Archives of in Childhood 1994; 70: F151-F154 F151 Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/fn.70.2.F151 on 1 March 1994. Downloaded from

PERSONAL PRACTICE

Diagnosis and management of non-immune hydrops in the newborn

Terence Stephenson, Jane Zuccollo, Mich Mohajer

Non-immune hydrops fetalis is a relatively rare infection and multiple births. In earlier series, and complex disorder that requires detailed no cause was found in approximately 50%/ of investigation and coordinated management by these cases,3 13 but more recent data suggest a multidisciplinary team. There is a lack of that with a complete prenatal and postnatal clear advice in the literature on the immediate evaluation,2 5 a precise diagnosis can be arrived management and investigation of neonatal at in 85%.14 Approximately 40% of cases will hydrops. The approach described here has have another congenital abnormality.3 The been used in our unit and has been welcomed, remainder of this article refers only to non- particularly by resident staff. immunological hydrops and is intended to Hydrops fetalis is associated with a large provide guidelines for staff confronted with a number of pathologies (see table 1) that are hydropic infant at birth. usually divided into: (1) Immunological. Anaemia results from maternal isoimmunisation against rhesus or Obstetric considerations other red cell antigens. The antenatal and Hydrops occurs more commonly if the mother postnatal aspects of investigation and manage- has had a previous or hydropic infant. ment of immune hydrops are well covered in There is also a greater incidence in twin preg- standard obstetric and neonatal textbooks. nancies, particularly This condition is now extremely rare in our between which twin-twin transfusion has experience, less than 1:10 000 deliveries, as a occurred, or if there is polyhydramnios.9 result of improved antenatal intervention. Antenatal diagnosis is usually made by (2) Non-immunological. Most cases of ultrasound examination, which should be a hydrops fetalis are now non-immunological. detailed scan looking at growth, liquor A wide range of associations have been volume, cardiac structure,4 15 16 rate and

reported in over 500 cases1-12 but the com- rhythm and anatomical abnormalities, includ- http://fn.bmj.com/ monest are chromosomal abnormalities, ing features that may point to chromosomal cardiac anomalies, pulmonary abnormalities, abnormalities. If fetal hydrops is found on

Table 1 Reported associations with fetal hydrops (not necessarily the cause of the hydrops)

