Fetal Hydrops - Clinical Tree

Key Points

Hydrops fetalis is a pathological condition of excessive fluid accumulation in at least two extravascular compartments, including fetal soft tissues and body cavities. Hydrops fetalis is a clinical finding and not a final diagnosis.
There are two main pathophysiologies for hydrops fetalis, immune and nonimmune. For nonimmune, the diagnostic categories are placental, cardiovascular, chromosomal, haematologic, lymphatic dysphasia, infection, thoracic malformations, genetic syndromes, inborn errors of metabolism, extrathoracic tumours and genitourinary tract and gastrointestinal malformations. Undiagnosed causes are still common.
Hydrops fetalis should be considered as an urgent finding with timely evaluation, which requires a directed ‘stepwise approach’.
Fetal hydrops can cause a maternal physiological disturbance, mirror syndrome, with possible severe maternal consequences.
Fetal therapy is an option for certain causes of hydrops but requires complete evaluation and informed consent before its use.
Prognosis and recurrence risk counselling is dependent on the underlying cause, but overall the mortality rate remains high. If no specific diagnosis is made prenatally, autopsy should be offered for all perinatal losses because a significant proportion of cases have a genetic cause with risk of recurrence in future pregnancies.

Introduction

Hydrops fetalis (fetal hydrops) is a pathologic condition of excessive accumulation of fluid in at least two extravascular compartments, including fetal soft tissues and body cavities. It is the physiological end-stage process in a number of fetal conditions and placental pathologies. The underlying causes are classified under two major categories, immune and nonimmune. In countries that have introduced immunoglobulin prophylaxis for Rhesus-D alloimmunisation, the incidence of immune fetal hydrops has significantly decreased, and in these countries, represents only 10% to 15% of fetal hydrops cases. Nonimmune fetal hydrops has a reported incidence of 1 in 2000 to 3000 pregnancies but accounts for a disproportionate share (3%) of overall mortality in the perinatal period. There is a broad spectrum of well-recognised causes, and with the use of next-generation sequencing (NGS) technology, an increasing number of single-gene disorders are being diagnosed in cases of fetal hydrops. Determining the cause of the fetal hydrops is important because some conditions are treatable. Furthermore, knowing the underlying cause provides additional information that may be useful to predict the prognosis and is a key element to determine recurrence risk in future pregnancies.

Diagnosis of Hydrops Fetalis by Ultrasound

The diagnosis of immune (IHF) or nonimmune hydrops fetalis (NIHF) requires an abnormal fluid accumulation in two or more fetal body compartments. Body compartments (and the fluid collections) are designated as subcutaneous space (skin oedema or cystic hygroma [CH]), pleural space (pleural effusion), pericardial space (pericardial effusion) and abdomen (ascites).

Subcutaneous skin or scalp oedema requires an ultrasound measurement or thickness of at least 5 mm ( Fig. 36.1 ). The fluid collection over the scalp or forehead can be identified with the use of both the transverse and sagittal planes. Skin thickening of at least 5 mm is required because some macrosomic fetuses may have thickened skin secondary to fat deposition measuring up to 5 mm.

• Fig. 36.1, Axial sections of the head ( A ) and abdomen ( B ) of a first trimester fetus with significance skin oedema.

Cystic hygroma is a cystic lymphatic lesion. It can be a single or multiple congenital cysts, most commonly found within the soft tissues of the neck. Generally, the CH is bilateral, asymmetric, with thin-walled, multiseptate cystic lesions, and often located posterior and lateral to the high cervical vertebrae. Nuchal CH is the clinical consequence of a delay in development or absence of the communications that normally develop between the jugular lymph sacs and the internal jugular veins at approximately 40 days of gestation.

Pleural effusion is an accumulation of fluid in the pleural space. Effusion composition can be either chylous or clear (hydrothorax) with most primary congenital effusions being chylous and occurring on the right. Ultrasound identifies an anechoic space peripherally around the compressed lung. If the effusion is unilateral and large, there may be additional mediastinal shift; bilateral effusions can be either symmetric with no shift or asymmetric with shift ( Fig. 36.2 ).

