Published on March 14, 2014
Managing Non immune hydrops fetalis Dr Vidya A Thobbi Professor and Head Department of OBG Al-Ameen medical college Bijapur
Non immune hydrops fetalis Accumulation of extracellular fluid in tissues and 2 or more serous cavities without evidence of circulating antibodies against red cell antigens. Diagnosis requires generalized skin edema >5mm and 2 or more of the following:- • Pericardial effusion • Pleural effusion • Ascites • Placental enlargement>6mm (McCoy and colleagues, Non-immune hydrops after 20 weeks gestation: review of 10 years’ experience with suggestions for management. Obstet Gynaecol. 1995;85(4):578–82)
Incidence •It is around 3 per 10 000 births. •However, the incidence is much higher at the first- and second- trimester ultrasounds because of higher fetal death rates. All patients with fetal hydrops should be referred promptly to a tertiary care centre for evaluation. Some conditions amenable to prenatal treatment represent a therapeutic emergency after 18 weeks.(by SOGC 2013) Milunsky A. Genetic disorders of the fetus: diagnosis, prevention and treatment. 5th ed. Baltimore: John Hopkins University Press; 2004)
Presentation of fetal hydrops • Ultrasound examination • Fetal heart rate recording • Ultrasound surveillance for twin to twin transfusion syndrome in monochorionic twin pregnancy. • Large for dates/hydramnios. • Reduced fetal movement. • Placental abruption. • Maternal diabetes. • Maternal pre-eclampsia/mirror syndrome. • Maternal parvovirus B19 infection.
USG findings Scalp edema Placentomegaly
Anasarca Pleural effusion
Pericardial Effusion Heart
Hydrocele can be an early manifestation in hydrops
Placenta of Hydropic Pregnancy Placenta of Normal Pregnancy
Soft Tissue shadow and pleural effusion in hydropic neonate
Hydrops fetalis, Sara Peeples, MD. ANGELS Perinatal Conference. May 5, 2010)
CATEGORIES OF DISORDERS CAUSING NIHF
Chromosomal abnormalities • These are found in around 13% of cases, some of which will be associated with structural fetal anomalies. • It is important to exclude aneuploidy before offering therapy, especially in fetuses with hydrothorax. • Aneuploidy with hydrops has a dismissal prognosis and option of termination of pregnancy should be offered to the patient. Fetal chromosome analysis and genetic microarray molecular testing should be offered where available in all cases of non-immune fetal hydrops where available. (REC SOGC 2013) (Keeling JW: Fetal hydrops fetal and neonatal pathology, 2nd ed. London, Springer Verlag, 1993, pp 253-271)
Anemia • It is important not to transfuse the fetus before all investigations especially the parents for alpha thalassemia trait and fetal karyotype are available. • Ill-advised intrauterine transfusions for the fetus with homozygous alpha thalassemia may result in life long transfusions, iron chelations and the associated morbidity. ( Yang Q, McDonell SM, Khoury MK, et al: Hemochromatosis associated mortality in the united states from 1979-1992: An analysis of multiple-cause mortality data. Ann Intern Med 1998;20:946-953)
Twin Twin Transfusion syndrome • Hydrops associated with TTTS has been treated with intrauterine placental vessel ablation, amniodrainage, umbilical cord occlusion, delivery and termination. • In some, intrauterine fetal transfusion was deemed necessary after selective laser therapy. (Ville Y, Hecher K, Ganong A, et al:Endoscopic laser coagulation in the management of severe twin-twin transfusion syndrome, BJOG 1998;105:44- 453.)
Cardiovascular defects • The prognosis is good in general with a survival rate of as high as 80%. • However, there may be neurologic morbididty associated with long duration hydrops. (Schade RP, Stoutenbeck P, de vries LS, neurological morbidity after supraventricular tachyarrhythmia. Ultrasound obstet Gynecol 1999:13:43-47) • Fetal myocarditis associated with congenital infection may have severe complications requiring perinatal heart transplantation. (Von Kalsenberg CS, Bender G, Scheewe J, et al: A case of fetla parvovirus B19 myocarditid, terminal cardiac failure and perinatal herat transplantation. Fetal Diagn Ther 2001;16:427-432)
• Fetal tachycardia with hydrops associated with thyrotoxicosis in a patient with history of Graves disease can be treated with antithyroid medications in utero. (Ibrahim H, Asamoah A, Krouskop RW, et al:congenital chylothorax in neonatal thyrotoxicosis, J Perinatol 1999;19:1:68-71.)