Cardiovascular: Gastrointestinal: Infective: Congenital tumour: on September 28, 2021 by guest. Protected copyright. Truncus arteriosus Jejunal atresia Parvovirus Calcific myocarditis (Coxsackie Mid-gut Neuroblastoma infection) Meconium Toxoplasmosis Haemangioma Arterial calcification Hepatic fibrosis Supraventricular tachycardia Polycystic disease of the liver Leptospirosis Placenta/umbilical Heart block (mother with Biliary atresia Chagas' disease cord: Department of Child systemic lupus or anti-Ro Hepatic vascular malformations Congenital True knot in the cord Health, University ) Familial with portal Umbilical vein Hospital, Nottingham Hypoplastic left heart hypertension Respiratory: thrombosis and Department of Endocardial fibroelastosis Congenital diaphragmatic Large chorioangioma Neonatal Medicine and Septal defects Genitourinary: of the placenta Pulmonary atresia Congenital nephrotic syndrome Congenital cystic adenomatoid Aneurysm of the Surgery, City Hospital, Asplenia syndrome Urethral obstruction and renal malformation umbilical artery Nottingham Large atrioventricular dysplasia Hamartoma Terence Stephenson malformation Polycystic kidneys Tracheo-oesophageal fistula Metabolic/storage: Premature closure of the Renal vein obstruction Atresia of the right main Gaucher's disease University Hospital, foramen ovale Congenital abnormalities of the bronchus Nottingham, Premature closure of the ductus vagina and uterus Maternal: Department of arteriosus (maternal Neurological: Diabetes Pathology indomethacin) Haematological: Encephalocele Toxaemia Cardiac tumour (usually Twin to twin transfusion Agenesis of the corpus Drugs (for example Jane Zuccollo rhabdomyoma) syndrome callosum indomethacin) Idiopathic arterial calcification Rhesus isoimmunisation Tuberose sclerosis Department of Any cause of cardiac failure in Fetomaternal haemorrhage Arthrogryposis Miscellaneous: utero (positive Kleihauer test) Retroperitoneal Mich Mohajer Homozygous alpha thalassaemia Skeletal: fibrosis Fetal anaemia of any cause Osteogenesis imperfecta Correspondence to: Chromosomal: Glucose-6-phosphate Asphyxiating thoracic Dr Terence Stephenson, Trisomy 21 (Down's syndrome) dehydrogenase deficiency dystrophy Department of Child Health, and other trisomies Thanatophoric dwarfism University Hospital, Triploidy Lymphatic: Achondrogenesis Nottingham NG7 2UH. 45X (Turner's syndrome) Congenital lymphangiectasia Hypophosphatasia of the neck Saldino-Noonan dwarfism No reprints available. F152 Stephenson, Zuccollo, Mohajer Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/fn.70.2.F151 on 1 March 1994. Downloaded from Table 2 Antenatal maternal investigations. The specimen bottles and volume required Paediatric aspects may varyfrom one laboratory to another Antenatal diagnosis allows delivery in a con- 1. Haemoglobin concentration 5 ml in EDTA tube trolled setting, sometimes by elective caesarean 2. ABO, Rhesus groups, haemolysins (for example section, with a neonatal team in attendance. anti-A IgG) and minor blood group antigens (for example B, C, Kell) 5-10 ml clotted blood The neonatal team should ensure in advance 3. Kleihauer test 3-5 ml in EDTA tube that fresh cytomegalovirus negative, 0 nega- 4. Venereal Disease Research Laboratory test 5 ml clotted blood 5. Random blood sugar 2 ml in fluoride tube tive blood is available, cross matched against 6. TORCH and parvovirus titres 5-10 ml clotted blood the mother. Exchange transfusion and full 7. Maternal autoantibody screen, anticardiolipin , and anti-Ro antibodies 5 ml clotted blood monitoring equipment should also be ready. 8. ot Fetoprotein Check the 15-18 week concentration Arterial blood pressure and central venous 9. Haemoglobin electrophoresis 3 ml in EDTA tube 10. Lupus anticoagulant Two 4 ml samples in sodium citrate pressure transducers should be set up and tubes calibrated before the baby is born. Initial 11. Glucose-6-phosphate dehydrogenase screen 3 ml in EDTA tube resuscitation may be difficult for three main reasons. is present in scanning (there may be any combination of 90%3 as a result of lung compression by , , , pleural fluid25 or gross abdominal ascites. generalised skin oedema of more than 5 mm or Intrapartum asphyxia is also common.6 In placental oedema), the minimum appropri- addition, endotracheal intubation may be ate maternal antenatal investigations are listed difficult because of laryngeal oedema. in table 2.4 9 17 Fetal tachyarrhythmia, most commonly supraventricular tachycardia, lead- ing to hydrops fetalis may be intermittent and IMMEDIATE NEONATAL MANAGEMENT can therefore be missed by a single ultrasound The infant almost always requires intubation4 scan. If suspected, repeated ultrasound scans and should be ventilated initially with high or a 24 hour cardiotocograph should be under- pressures (for example 30 cm H20) and taken. positive end expiratory pressure of 4-8 cm H20. It is often difficult to establish intra- venous access because of the skin oedema and ANTENATAL MANAGEMENT so there should be a low threshold for umbili- It may be appropriate to undertake other more cal vein catheterisation. Pleural effusions and invasive investigations aimed towards making a ascites should be drained in the delivery room diagnosis in utero. The fetal karyotype can be if severe and obstructing respiration.3 A peri- obtained by amniocentesis or cordocentesis. cardial effusion should only be drained if there Cordocentesis has the advantages that a more is frank tamponade. rapid karyotype is obtained and in addition fetal viral studies,'8 haemoglobin concen- tration, haemoglobin electrophoresis,19 and Thoracocentesis blood groups can be included.20 If the is Ventilation is briefly stopped. A 21 gauge anaemic, may be butterfly needle attached to a three way tap appropriate. Placental biopsy offers the and 50 ml syringe is inserted in the mid-

advantage of a rapid karyoptype.21 axillary line, fourth intercostal space, immedi- http://fn.bmj.com/ The information provided by the detailed ately above the rib and aspirated while being ultrasound scan may direct the clinician advanced, until fluid is obtained. Ventilation is toward appropriate fetal treatment. An example is the considerable success with the Table 3 Neonatal investigation ofnon-immune hydrops use of maternal digoxin16 or flecainide22 to A. Blood treat fetal tachyarrhythmias. Fetal thoracocen- 1. 2 ml in lithium heparin tube for:

