most case series. Liveborn infants who have NIHFhave a mortality of approximately 50%. Diagnosis ofNIHF before 24 weeks’ gestation with subsequent laterdelivery is associated with a very low survival rate of 4% to6%.

The cause of the NIHF has a profound influence oninfant outcome. Homozygous alpha thalassemia is asso-ciated with virtually 100% mortality. SVT has the bestprognosis for survival and has been controlled success-fully with digoxin or other agents. In North America,NIHF due to congenital syphilis has a good prognosis forsurvival if treated early and effectively with antibiotics,but the same disease has a very poor prognosis for sur-vival in Africa. Red blood cell transfusion for the fetusthat has anemia due to parvovirus has improved fetal andneonatal survival. Poor prognosis has been associatedwith lethal genetic conditions, presence of pleural effu-sions, and preterm delivery. Carlton and associates notedthat 90% of affected infants dying within 24 hours ofbirth had pleural effusions. The diagnosis of persistentpleural effusions before 26 weeks’ gestation is associatedwith a higher mortality, which likely is due to diseaseseverity and underlying pulmonary hypoplasia. Massivefetal pleural effusions at any point in the gestation have apoor prognosis for survival.

Fetal prognostic indicators include cardiac biventricu-lar outer diameter (BVOD) on M-mode echocardiogra-phy. Carlton and colleagues found that a BVOD greaterthan 95% of normal had a 100% predictive value fordeath, and a normal BVOD had an 86% predictive value.Wy and coworkers found that proven infection or twofluid-filled body cavities were associated with a worseoutcome. In a comparison of patients from 1990through 1993 with patients from 1994 through 1997,use of steroids, surfactant, or high-frequency ventilationdid not influence ultimate survival outcome but didprolong the interval to death (6.5 days and 20.5 days,respectively). The average length of stay for survivors was28 days (range, 7 to 90 days).

Therapy continues to be directed toward close fetalmonitoring, diagnosis, and intense, complex neonatalmanagement. Individual perinatal and neonatal care cen-ters have too few patients to permit statistical comparisonof treatment and outcome, but with the advent of in-






creasing opportunities for multicenter collaborativestudies, more data may be available in the future. Data onneurologic outcome for survivors are sparse, but anyindividual survivor of NIHF should receive close neuro-developmental follow-up.

Suggested ReadingApkon M. Pathophysiology of hydrops fetalis. Semin Perinatol.

1995;19:437–446Buettiker V, Hug MI, Burger R, Baenziger O. Somatostatin: a new

therapeutic option for the treatment of chylothorax. IntensiveCare Med. 2001;27:1083–1086

Carlton DP, McGillivray BC, Schrieber MD. Nonimmune hydropsfetalis: a multidisciplinary approach. Clin Perinatol. 1989;16:844–851

Cheung YF, Leung M, Yip MM. Octreotide for treatment ofpostoperative chylothorax. J Pediatr. 2001;139:157–159

Heikenen JB, Pohl JF, Werlin SL, Bucuvalas JC. Octreotide inpediatric patients. J Pediatr Gastroenterol Nutr. 2002;35:600–609

Heinonen S, Ryynanen M, Kirkinen P. Etiology and outcome ofsecond trimester non-immunologic fetal hydrops. Acta ObstetGynecol Scand. 2000;79:15–18

Jauniaux E. Diagnosis and management of early non-immunehydrops fetalis. Prenat Diag. 1997;17:1261–1268

Jones DC. Nonimmune fetal hydrops: diagnosis and obstetricalmanagement. Semin Perinatol. 1995;19:447–461

Norton ME. Nonimmune hydrops fetalis. Semin Perinatol. 1994;18:321–332

Potter EL. Universal edema of the fetus unassociated with erythro-blastosis fetalis. Am J Obstet Gynecol. 1943;46:30