• Fig. 36.2, A, Moderate pleural effusion that is essentially unilateral. B, Severe bilateral pleural effusion.

Pericardial effusion is identified by the appearance of an echolucent rim greater than 2 mm around both cardiac ventricles ( Fig. 36.3 ). Pericardial effusions of 1 to 2 mm are considered a physiological fluid collection.

• Fig. 36.3, Transverse four-chamber view of the heart showing an abnormal pericardial effusion.

Fetal ascites is identified by ultrasound by visualisation of an echolucent fluid rim encompassing the entire fetal abdomen in the transverse view, usually at the level of the umbilical cord insertion or liver. The echolucent collection of fluid outlines the visceral contents ( Fig. 36.4 ).

• Fig. 36.4, Axial sections of the fetal abdomen showing a subtle rim ( A ) and a moderate collection of fetal ascites ( B ).

Pathophysiology

Fetal hydrops is the result of abnormal fluid movement between the plasma and tissues that leads to excess fluid in both the tissues and serous cavities (skin oedema, ascites, pleural and pericardial effusions). Four main mechanisms have been postulated to explain this abnormal distribution of body fluids: (i) an increase in hydrostatic capillary pressure (resulting for primary or secondary heart failure or from obstruction of venous return), (ii) a reduction in plasma osmotic pressure (from decreased albumin production or increased albumin loss), (iii) obstruction or reduction of lymphatic flow and (iv) damage to peripheral capillary integrity. Table 36.1 provides examples of conditions linked to each mechanism. In some conditions, more than one mechanism may be involved.

TABLE 36.1

Mechanisms of Abnormal Fluid Distribution in Hydrops Fetalis Conditions

Adapted from Randenberg AL. Nonimmune hydrops fetalis part I: etiology and pathophysiology. Neonatal Netw 29 (5):281–295, 2010.

Mechanism	Hydrops fetalis conditions
Increased hydrostatic capillary pressure	Fetal congestive heart failure caused by fetal arrhythmias, congenital heart disease, obstructive intracardiac tumour, fetal anaemia Elevated central venous pressure secondary to high intrathoracic pressure caused by intrathoracic masses or heart failure
Reduced intravascular osmotic pressure	Fetal hypoalbuminaemia secondary to haepatic failure seen in metabolic conditions or increased albumin loss seen in chylothorax or nephrotic syndrome
Obstructed or reduced lymphatic flow	Disorders associated with abnormal lymphatic development (e.g., Down syndrome, Noonan syndrome, primary lymphangiectasia) or with decreased lymph flow associated with reduced fetal movement (e.g., fetal akinesia sequence, multiple pterygium syndrome)
Damaged peripheral capillary integrity	Conditions of fetal hypoxemia caused by fetal anaemia or placental insufficiency Conditions of fetal inflammation caused by fetal infection

Aetiology

Immune Fetal Hydrops

Maternal sensitisation to a fetal red blood cell (RBC) antigen (usually from a previous pregnancy) is followed in the next pregnancy by transplacental passage of the circulating maternal IgG antibody against that red blood cell antigen resulting in fetal haemolytic anaemia, and if severe, fetal hydrops. The severity of the haemolytic process is dependent on the antigen–antibody involved and the maternal antibody load. Chapter 40 details the diagnosis and management of RBC alloimmunisation. This aetiology for hydrops will not be further discussed in this chapter. However, in the approach to a fetus with fetal hydrops, immune fetal hydrops is an important condition to consider because it is one of the treatable causes with strong evidence-based approaches.

Nonimmune Hydrops Fetalis

Nonimmune hydrops fetalis has a variety of aetiologies. A systematic review of the aetiology of NIHF divided the affected cases into 14 classification groups ( Table 36.2 ). This section reviews the different NIHF aetiologies according to the same classification. Some of the aetiologies of NIHF are the focus of other chapters in this book. These aetiologies will only be mentioned briefly in this chapter.