(a) Urea, electrolytes, and creatinine on September 28, 2021 by guest. Protected copyright. tesis (and insertion of pleuroamniotic shunts) (b) Total protein, , and protein electrophoresis or abdominal paracentesis have also been (c) Liver function tests (d) : conjugated and unconjugated advocated to decompress these cavities and (e) Osmolality thereby limit pulmonary hypoplasia.14 2. 0 5 ml in EDTA tube for: (a) Packed cell volume There is a higher incidence of obstetric (b) Full blood count complications at delivery, especially vaginal (c) Film (d) Blood group and direct Coombs test delivery.23 The decision to undertake elective (e) Haemoglobin electrophoresis caesarean section will, among other obstetric 3. 2 ml in clotted tube for: (a) TORCH screen and paravovirus titre, including considerations, depend on the cause of the specific IgM hydrops, the degree of severity, and the like- (b) Venereal Disease Research Laboratory test (usually already performed antenatally on the mother) lihood of a favourable outcome. The decision 4. 2 ml in lithium heparin tube for: to deliver the infant early must only be Karyotype undertaken when there is consensus between 5. Check reagent strip for blood sugar B. Urine the obstetrician and the paediatrician that this Albumin concentration to exclude congenital nephrotic syn- is significantly likely to improve outcome. The drome hazards of preterm delivery, in addition to C. Ascitic or pleural fluid 1. Sterile container for total protein and albumin hydrops, should not be taken lightly and we 2. Sterile container for lipid analysis to exclude chylous have seen spontaneous intrauterine resolution effusion 3. Sterile containers for microbiology and virology cultures of fetal ascites and pericardial effusions 4. Lithium heparin tube to cytogenetics for karyotype observed during the middle trimester.24 D. Chest radiograph Unfortunately, stillbirth is common,4 spon- E. Electrocardiogram with rhythm strip the taneous preterm delivery may occur, and F. Ultrasound scans ofheart, kidneys, and brain infant is often small for gestational age. Diagnosis and management of non-immune hydrops in the newborn F153 Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/fn.70.2.F151 on 1 March 1994. Downloaded from then recommenced and aspiration continued infusion (10 ,ug/kg/min) is preferable to a until no further fluid is obtained. The volume plasma expander if blood pressure support is aspirated is noted and the fluid saved for required. Once the infant has been stabilised, further investigation (see table 3). Pneumo- colloid is appropriate if the investigations show thorax may occur ifthe lung is damaged during hypoproteinaemia6 but must be given slowly. this procedure - a chest drain should be In theory, each 2 ml/kg of 25% albumin will inserted immediately. Syncope or bradycardia raise the plasma albumin by 5 g/l and this may occur if fluid is removed too quickly. carries less risk of acute hypervolaemia than Ideally, the heart rate should be monitored if larger volumes of 40/o human albumin are throughout the procedure. used. Moderate fluid restriction (two thirds of recommended maintenance)27 and diuretics (frusemide 1 mg/kg and spironolactone 1 Abdominal paracentesis mg/kg, both twice a day) are employed ini- The lower borders of the liver and the spleen tially.6 Coagulation studies should be checked should be determined by palpation. A 21 daily, initially, as disseminated intravascular gauge butterfly needle is inserted at the mid- coagulopathy may ensue. point of a line drawn from the umbilicus to the left anterior superior iliac spine. The volume of fluid aspirated is noted and the fluid saved for POSTNATAL INVESTIGATION OF NON-IMMUNE investigation (see table 3). HYDROPS FETALIS The minimum investigations are listed in table 3. The sample volumes required may differ Pericardiocentesis from laboratory to laboratory, as may the A 25 gauge needle is inserted immediately normal ranges. Normal ranges may also vary under the xiphisternum and advanced upward, with gestation.28 Despite full investigation, a backward, and laterally aiming for the tip of number of infants may remain in whom no the left shoulder, aspirating continuously. The cause for the hydrops can be found. pericardial sac should be entered within 1-2 Nevertheless, investigations in these infants cm. This can be done under echocardiographic may give a clue as to prognosis (see below).4 guidance. An electrocardiograph lead attached with a crocodile clip to the proximal end of the needle will show an injury potential if contact NEONATAL OUTCOME is made with the myocardium. The fluid Hydrops fetalis detected in the first and second should be sent for investigation (table 3). trimesters may resolve by term (for example When the infant has been stabilised, he or Turner's syndrome). Many of those detected she can be transferred to the neonatal unit for by midtrimester ultrasound scan will not be further assessment. If there are severe associ- liveborn as some of the will be ated congenital abnormalities, this may be an electively terminated and others will be still- appropriate stage at which to consider, in con- born. In approximately 50% of cases, no cause junction with the parents, withdrawal of active is found. The mortality in different series treatment. Otherwise, an umbilical venous ranges from 50-95%,3 4 9 29 partly depending catheter should be inserted, ensuring that the on the severity of the hydrops,29 the cause and http://fn.bmj.com/ tip is above the diaphragm and in the right the serum protein concentrations at birth.4 atrium so that the pressure measured is the The mortality is lower if the hydrops is due true central venous pressure and not the intra- to fetal supraventricular tachycardia that abdominal pressure. If the central venous responds to maternal treatment. The recur- pressure is greater than 12 mm Hg (16 cm rence risk is low,23 unlike isoimmune hydrops

