Nonimmune Hydrops Case File

Nonimmune Hydrops Case File

Eugene C. Toy, MD, Edward Yeomans, MD, Linda Fonseca, MD, Joseph M. Ernest, MD

Case 44

A 32-year-old G4P1113 woman presents for a routine prenatal visit at 22 weeks’ gestation by a sure LMP consistent with an 8-week sonogram. She has no significant past medical or surgical history. Her obstetric history is significant for a full-term vaginal delivery followed by a twin vaginal delivery at 36 weeks. She also had a first-trimester miscarriage between the first and second pregnancies.

She is employed as a youth counselor at the local elementary school. Her children are in daycare 2 days per week. She denies use of alcoholand tobacco, and is a vegetarian. She reports having had “cold” symptoms 3 to 4 weeks ago when her children were all sick for 2 days.

On physical examination, her blood pressure is 108/62 mm Hg, pulse of 74 bpm, respiratory rate of 18 breaths/min. Her weight is 165 lb and the urine dipstick is negative for protein or glucose. The fundal height is 26 cm. She reports the sensation of fetal movement and denies contractions. The patient undergoes a fetal anatomical survey which is significant for a single intrauterine gestation. The fetal growth parameters are consistent with the established gestational age. There is polyhydramnios of 24 cm and bilateral pleural effusions are noted. There is a small rim of ascites at the level of the fetal abdominal circumference. There are no gross structural anomalies noted. The placenta is posterior and unremarkable.

➤ What is the most likely diagnosis?

➤ What is the next step in evaluating this patient?

➤ What are the potential maternal risks?

➤ What are the potential fetal risks?

ANSWERS TO CASE 44:

Nonimmune Hydrops

Summary: A multigravida at 22 weeks’ gestation with increased fundal height and ultrasound findings of polyhydramnios, bilateral pleural effusions, and ascites.

➤ Most likely diagnosis: The diagnosis is fetal hydrops. Fetal hydrops can be immune or nonimmune. As the patient’s blood type is Rh+ with a negative antibody screen, a nonimmune process is likely responsible for the fetal hydrops.

➤ Next step: The next step is to evaluate for causes of nonimmune hydrops fetalis (NIHF). In addition to fetal anomalies, placental abnormalities should be considered. Other common etiologies of NIH include genetic, infectious, and hematologic disorders and an evaluation of these should be performed.

➤ Potential maternal risks: It is important to be aware that maternal birth trauma from delivery of a large edematous fetus is possible. Mirror syndrome is a rare complication in which maternal pulmonary edema and preeclampsia develop. In addition, there is also an increased risk of cesarean delivery, postpartum hemorrhage, and retained placenta.

➤ Potential fetal risks: There is an increased risk of premature labor and/or premature rupture of membranes due to uterine overdistension. Dystocia at the time of delivery may also occur due to an edematous fetus. Pleural effusions may make resuscitation more difficult and may require drainage in the early neonatal period to improve the ability to ventilate. Lung hypoplasia due to the pleural effusions may make neonatal resuscitation impossible.

ANALYSIS

1. Describe the clinical presentation of hydrops fetalis.
2. Describe the causes of hydrops fetalis including immune and nonimmune causes.
3. Describe the diagnostic strategy of hydrops.

Considerations

The incidence of nonimmune hydrops fetalis (NIHF) ranges from 1/1500 to 1/3800 births1-4,5 (Level III, Level II-2). This variation is likely due to differences in the definitions, populations studied, and the extent of the fetal evaluation when hydrops is noted. In addition, cases of fetal demise and pregnancy terminations are included in some studies and excluded in others.

Immune hydrops occurs in relation to red blood cell alloimmunization, most commonly to Rh(D) and Kell antibodies. In contrast, NIHF includes the causes of fetal hydrops that are not mediated by an immune mechanism. Prior to the widespread use of RhIg, red cell alloimmunization was the most common cause of fetal hydrops. However, nearly 90% of fetal hydrops cases are now related to nonimmune hydrops1 (Level III).