TABLE 36.2

Aetiologic Classification of Nonimmune Hydrops Fetalis With Percentage of Total Cases Each Category Represents, Most Frequent Pathologies and Fetal Therapy Specific to Each Aetiology

Category	Organ or System	Most Frequent Pathologies	Fetal Therapy
Placental or umbilical cord	Placenta or umbilical cord (5.3%)	Vascular shunting, TTTS, TRAP, chorioangioma	Endoscopic laser, RFA


Cardiovascular (21.4%)	Abnormal structural Arrhythmias Tumour	Balloon dilatation for stenotic valves Systemic or fetal medication No prenatal option
Chromosomal (12.5%)	Trisomy 21, trisomy 18, Turner syndrome	No option
Haematologic (10.1%)	α-Thalassemia other rare inherited forms of anaemia	IUT in selected cases
Lymphatic dysplasia (7.5%)	Chylothorax Congenital lymphatic dysplasia Noonan syndrome	Percutaneous shunt or pleurodesis
Infection (6.8%)	Parvovirus B19, CMV, toxoplasmosis, syphilis, varicella, rubella	IUT for anaemia seen with parvovirus B19 only
Thoracic malformations (5.3%)	Diaphragmatic hernia CPAM	Experimental balloon tracheal occlusion Steroids, RFA, percutaneous shunt, pleurodesis
Syndromic (4.6%)	Multiple pterygium, fetal akinesia, skeletal dysplasias	No option
Genitourinary tract (2.0%)	Finnish nephrosis Bladder outlet obstruction	No option Shunt, percutaneous cystoscopy
Inborn errors of metabolism (1.1%)	Lysosomal storage disorders	No option
Extrathoracic tumours (0.7%)	SCTs	Open fetal surgery
Gastrointestinal (0.7%)	Meconium peritonitis, intestinal atresias	No option
Miscellaneous (3.7%)
Idiopathic (18.2%)		Case by case

CPAM, Congenital pulmonary airway malformation; CMV, cytomegalovirus; IUT, intrauterine transfusion; RFA, radiofrequency ablation; SCT, sacrococcygeal teratoma; TRAP, twin-reversed arterial perfusion; TTTS, twin-to-twin transfusion syndrome.

Twin-to-Twin Transfusion Syndrome and Placental Abnormalities

Twin-to-twin transfusion syndrome (TTTS) is a complication associated with monochorionic twins caused by an imbalance of the vascular communications in the placenta between the two fetuses and represents approximately 5% of cases of NIHF. Haemodynamic and osmotic changes in the fetuses can lead to fetal hydrops in the recipient twin most commonly, but donor fetal hydrops has been identified as well. (See Chapter 44 for more details on TTTS.)

Placental chorioangiomas are rare benign placental tumours. Large chorioangiomas act as peripheral arteriovenous shunts, leading to increased cardiac output, cardiomegaly and finally heart failure and hydrops. Some cases are complicated by fetal anaemia, which further contributes to the development of the heart failure and hydrops. Umbilical cord haemangiomas have also been reported with NIHF. (See Chapter 9 for more on placental pathology.)

Cardiovascular Conditions

Cardiovascular conditions are the primary aetiology in 21% of NIHF cases and are identified as the most common group of disorder leading to NIHF. The cardiovascular aetiology can be divided into structural malformations, arrhythmias, cardiac tumours and cardiomyopathy ( Table 36.3 ). (See Chapter 29 for more details on cardiovascular conditions.)