H20), blood should be removed in 10 ml fetalis. on September 28, 2021 by guest. Protected copyright. aliquots until the central venous pressure is less than 6 mm Hg.26 The central venous pressure may fall further if the pH and arterial oxygen Procedure for stillbirth or neonatal death tension (Pao2) improve. If anaemia is the cause If the infant is stillborn or dies in the immedi- of the hydrops, partial exchange transfusion ate neonatal period, as many of the maternal with packed cells is indicated. It may be neces- and neonatal investigations as possible should sary to complete the transfusion with a volume be done as specified in this protocol (see tables deficit if the central venous pressure remains 2 and 3). It is highly desirable that a full post- above 12 mm Hg. mortem examination is performed, as soon as An umbilical artery catheter is inserted and possible after death, in order to determine the the ventilation and inspired oxygen concentra- cause of the hydrops and to assist counselling tion adjusted to aim for a Pao2 of at least of the family with regard to future pregnancies. 8 kPa. As the pulmonary oedema decreases, Parental permission should be sought for a full the initial high inspiratory pressures and postmortem examination. If the parents do not positive end expiratory pressure may obstruct wish a full postmortem to be performed, a the pulmonary circulation and therefore a limited postmortem may be carried out. reduction in pressure may aid oxygenation Ensure that the limitations are annotated on paradoxically. If metabolic acidosis is severe the request form. (pH less than 7- 1), sodium bicarbonate should If the parents do not wish a limited post- be given slowly as the extracellular fluid space mortem examination to be performed, an is already expanded and there may be incipient attempt to gain permission for skin biopsy and or overt . Initially, a dopamine needle biopsy of the liver should be made. The F154 Stephenson, Zuccollo, Mohajer Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/fn.70.2.F151 on 1 March 1994. Downloaded from skin specimen should be placed in sterile saline 7 KeelingJW, Gough DJ, IliffP. The pathology ofnon-rhesus hydrops. Diagnostic Histopathology 1983; 6: 89-111. and sent to the cytogenetics department. 8 Pesonen E, Haavisto H, Ammala P, Teramo K. Intrauterine Inform the staff that a skin biopsy is on its way hydrops caused by premature closure of the foramen ovale. Arch Dis Child 1983; 58: 1015-6. and that it is for fibroblast culture and 9 Holzgreve W, Curry CJR, Golbus MS, Callen PW, Filly karyotype. If the infant dies out of hours, the RA, Smith JC. Investigation of nonimmune hydrops fetalis. Am J Obstet Gynecol 1984; 150: 805-12. biopsy specimen should still be taken but 10 Windebank KP, Bridges NA, Ostman-Smith I, Stevens JE. placed in saline in a refrigerator until the Hydrops fetalis due to abnormal lymphatics. Arch Dis Child 1987; 62: 198-200. laboratory is open. Ensure that the specimen 11 Jauniaux E, Van Maldergem L, De Munter C, Moscos G, reaches the laboratory at the earliest possible Gillerot Y. Nonimmune hydrops fetalis associated with genetic abnormalities. Obstet Gynecol 1990; 75: 568-72. time. The liver cores should be snap frozen in 12 Van Maldergem L, Jauniaux E, Fourneau C, Gillerot Y. liquid nitrogen and stored at -70°C. One core Genetic causes of hydrops fetalis. Pediatrics 1992; 89: 81-6. should be sent for routine histopathology. 