Fetal hydrops is diagnosed by the presence of excess fluid in two or more fetal compartments including the pleural cavity (Figure 44-1), pericardial cavity, abdominal cavity (ascites; Figure 44-2), amniotic sac (polyhydramnios; Figure 44-3), and skin edema. Abnormalities within each organ system may lead to nonimmune hydrops fetalis. A brief list of some of the more common causes of NIHF will be presented as a comprehensive list of etiologies is beyond the scope of this chapter. Unfortunately, antenatal determination of the etiology of hydrops is only successful 50% to 85% of the time. An additional 5% of cases may have an underlying etiology that can be determined after delivery while the remainder will be classified as idiopathic. Some of the more common causes of NIHF include disorders of the systems shown in Table 44–1.

This patient’s pregnancy has been relatively uncomplicated to date except for a cold approximately 1 month ago. The initial evaluation of a patient with nonimmune fetal hydrops includes a detailed anatomy ultrasound, evaluation for fetal anemia by measuring peak systolic velocity (PSV) of the middle cerebral artery (MCA),

Figure 44–1. Bilateral pleural effusions.The fetal chest is filled with echolucent material,

which represents pleural fluid. (Reproduced, with permission, from Dr. Svena Julien.)

Figure 44–2. Rim of ascites. Fetal abdomen has a moderately large echolucent

border which constitutes ascites. (Reproduced, with permission, from Dr. Svena Julien.)

and serologic testing for infection. Amniocentesis for fetal karyotype should also be offered to exclude a chromosomal abnormality. Prognosis depends on the underlying etiology and gestational age at which hydrops has occurred. In general, when nonimmune hydrops develops, the prognosis is uniformly poor.

Figure 44–3. Polyhydramnios.Ultrasound image of significant amniotic fluid.Note

large amount of echolucent space from anterior uterine wall to posterior placenta

(cursor at 11.7 cm). (Reproduced, with permission, from Dr. Svena Julien.)

Table 44–1 ETIOLOGIES OF FETAL HYDROPS

• Genetic disorders (10%) • Aneuploidy including monosomy X, trisomy 21, trisomy 18 • Syndromes including skeletal dysplasias • Metabolic storage diseases including Hurler syndrome, Gaucher disease • Cardiovascular (40%) • Structural lesions such as AVSD, hypoplastic left and right heart syndrome, cardiomyopathy • Arrhythmias including tachyarrhythmia and bradyarrhythmia • Pulmonary (10%) • Pulmonary sequestration • Congenital cystic adenomatoid malformation of the lung • Diaphragmatic hernia • Pulmonary neoplasia and lymphangiectasia • Bronchogenic cysts • Infectious diseases (8%) • Parvovirus • Cytomegalovirus • Syphilis • Coxsackie virus • Toxoplasmosis • Rubella virus • Gastrointestinal and renal • Gut duplications and malrotation • Hepatobiliary vascular malformation and tumor • Congenital Finnish-type nephrosis • Posterior urethral valves • Prune belly syndrome • Hematologic (10%-27%) • á Thalassemia • Aplastic anemia related to parvovirus infection • Other red cell aplasias • Fetal hemorrhage • Placental abnormalities including AV fistulas, chorioangiomas, umbilical cord thrombosis, and aneurysms • Other • Twin-to-twin transfusion sequence

APPROACH TO

Nonimmune Hydrops Fetalis

The diagnosis of nonimmune fetal hydrops is made by the ultrasound findings of abnormal fluid in two or more fetal compartments. Pleural effusions may be visualized as echolucent fluid outlining the lungs. They may be unilateral or bilateral, and may lead to compression of lung tissue giving the appearance of small lungs. Over time, effusions may restrict the growth of the fetal lungs and put the fetus at risk for pulmonary hypoplasia. This is more common when hydrops develops prior to 20 weeks of gestation and is a common cause of neonatal mortality in infants surviving to delivery. A number of authors have described ultrasound techniques to determine the severity of lung hypoplasia, but none are consistently reliable6 (Level III).