Pulmonary defects • The survival of solid congental cystic adenomatoid malformation masses ranges from as low as 0% with hydrops to 90% with no hydrops, and has led some to offer open fetal surgery to those with solid lesions and hydrops. It is associated with 50% survival and significant maternal and fetal morbidity. (Adzick NS, Harrison MR, Crombleholme TM et al: fetal lung lesion management and outcome, Am J Obstet and Gynecol 1998;179:884-889) • Percutaneous ultrasound guided injection of a vascular sclerosant and laser vaporization. There are reports of spontaneous resolution of hydrops associated with regression of lesion. (Da Silva OP, Ramanan R, Romano W, Evans M : nonimmune hydrops fetalis, pulmonary sequestration and favorable neonatal outcome. Obstet Gynecol 1996;88:681-683)
Pulmonary defects • The survival rates in hydrops and pleural effusion treated conservatively is 12%, however survival rate in cases treated with pleuroamniotic shunt is 50%. Pathogenesis is unknown, but may be due to abnormalities of lymphatic system. • Serial intrapleural injection of OK-432 were used to treat the hydropic fetus, resulting in a live born infant. • Termination of pregnancy is also an option if there is no improvement in the hydrops after treatment. (Rodeck CH, Fisk NM, Fraser DI, Nicolini U, Long term inutero drainage of fetal hydrothorax. N Engl J Med 1988;319:1135-1138) (Tanemura M, Nishikawa N, Kojima K, et al A case of successful fetal therapy fr congenital chylothorax by intrapleural injection of OK-432. Ultrasound Obstet Gynecol 2001:18(4):371- 375)
Tumors • Open fetal surgery has been used in small number of surgically correctable conditions, solid pulmonary and sacrococcygeal tumors. • Other less invasive procedures like percutaneous alcohol, radiofrequency ablation, thermocoagulation and ultrasound guided instillation of alcohol. (Coleman BG, Adzick NS, Crombleholme TM, et al: fetal therapy: state of art. J Ultrasound Med 2002:21:1257-1288) (Lam YH, Tang MH, Shek TW: thermocoagulation of fetal sacrococcygeal teratoma. Prenat Diagn 2002; (2):22:99-101)
Infections • Risk of fetal hydrops is higher in mothers with asymptomatic parvovirus B19 infection. It may be due to profound hypoplastic anaemia. The risk of fetal loss is greater in 1st half of pregnancy, with most reported cases between 16 and 32 weeks. • Absence of thrombocytopenia, acidemia and presence of increased retic count suggests spontaneous recovery. • In non reassuring haematological profile intrauterine transfusion is indicated. • The risk of fetal loss is increased, but in majority of the cases there is successful outcome. (Fairely CK, Miller E:observational study of effect of intrauterine transfusion on outcome of fetal hydrops after parvovirus B19 infection. Lancet 1995;346:1335-1337) (Schild RL, Bald R et al: intrauterine management of fetal parvovirus B19 infection. Ultrasound Obstet Gynecol 1999;13:161-166)
Parvovirus B19 • The predominant ultrasound feature in fetuses infected by Parvovirus B19 is ascites, sometimes associated with poorly contractile echogenic myocardium. • Early diagnosis of maternal infection will allow fetal assessment and treatment by intrauterine blood transfusion. • Recommended investigation is ELISA IgM and IgG assays based on recombinant conformational epitopes of polyomavirus capsid proteins 1 and 2 or polyomavirus capsid protein 2 alone, and to use amniotic fluid or fetal serum for detection of fetal infection by the most sensitive molecular methods available (nested PCR or RT-PCR). Investigation for maternal–fetal infections, and alpha- thalassemia in women at risk because of their ethnicity, should be performed in all cases of unexplained fetal hydrops(REC SOGC 2013) (Valérie Désilets, François Audibert, Investigation and Management of Non-immune Fetal Hydrops, J Obstet Gynaecol Can 2013;35(10):e1–e14)
Clinical evaluation • A detailed history should be taken focusing on the mother’s past medical and reproductive history, including previous fetal, neonatal, or infantile deaths. • A clear determination of gestational age and history of viral exposure/illness, travelling, bleeding, or use of medication during the pregnancy should be obtained. • Parental past medical history, ethnic background, and consanguinity should be documented. • A 3-generation pedigree, including specific questions on fetal loss, death in infancy, developmental delay, congenital malformation, genetic syndrome, skeletal dysplasia, chronic infantile illness, inherited cardiomyopathies, and neurodegenerative disorders should be completed. • Maternal history, physical examination, and laboratory tests should be used to rule out developing preeclampsia (mirror syndrome) and underlying chronic illness associated with fetal hydrops (e.g., Sjogren, lupus, uncontrolled diabetes, Graves disease). (Valérie Désilets, François Audibert, Investigation and Management of Non-immune Fetal Hydrops, J Obstet Gynaecol Can 2013;35(10):e1–e14)