TABLE 36.3

Cardiovascular Conditions Associated With Nonimmune Fetal Hydrops

Cardiovascular Condition	Specific Diagnosis	Key Points
Congenital heart defect (CHD)	Hypoplastic left heart syndrome (HLHS)	Spectrum of disorders involving aortic atresia with or without mitral atresia or stenosis
	Atrioventricular (AV) canal defect	Involves both lower atrial and upper ventricular septal defects and a common AV valve orifice; prenatal prognosis is variable 70% are associated with other cardiac malformations Associated with trisomy 21
	Atrial septal defect	If large, may result in RV overload
	Ventricular septal defect	Most common congenital cardiac lesion Can be associated with tetralogy of Fallot or transposition of the great vessels
	Tetralogy of Fallot	Complex congenital cardiac malformation consisting of varying degrees of RV outflow tract obstruction, overriding aorta and RV hypertrophy
	Hypoplastic right heart syndrome	Less common than hypoplastic left heart syndrome
	Ebstein anomaly	Malformation of the tricuspid valve causing insufficiency and atrialisation of a significant portion of the RV Progression creates RV outflow tract obstruction and arrhythmias Prenatal diagnosis of Ebstein anomaly increases the obstructive or arrhythmia risk because of the possible severity, thereby allowing prenatal identification
	Truncus arteriosis	Fetal hydrops is rare Single cardiac outflow tract gives rise to the pulmonary, coronary and systemic circulations 40% associated with 22q11 deletion;
	Transposition of the great arteries (TGA)	Complete TGA results in separation of the systemic and pulmonary circulations and with the AV discordance results in severe hypoxia postnatally
	Aortic stenosis or atresia	Rare cases of critical aortic stenosis associated with hydrops
	Cardiomyopathy	Hypertrophic: most common causes are maternal diabetes, TTTS, Noonan syndrome and inborn errors of metabolism Dilated: most common causes are infection, endocardial fibroelastosis, dysrhythmia and carnitine deficiency
	Endocardial fibroelastosis	Thickening of the endocardium caused by a proliferation of cellular and elastic tissue; it can be associated with obstruction of the great vessels and familial inheritance Ultrasound imaging shows bright echogenic areas within the ventricular walls
	Premature closure of ductus arteriosus	Inhibitors of prostaglandin synthesis (e.g., indomethacin) can constrict the fetal ductus arteriosus both in vitro and in vivo This constriction effect is most pronounced after 30 weeks of gestation
	Premature closure of foramen ovale	Rare cardiac abnormality
Cardiac arrhythmia	Supraventricular tachycardia (SVT)	Prolonged duration with rate >200 beats/min is associated with hydrops Congenital heart disease is associated with SVT in 5%–10%
	Atrial flutter	Rate of 300–500 beats/min
	Bradyarrhythmia or congenital heart block (CHB)	Immune-mediated CHB (maternal SS-A and SS-B antibodies) can lead to permanent heart damage Congenital heart defects can be associated with CHB Associated cardiac malformations with CHB: LA isomerism, TGA, ASD, pulmonic atresia, anomalous pulmonary venous connection, double outlet right ventricle, AV discordance, absent right AV connection,double inlet ventricle, right atrial isomerism, pulmonic stenosis
Cardiac tumours	Rhabdomyoma	60%–80% fetal intracardiac tumours are caused by rhabdomyomas 60%–95% of rhabdomyomas are secondary to tuberous sclerosis (AD inheritance with a high rate of new mutations) Fetuses with intramural cardiac tumours are at an increased risk for cardiac arrhythmias and WPW syndrome
	Intrapericardial teratoma, fibroma, myoma	Fetuses with intramural cardiac tumours are at an increased risk for cardiac arrhythmias and WPW syndrome

AD, Autosomal dominant inheritance; ASD, atrial septal defect; AV, atrioventricular; LA, left atrial; RV, right ventricle; SVT, supraventricular tachycardia; TTTS, twin to twin transfusion syndrome; WPW, Wolf-Parkinson-White.

For structural cardiac malformations, fetal hydrops can result from lesions that place a burden on the right-sided cardiac chambers, resulting in increased right atrial pressure such as left-sided obstructive lesions, hypoplastic left heart syndrome or premature closure or restriction of the ductus venosus and right-sided obstructive lesions such as pulmonary and tricuspid atresia. Nonobstructive lesions that result in right atrial volume overload such atrioventricular canal defect are reported in fetal hydrops.

Fetal tachyarrhythmias are the second most common cardiovascular abnormality associated with fetal hydrops. This aetiology has evidenced-based treatment protocols with secondary reversal of the fetal hydrops. Fetal bradyarrhythmias are less commonly associated with fetal hydrops and are not easily treatable.

Intracardiac tumours represent a rare cause of fetal hydrops. The most common fetal cardiac tumour is a rhabdomyoma with fetal hydrops caused by tumour obstruction to cardiac flow or an associated arrhythmia. Cardiac rhabdomyomas are frequently a fetal manifestation of tuberous sclerosis (autosomal dominant condition) and when suspected prenatally should result in a careful family history and assessment of the couple. (Details on fetal tumours are provided in Chapter 37 .)

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