Rodriguez MM, Chaves F, Romaguera RL, Ferrer P, De la GuardiaC, Bruce J. Value of autopsy in nonimmune hydrops fetalis:series of 51 stillborn fetuses. Pediatr Dev Pathol. 2002;5:365–374

Swain S, Cameron AD, McNay MB, Howatson AG. Prenatal diag-nosis and management of nonimmune hydrops fetalis. Aust NZObstet Gynaecol. 1999;39:285–290

Tsao KJ, Hawgood S, Vu L, et al. Resolution of hydrops fetalis incongenital cystic adenomatoid malformation after prenatal ste-roid therapy. J Pediatr Surg. 2003;38:508–510

Wafelman LS, Pollock BH, Kreutzer J, Richards DS, HutchisonAA. Nonimmune hydrops fetalis: fetal and neonatal outcomeduring 1983–1992. Biol Neonate. 1999;75:73–81

Wraith JE. Lysosomal disorders Semin Neonatol. 2002;7:75–83Wy CAW, Sajous CH, Loberiza F, Weiss MG. Outcome of infants

with a diagnosis of hydrops fetalis in the 1990s. Am J Perinatol.1999;16: 561–567

Yang Y-H, Teng R-J, Tang J-R, Yau K-I T, Huang L-H, Hsieh F-J.Etiology and outcome of hydrops fetalis. J Formos Med Assoc.1998;97:16–20






NeoReviews Quiz

1. Anemia resulting in heart failure is the usual mechanism by which hematologic disorders result innonimmune hydrops fetalis. Of the following, the most common hematologic disorder that results innonimmune hydrops fetalis in Southeast Asia is:

A. Alpha thalassemia.B. Congenital leukemia.C. Glucose-6-phosphate dehydrogenase deficiency.D. Polycythemia.E. Pyruvate kinase deficiency.

2. The production of interstitial fluid is a function of hydrostatic and osmotic pressures within the capillaryand interstitial space as well as the integrity of the capillary endothelium. This relationship is expressedbest by the Starling equation, in which Pcap is hydrostatic pressure in the capillary, Ptiss is hydrostaticpressure in the interstitial tissue, Oplas is osmotic pressure of plasma, Otiss is osmotic pressure ofinterstitial tissue fluid, k is filtration coefficient, and r is reflection coefficient. Of the following, the mostaccurate expression of the Starling equation for fluid filtration (FF) is:

A. FF � k [ (Oplas – Otiss) – r (Pcap – Ptiss)].B. FF � k [ (Pcap – Ptiss) – r (Oplas – Otiss)].C. FF � k [ (Pcap – Ptiss) – r (Otiss – Oplas)].D. FF � k [ (Ptiss – Pcap) – r (Oplas – Otiss)].E. FF � k [ (Ptiss – Pcap) – r (Otiss – Oplas)].

3. Fetal ultrasonography at 32 weeks of estimated gestational age reveals bilateral pleural effusions andascites. Previous ultrasonography performed at 20 weeks had normal results. Of the following, the mostlikely cause of hydrops fetalis in this patient is:

A. Cardiac abnormality.B. Genetic malformation.C. Hepatic dysfunction.D. Parvovirus infection.E. Renal anomaly.

4. Fetal chromosomal abnormalities often are associated with nonimmune hydrops fetalis. Of the following,the most common chromosomal abnormality associated with nonimmune hydrops fetalis is:

A. Trisomy 13.B. Trisomy 15.C. Trisomy 16.D. Trisomy 18.E. Trisomy 21.

5. Despite advances in fetal diagnosis and fetal/neonatal therapy for nonimmune hydrops fetalis, the mortalityin this disease remains extremely high in most case series. Of the following, the best prognosis for survivalin nonimmune hydrops fetalis is associated with:

A. Alpha thalassemia.B. Chondrodysplasia.C. Congenital syphilis.D. Parvovirus infection.E. Supraventricular tachycardia.






DOI: 10.1542/neo.5-1-e52004;5;e5Neoreviews

Janet H. MurphyNonimmune Hydrops Fetalis

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