Counselling • Various options available have to be explained to the parents. • Option of medical termination of pregnancy to be given in those having structural/anatomical and chromosomal abnormalities. • Antenatal management should be directed towards making a diagnosis, with the aim of identifying those in whom either prenatal or immediate post-natal intervention may be effective. • In case of dead fetus in utero, the importance of autopsy has to be explained to the parents i.e to identify the cause and prevent recurrence in future pregnancies. (Valérie Désilets, François Audibert, Investigation and Management of Non-immune Fetal Hydrops, J Obstet Gynaecol Can 2013;35(10):e1–e14)
Step-wise investigation of non-immune fetal hydrops Fetal imaging 1)Detailed morphology obstetrical ultrasound in a tertiary care centre- -Look for site and severity of hydrops. -Amniotic fluid volume. -Detailed ultrasonography for congenital abnormalities and abnormalities of placenta and cord. -Biophysical assessment . (2)Doppler (MCA, venous, arterial). (3)Fetal echocardiogram. IMAGING STUDIES SHOULD INCLUDE COMPREHENSIVE OBSTETRIC ULTRASOUND(INCLUDING ARTERIAL AND VENOUS FETAL DOPPLER) AND FETAL ECHOCARDIOGRAPHY. (REC SOGC 2013)
Ultrasound findings in fetal infections causing fetal hydrops
Doppler ultrasound • After 16 weeks of gestation, there is a significant association between delta-MCA peak flow and delta hemoglobin concentration, especially when the fetal Hb concentration is very low. A peak systolic above 1.5 multiples of the median has a 100% sensitivity for detecting fetal anemia from various causes. • The most useful predictor of perinatal death is the presence of umbilical venous pulsations, because the most common pathway of perinatal demise is fetal congestive heart failure. In foetuses with congenital heart defects and hydrops, abnormal hepatic vein and ductus venosus blood velocities, along with umbilical venous pulsations were strongly associated with mortality. Hernandez-Andrade E, Scheier M, Dezerega V, Carmo A, Nicolaides KH. Fetal middle cerebral artery peak systolic velocity in the investigation of non-immune hydrops. Ultrasound Obstet Gynecol 2004;23:442–5.
MCA Doppler in anaemic fetus
Doppler ultrasound • Absent or reversed end diastolic flow in the umbilical artery reflects elevated placental resistance. Absent end diastolic flow is common in non-survivors, and often associated with increased cardiac afterload. Changes in UA Doppler appear later than venous Doppler and cardiac function alterations. (Mari G, Zimmermann R, Moise KJ, Deter RL, Correlation between middle cerebral artery peak systolic velocity and fetal hemoglobin after 2 previous intrauterine transfusions, Am J Obstet Gynecol, 2005 Sep;193(3 Pt 2):1117-20)
Role of uterine venous pressure • If UVP is raised and therapy reduces it then prognosis is good. • Hydrops characterized by elevated UVP not remedied by surgical or medical therapy, is usually progressive and the fetus dies in utero or requires preterm delivery for postnatal therapy. • Hence, measurement of fetal UVP should be viewed as a guide to therapy when fetal blood sampling is planned but it is not itself an indication for the sampling. (Moise KJ, Carpenter RJ et al, Do abnormal starlings forces cause fetal hydrops in red cell alloimmunisation? Am J Obstet Gynecol 1992;167:907-912)
Fetal echocardiography • Cardiac arrhythmias may be primary or secondary to systemic etiology in mothers such as hyperthyroidism or autoimmune conditions associated with high titres of circulating anti SS-A or anti SS-B antibodies. • Most common arrhythmias are supraventricular arrhythmias or severe bradyarrhythmias associated with complete heart block. • Enlargement of cardiac chambers is the most common sign of heart failure. • The right atrium is the final pathway for venous return and frequently shows enlargement in situations of relative foramen obstruction, volume overload, tricuspid valve regurgitation, and increased afterload. (Pajkrt E, Weisz B, Firth HV, Chitty LS. Fetal cardiac anomalies and genetic syndromes. Prenat Diagn 2004;24:1104–15)
Maternal blood sampling CBC ( microcytosis-alpha thalassemia ) Electrophoresis Alpha fetoprotein Kleihauer-Betke ABO blood type and antigen status Indirect Coombs (antibody screen) Venereal disease research laboratory test for syphilis Acute phase titers (parvovirus, toxoplasmosis, cytomegalovirus, rubella) Liver function tests, uric acid, coagulation tests (suspected mirror syndrome) SS-A, SS-B antibodies (fetal bradyarrhythmia) G6PD deficiency screening. Thyroid function test including antibodies. Blood urate, urea and electrolytes. (Valérie Désilets, François Audibert, Investigation and Management of Non-immune Fetal Hydrops, J Obstet Gynaecol Can 2013;35(10):e1–e14)