13 Im SS, Rizos N, Joutsi P, Shime J, Benzie RJ. Other helpful investigations are skeletal Nonimmunologic hydrops fetalis. Am J Obstet Gynecol 1984; 148: 566-9. radiographs and clinical photographs. The 14 Holzgreve W, Holzgreve B, Curry CJR. Nonimmune placenta should be sent fresh to the histo- hydrops fetalis: diagnosis and management. Semin Perinatol 1985; 9 (2): 52-67. pathologist in all cases and not placed in 15 Devore GR, Acherman RJ, Cabal LA, Siassi B, Bieniarz A, formalin. If out of hours, the placenta may be Platt LD. Hypoalbuminaemia: the etiology of antenatally diagnosed pericardial effusion in rhesus-hemolytic stored in a conventional refrigerator overnight. disease. AmJI Obstet Gynecol 1982; 142: 1056-7. 16 Kleinman CS, Donnerstein RL, DeVore GR, et al. Fetal echocardiography for evaluation of in utero congestive heart failure. A technique for study of nonimmune fetal Conclusion hydrops. NEnglJMed 1982; 306: 568-75. 17 Tuberville DF, Killam AP, Davis PC, Heath RE, Fearnow Care must be taken to distinguish between the RG, Pearson JW. Non-immunologic hydrops fetalis. causes ofhydrops in the midtrimester fetus and Obstet Gynecol 1974; 43: 567-70. 18 Peters MT, Nicolaides KH. Cordocentesis for the diagnosis the liveborn infant when considering the many and treatment of human parvovirus infection. Obstet published associations. Experience will also Gynecol 1990; 75: 501-4. 19 Beaudry MA, Ferguson DJ, Pearse K, Yanofsky RA, Rubin vary depending on whether the centre practises EM, Kan WY. Survival of hydropic infant with termination of and on the ethnic homozygous alpha-thalassemia. Jf Pediatr 1986; 108: 713-6. and religious mix of the population. Our 20 Nicolaides KH, Rodeck CH, Millar DS, Mibashan RS. experience is that chromosomal abnormalities Fetal haematology in rhesus isoimmunisation. BMJ 1985; 290: 661-3. are now uncommonly seen as a cause of 21 Rosevear S. Placental biopsy. Br J Hosp Med 1989; 41: hydrops in the live newborn and that, despite 334-48. 22 Allan LD. Diagnosis offetal cardiac abnormalities. Arch Dis extensive investigation in life and at post- Child 1989; 64: 964-8. mortem, the underlying explanation may 23 Gough JD, Keeling JW, Castle B, Iliff PJ. The obstetric management of non-immunological hydrops. Br Jf Obstet remain elusive. Gynaecol 1986; 93: 226-34. 24 Platt LD, Collea JV, Joseph DM. Transitory fetal ascites: an ultrasound diagnosis. Am Jf Obstet Gynecol 1978; 132: 1 Macafee CAJ, Fortune DW, Beischer NA. 906-8. Nonimmunologic hydrops fetalis. Br J Obstet Gynaecol 25 Van Aerde A, Campbell AN, Smyth JA, Lloyd D, Bryan 1970; 77: 226-37. HM. Spontaneous chylothorax in newborns. Am J Dis 2 Maidman JE, Yeager C, Anderson V, et al. Prenatal diag- Child 1984; 138: 961-4. nosis and management of nonimmunologic hydrops 26 Skinner JR, Milligan DWA, Hunter S, Hey EN. Central fetalis. Obstet Gynecol 1980; 56: 571-6. venous pressure in the ventilated neonate. Arch Dis Child 3 Hutchison AA, Drew JH, Yu VYH, Williams ML, Fortune 1992; 67: 374-7. DW, Beischer NA. Non-immunologic hydrops fetalis: a 27 Stephenson TJ, Rutter N. Fluid balance. In: McIntosh N, review of 61 cases. Obstet Gynecol 1982; 59: 347-52. Campbell AGM, eds. Forfar and Arneil's textbook ofpaedi- http://fn.bmj.com/ 4 IliffPJ, Nicholls JM, KeelingJW, Gough JD. Non-immuno- atrncs. 4th Ed. London: Churchill Livingstone, 1992: logic hydrops fetalis: a review of 27 cases. Arch Dis Child 158-65. 1983; 58: 979-82. 28 Cartlidge PHT, Rutter N. Serum albumin concentrations 5 Salzman DH, Frigoletto FD, Harlow BL, Barss VA, and oedema in the newborn. Arch Dis Child 1986; 61: Benacerraf BR. Sonographic evaluation ofhydrops fetalis. 657-60. Obstet Gynecol 1989; 74: 106-11. 29 Etches PC, Lemons JA. Non-immune hydrops fetalis: 6 Giacoia GP. Hydrops fetalis (fetal ). Clin Pediatr report of 22 cases including 3 siblings. Pediatrics 1979; 64: (Phila) 1980; 19: 334-9. 326-32. on September 28, 2021 by guest. Protected copyright.