Pericardial effusions can be seen in fetuses with fetal hydrops and are described when the rim of fluid within the pericardial sac is greater than 4 to 5 mm. It is important not to mistake physiologic pericardial fluid for an effusion as 2 mm of fluid is normal7 (Level II-2).

Fetal ascites is noted when a rim of fluid outlines the abdominal cavity and often the intraabdominal organs. It is important to distinguish true ascites from pseudoascites. Pseudoascites is an echolucent rim around the abdomen that actually represents prominent abdominal wall muscles. As the amount of ascites increases, the bowel may appear compressed and echogenic8,9 (Level III).

An amniotic fluid index of greater than 24 cm or a maximum vertical pocket greater than 8 cm is consistent with polyhydramnios.10 It is present in 40% to 75% of pregnancies complicated by nonimmune hydrops. Size greater than dates related to polyhydramnios is often the initial indication for a growth sonogram evaluation of the pregnancy.

Pathologic skin edema is a late finding in hydrops fetalis. It is defined as a tissue thickness of the subcutaneous tissue greater than 5 mm.10 However, during the sonographic evaluation, subcutaneous fat should not be included in the measurement of edema (Figure 44-4).

Placentomegaly may occur due to edema of the intervillous spaces and may be a manifestation of nonimmune hydrops. However, be aware that significant polyhydramnios may lead to a thinned or compressed appearing placenta. In general, a placental thickness of greater than 4 to 6 cm is considered abnormal and should prompt further investigation11,12 (Level III).

Once fetal hydrops is confirmed, an extensive examination of the fetal anatomy and placenta should be done. A number of potential causes of hydrops can be excluded based upon the finding of normal fetal anatomy. In addition, a thorough maternal history including ethnicity, family history of inherited disorders, travel history, and infectious agent exposure should be done. Given the vast number of etiologic possibilities, several laboratory studies may need to be undertaken concomitantly.

Figure 44–4. Scalp edema. Ultrasound image of significant scalp edema.

(Reproduced, with permission, from Dr. Svena Julien.)

The initial evaluation includes the fetal anatomical survey. Following this examination, maternal blood type and antibody screen should be obtained. An amniocentesis for karyotype should be offered. Additional amniotic fluid should be obtained in order to test for viral pathogens using amniotic fluid PCR, and fluid may be frozen for analysis to exclude metabolic storage diseases in an at risk population. Additional sonographic evaluation can include a fetal echocardiogram to exclude a cardiac etiology of the hydrops, and interrogation of the fetal middle cerebral artery (MCA). The peak systolic velocity assessment of the MCA may be used to determine the presence of fetal anemia. If MCA Dopplers are found to be elevated, fetal blood sampling may be indicated. Other components of the evaluation include maternal CBC, serologic assessment for the TORCH pathogens including toxoplasmosis, CMV, HSV, rubella, as well as other viruses such as parvovirus B19, Coxsackie, and adenovirus.

Once the diagnosis has been established, the patient must be counseled regarding the prognosis for the pregnancy. The perinatal mortality rate remains greater than 50%, and may be as high as 100% according to some studies13-16 (Level III). The overall prognosis is related to the underlying etiology of the hydrops. In addition, the gestational age at which the hydrops was noted impacts the prognosis. As noted earlier, hydrops with pleural effusions that develops prior to 20 weeks of gestation is associated with an increased risk of pulmonary hypoplasia and its associated morbidity. Aneuploid fetuses, as well as those with structural abnormalities are at greater risk of fetal demise17,18 (Level III). Additional risks include preterm labor and premature rupture of membranes due to uterine overdistention. Premature delivery is independently associated with adverse outcomes, and these may be potentiated in a compromised fetus.