Amniotic fluid FISH or QF-PCR on uncultured amniocytes followed by karyotype or microarray analysis. PCR for CMV. PCR for parvovirus-B19/toxoplasmosis (selected cases), CMV and bacterial cultures. DNA extraction if alpha-thalassemia suspected. Fetal lung maturity testing (depending on gestational age). (Valérie Désilets, François Audibert, Investigation and Management of Non-immune Fetal Hydrops, J Obstet Gynaecol Can 2013;35(10):e1–e14) STEP 2: Invasive / referral / treatment-
Fetal blood sampling It is collected from the following sites- •Placental insertion of umbilical cord. •Fetal insertion of umbilical cord. •Intrahepatic veins. •Heart [Complication – fetal loss]
Fetal blood sampling for- • CBC, white blood cell count differential, platelets • Direct Coombs’ test • Blood group and type • Karyotype (standard) with genetic microarray consideration • TORCH/viral serologies • Protein/albumin/liver function tests (not on all cases) • Hemoglobin electrophoresis (depending on ethnicity) • Umbilical venous pressure •PCR IgM antibodies for infection (Valérie Désilets, François Audibert, Investigation and Management of Non-immune Fetal Hydrops, J Obstet Gynaecol Can 2013;35(10):e1–e14)
Cavity aspiration (may be done at the time of amniocentesis)- •Lymphocyte count •Protein/albumin •Creatinin/ionogram (ascites) •PCR for CMV and viral and bacterial cultures Consider consultation with neonatalogy (depending on gestational age) (Valérie Désilets, François Audibert, Investigation and Management of Non-immune Fetal Hydrops, J Obstet Gynaecol Can 2013;35(10):e1–e14)
Step – 3 Post - delivery Neonatal survival Cardiac monitoring Cranial ultrasound Abdominal ultrasound Cardiac monitoring Echocardiography CBC, liver function tests, creatinine kinase, albumin, protein TORCH, viral culture Specialized testing guided by results of prenatal work-up Neonatal / fetal demise Freeze fetal tissues and AF supernatant Bank fetal DNA Skeletal survey Placental pathology Autopsy (Valérie Désilets, François Audibert, Investigation and Management of Non- immune Fetal Hydrops, J Obstet Gynaecol Can 2013;35(10):e1–e14)
Management • It is an orderly diagnostic and multidisciplinary approach. • Fetal hydrops is a medical emergency because the hydropic fetus is usually in a precarious state and even minimal delays may prevent access to life-saving procedures. • Fetal treatment options for NIHF depend on the etiology and the gestational age at diagnosis. • A maternal–fetal specialist should undertake this evaluation. • Fetuses diagnosed with a treatable cause of NIHF should be delivered in a tertiary care centre with prenatal consultation with appropriate subspecialties including maternal–fetal medicine specialists, geneticists, neonatologists, and pediatric surgeons. (Valérie Désilets, François Audibert, Investigation and Management of Non-immune Fetal Hydrops, J Obstet Gynaecol Can 2013;35(10):e1–e14)
Fetal therapies in non immune hydrops INTRAUTERINE TRANSFUSION FOR ANAEMIA Maternal acquired red cell aplasia and maternal fetal haemorrhage. Fetal hemolysis and parvovirus B19 infection. REPEATED CENTESIS OR SHUNT INSERTION Ascitis and pleural effusion Pulmonary sequestration and lymphangectasis. INTRAVASCULAR OR MATERNAL TREATMENT WITH ANTI- ARRHYTHMIC DRUGS Fetal tachyarrhythmia and atrioventricular block. FETAL PROCEDURES-open fetal surgery and laser vessel ablation ANTI-THYROID DRUGS-thyrotoxicosis
Pleuroamniotic shunting INDICATIONS •Pleural effusion •Thoracic cystic lesions •Congenital cystic adenomatoid malformation •Pulmonary sequestration •Pulmonary lymphangiectasia
Fetal albumin therapy • Fetal hypoproteinemia appears to be a secondary effect. • It may occur in a third of non immune hydrops fetus. • It is distributed equal in frequency in groups with a high and low UVP exception being twin to twin transfusion syndrome. • Practice of giving fetal albumin in absence of knowing cardiac status and albumin level cannot be recommemded, but some suggest its use. (Maeda H, Koyanagi T et al : intrauterine treatment of nonimmune hydrops fetalis. Early Hum Dev 1994;29:241-249 )
• Most of the times such fetuses are delivered with elective cesarean section. • No evidence that mode of delivery has a marked effect on outcome. • Pediatric team should be aware about the nature of fetal problem before delivery as resuscitation is often difficult and adequate senior assistance must be available. • High incidence of third stage complications should not be overlooked.