Given the poor prognosis associated with nonimmune hydrops, termination of the pregnancy may be considered. Management of an ongoing pregnancy should include therapeutic interventions specific to the etiology of the hydrops. For example, in cases of fetal anemia due to parvovirus infection, red blood cell transfusion should be considered. Antenatal surveillance should include serial fetal testing to assure overall fetal well-being. There is no established frequency for antenatal fetal testing, but several authors recommend weekly or twice weekly fetal surveillance. Delivery may be indicated depending upon the results of such testing, and should occur at a tertiary care center with neonatal staff available. A neonatal consultation and possibly pediatric subspecialty consultations should be obtained prior to delivery.

Maternal risks at the time of delivery include soft tissue trauma due to an edematous fetus, postpartum hemorrhage, and retained placenta. However, cesarean delivery should be reserved for the usual obstetric indications.

Comprehension Questions

44.1 In a fetus with new-onset hydrops related to parvovirus B19 infection at 29 weeks, what is the most appropriate screening test for fetal anemia?

A. Fetal blood sampling

B. Biophysical profile testing

C. Umbilical artery Doppler study

D. Middle cerebral artery Doppler study

E. Delivery and neonatal CBC

44.2 A 26-year-old G2P0 presents at 21 weeks with fetal hydrops. What is the initial workup for this patient following the anatomy ultrasound?

A. Fetal blood sampling

B. Fetal surveillance with BPP

C. Fetal karyotype

D. Fetal MRI

44.3 A 38-year-old G3P2 with Graves disease presents with size greater than dates at 23 weeks. She has two small children at home with a viral illness and nausea/vomiting. An ultrasound shows fetal hydrops. What is the most likely etiology of the hydrops?

A. Fetal cardiac anomaly

B. Acute parvovirus infection with fetal anemia

C. Listeria transplacental infection

D. Antibody mediated high-output cardiac failure

E. Feto-maternal hemorrhage

ANSWERS

44.1 D. Middle cerebral artery Doppler study has a high sensitivity for predicting fetal anemia.

44.2 C. Amniocentesis for fetal karyotype is the next step in the evaluation of fetal hydrops.

44.3 A. Fetal cardiac abnormality is the most likely underlying etiology for NIH accounting for approximately 40% of all cases.

Clinical Pearls

See US Preventive Services Task Force Study Quality levels of evidence in Case 1

➤ Hydrops fetalis is the sonographic finding of excess fluid in two or more fetal compartments (Level III).

➤ NIHF includes fetal hydrops not mediated by red cell antigens (Level III).

➤ The causes of NIHF are numerous and include infectious, genetic, metabolic, and structural organ system anomalies (Level II-3).

➤ Amniocentesis or CVS should be considered in all cases of NIHF (Level III).

➤ Infectious studies that should be obtained in NIHF include assays for toxoplasmodium, rubella, CMV, HSV, Coxsackie, adenovirus, parvovirus, and syphilis. These may be from maternal serology or amniotic fluid PCR studies (Level III).

➤ Coordination of care in continuing pregnancies should include consultation with neonatal staff and possibly pediatric subspecialists along with maternal-fetal medicine specialists (Level III).

REFERENCES

1. Sohan K, Carroll SG, De La Fuente S, et al. Analysis of outcome in hydrops fetalis in relation to gestational age at diagnosis, cause and treatment. Acta Obstet Gynecol Scand. 2001;80:726. Database review of fetal hydrops cases and survival rates. Prior to 24 weeks the most common association was fetal aneuploidy. After 24 weeks fetal cardiac arrhythmias, especially tachyarrhythmias and hydrothorax were the most common causes of hydrops. Though overall prognosis is still quite dismal, appropriate prenatal investigation and therapy may improve survival rates (Level III). 

2. Carlson DE, Platt LD, Medearis AL, Horenstein J. Prognostic indicators of the resolution of nonimmune hydrops fetalis and survival of the fetus. Am J Obstet Gynecol. 1990;163:1785 (Level III). 