The ABCs of resuscitation of newborn with hydrops
Delivery room resuscitation of newborns with hydrops
A hydropic neonate under extensive intensive care
Complications • Prenatal complications – preterm rupture of membranes – risk of chorioamnionitis, preeclampsia, anaemia, hydramnios, and placental abruption. In event of fetal surgery, the maternal risk include anaesthetic risk, fluid overload and electrololyte imbalance and uterine hemorrhage. • Maternal mirror syndrome- mother developes pre eclampsia along with severe edema similar to that of fetus. It is caused by vascular changes in swollen hydropic placenta(Midgley and hardrug 2000) or by antiangiogenic factors produced by hyperplacentosis(kusanour’s and co-work 2008). • During labor and delivery – 1.Preterm labor and dystocia. 2.Caesarean may be required in those associated with malpresentations and cord prolapse. 3.Abruption associated with membrane rupture in polyhydramnios. 4.Postpartum hemorrhage(primary and secondary). 5.Retained placenta. (Ville Y, Hecher K, Ganong A, et al:Endoscopic laser coagulation in the management of severe twin-twin transfusion syndrome, BJOG 1998;105:44- 453.)
Summary of management options of fetal hydrops
Autopsy • Autopsy should be recommended in all cases of fetal or neonatal death or pregnancy termination. Amniotic fluid and/or fetal cells should be stored for future genetic testing. (by SOGC 2013) • Detailed postnatal evaluation by a medical geneticist should be performed on all cases of newborns with unexplained non-immune hydrops. Knisely AS. The pathologist and the hydropic placenta, fetus, or infant. Semin Perinatol 1995;19:525–531.
Prognosis • Perinatal death rate is 40-98%. • Worst prognosis is seen in anatomic malformations found in 40% of cases. • Only cases with CMV and arrhythmias without structural malformations have spontaneous resolution. • If hydrops was evident before 24 weeks then fetal mortality rate was 95%. Euploid fetuses with hydrops who survived upto 24weeks and have a structurally normal heart had survival rate of 20%.(Mc Coy and colleagues, 1995). • Risk of recurrence is low unless etiology is genetic. • Hydrops usually persists or worsens with time, it occasionally resolves spontaneously. • OVERALL OUTCOME FOR HYDROPS FETALIS OF ANY CAUSE IS GENERALLY POOR. Huang HR, Tsay PK, Chiang MC, Lien R, Chou YH. Prognostic factors and clinical features in liveborn neonates with hydrops fetalis. Am J Perinatol 2007;24:33– 38.
RECOMMENDATIONS BY SOGC – • All patients with fetal hydrops should be referred promptly to a tertiary care centre for evaluation. Some conditions amenable to prenatal treatment represent a therapeutic emergency after 18weeks. • Fetal chromosome analysis and genetic microarray molecular testing should be offered where available in all cases of non-immune fetal hydrops. • Imaging studies should include comprehensive obstetrical ultrasound and fetal echocardiography. • Investigation for maternal–fetal infections, and alpha-thalassemia in women at risk because of their ethnicity, should be performed in all cases of unexplained fetal hydrops. • To evaluate the risk of fetal anemia, Doppler measurement of the middle cerebral artery peak systolic velocity should be performed in all hydropic fetuses after 16 weeks of gestation. • Detailed postnatal evaluation by a medical geneticist should be performed on all cases of newborns with unexplained non-immune hydrops. • Autopsy should be recommended in all cases of fetal or neonatal death or pregnancy termination.
Conclusion • Fetal hydrops is uncommon, but serious condition with a complex pathophysiology; it is associated with a wide range of etiologies and carries a poor prognosis. • Comprehensive antenatal and postnatal investigatios are necessary if the cause has to be identified, as the diagnosis may not be made in as many as quarter of cases. • Antenatal therapy should be directed at a specific pathological condition, but is possible in less than a third of cases. • In short, the largest impact of NIH is made by implementing screening programs both preconceptually(E.g. populations at risk for alpha thalassemia) and antenatally(E.g. nuchal translucency; monochorionicity and TTTS surveillance; anomaly scan, especially cardiac scans and being alert to outbreaks of parvovirus B19 infections)
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