3. Castillo RA, Devoe LD, Hadi HA, Martin S, Geist D. Nonimmune hydrops fetalis: clinical experience and factors related to a poor outcome. Am J Obstet Gynecol. 1986;155:812. A review of the sonographic detection of 21 cases of fetal hydrops. The perinatal mortality rate was 95% and the most common cause was lung hypoplasia. Two factors that were consistently associated with poor perinatal outcomes were sonographically detected malformation and the presence of persistent pleural effusions (Level III). 

4. Anandakumar C, Biswas A, Wong YC, et al. Management of non-immune hydrops: 8 years’ experience. Ultrasound Obstet Gynecol. 1996;8:196. By sonography 100 fetuses with NIFH were identified. Ten percent were related to aneuploidy. Twenty-six fetuses were candidates for in-utero therapies including IUT, direct fetal drug therapy, and fetal pleuro-amniotic shunting. In carefully selected cases, in-utero therapy may lead to improvements in fetal and neonatal survival (Level III). 

5. Moise KJ Jr, Carpenter RJ Jr, Hesketh DE. Do abnormal Starling forces cause fetal hydrops in red blood cell alloimmunization? Am J Obstet Gynecol. 1992;167:907 (Level II-2). 

6. Dizon-Townson DS, Dildy GA, Clark SL. A prospective evaluation of fetal pericardial fluid in 506 second-trimester low-risk pregnancies. Obstet Gynecol. 1997;90:958 (Level III). 

7. Di Salvo DN, Brown DL, Doubilet PM, et al. Clinical significance of isolated fetal pericardial effusion. J Ultrasound Med. 1994;13:291 (Level II-2). 

8. Callen P. Ultrasonography in Obstetrics and Gynecology. 4th ed. Philadelphia, PA: WB Saunders; 2000. 

9. Jones DC. Nonimmune fetal hydrops: diagnosis and obstetrical management. Semin Perinatol. 1995;19:447 (Level III). 

10. Romero R, Pilu G, Jeanty P, Ghidini A, Hobbins J. Prenatal Diagnosis of Congenital Anomalies. Norwalk, CT: Appleton and Lange; 1988. 

11. Arcasoy MO, Gallagher PG. Hematologic disorders and nonimmune hydrops fetalis. Semin Perinatol. 1995;19:502 (Level III). 

12. Chitkara U, Wilkins I, Lynch L, et al. The role of sonography in assessing severity of fetal anemia in Rh- and Kell-isoimmunized pregnancies. Obstet Gynecol. 1988;71:393 (Level III). 

13. Ismail KM, Martin WL, Ghosh S, et al. Etiology and outcome of hydrops fetalis. J Matern Fetal Med. 2001;10:175 (Level III). 

14. Graves GR, Baskett TF. Nonimmune hydrops fetalis: antenatal diagnosis and management. Am J Obstet Gynecol. 1984;148:563 (Level III). 

15. Heinonen S, Ryynanen M, Kirkinen P. Etiology and outcome of second trimester non-immunologic fetal hydrops. Acta Obstet Gynecol Scand. 2000;79:15 (Level III). 

16. Wy CA, Sajous CH, Loberiza F, Weiss MG. Outcome of infants with a diagnosis of hydrops fetalis in the 1990s. Am J Perinatol. 1999;16:561 (Level III). 

17. McCoy MC, Katz VL, Gould N, Kuller JA. Non-immune hydrops after 20 weeks’ gestation: review of 10 years’ experience with suggestions for management. Obstet Gynecol. 1995;85:578 (Level III). 

18. Iskaros J, Jauniaux E, Rodeck C. Outcome of nonimmune hydrops fetalis diagnosed during the first half of pregnancy. Obstet Gynecol. 1997;90:321 (Level III).

HomeHigh-Risk Obstetrics Case FileNonimmune Hydrops Case File