Pediatric Hydrops Fetalis
- Author: Ashraf H Hamdan, MD, MBBCh, MSc, MRCP; Chief Editor: Ted Rosenkrantz, MD more...
Background
Hydrops fetalis (fetal hydrops) is a serious fetal condition defined as abnormal accumulation of fluid in 2 or more fetal compartments, including ascites, pleural effusion, pericardial effusion, and skin edema. In some patients, it may also be associated with polyhydramnios and placental edema. Hydrops is usually first recognized by ultrasound examination during the first or second trimester of gestation. Significant fluid collections are easily detected, but fluid accumulation may also be limited and thus escape routine ultrasound detection.
Hydrops fetalis has been a well-recognized fetal and neonatal condition throughout history. Until the latter half of the 20th century, it was believed to be due to Rhesus (Rh) blood group isoimmunization of the fetus. More recent recognition of factors other than isoimmune hemolytic disease that can cause or be associated with fetal hydrops led to the use of the term nonimmune hydrops to identify those cases in which the fetal disorder was caused by factors other than isoimmunization.
In the 1970s, the major cause of immune hydrops (ie, Rh D antigen) was conquered with the use of immunoglobulin (Ig) prophylaxis in at-risk mothers. Before routine immunization of Rh-negative mothers, most cases of hydrops were due to erythroblastosis from Rh alloimmunization. Currently, nonimmune hydrops fetalis is more common, comprising 76-87% of all described cases.
Pathophysiology
Several hypotheses regarding the pathophysiologic events that lead to fetal hydrops have been suggested. The basic mechanism for the formation of fetal hydrops is an imbalance of interstitial fluid production and the lymphatic return. Fluid accumulation in the fetus can result from congestive heart failure, obstructed lymphatic flow, or decreased plasma osmotic pressure. The fetus is particularly susceptible to interstitial fluid accumulation because of its greater capillary permeability, compliant interstitial compartments, and vulnerability to venous pressure on lymphatic return.
Compensatory mechanisms for maintaining homeostasis during hypoxia that results from underlying disease include increased efficiency of oxygen extraction, redistribution of blood flow to the brain, heart, and adrenals, thus causing renal tubular damage, volume augmentation to enhance cardiac output, and marked activation of the renin-angiotensin system. Unfortunately, these mechanisms increase venous pressure and ultimately produce interstitial fluid accumulation and characteristic hydropic changes in the fetus. Increased venous pressure and contributes to edema and effusion by increasing the capillary hydrostatic pressure and decreasing the lymphatic return. Impaired renal function causes oliguria or anuria and subsequently hydrops.[1]
Furthermore, the hepatic synthesis of albumin may be impaired because of decreased hepatic perfusion and increased extramedullary hematopoiesis. Because albumin acts as the predominant oncotically active plasma protein, hypoalbuminemia increases transcapillary fluid movement at times of circulatory compromise.
Hydrops has been produced in the ovine fetus by anemia, tachyarrhythmia, occlusion of lymphatic drainage, and obstruction of cardiac venous return. Hypoproteinemia and hypoalbuminemia are common in human hydrops, and reduced intravascular oncotic pressure has been speculated to be a primary cause for the disorder. However, in the sheep model, a 41% reduction in total serum protein accompanied by a 44% decline in colloid osmotic pressure failed to produce fetal hydrops. Furthermore, a study in humans showed that, despite a significant negative correlation between the fetal serum albumin level and the degree of fetal hydrops, most fetuses with hydrops had albumin levels within the reference range.[2] These results suggest that hypoalbuminemia is unlikely to cause the primary onset of hydrops.
A closer look at the animal studies provides the clues necessary to understand the pathophysiology of hydrops. In one study, profound anemia was induced in fetal sheep; the hydrops that resulted was unrelated to hematocrit levels, blood gas levels, acid-base balance, plasma proteins, colloid oncotic pressure, or aortic pressure.[3] A difference was found in central venous pressure (CVP), which was much higher in persons with hydrops. The hematocrit level was reduced by 45% in a study of particular notation; however, CVP was maintained unchanged, and no fetus developed hydrops under these conditions.
Induced fetal tachyarrhythmia has led to fetal hydrops in several studies. Key to the development of fetal hydrops in these studies was an elevation in CVP; the anemia was only of indirect importance. CVP was markedly elevated, with a range of 25-31 mm Hg in one study. In other reports, hydrops induced by sustained fetal tachycardia was unrelated to blood gases, plasma protein, or albumin turnover; however, a 75-100% increase in CVP was observed in the fetuses that developed hydrops.
Excision of major lymphatic ducts produces fetal hydrops in the sheep model. A related study demonstrates an exquisite, linear, inverse relationship between lymphatic outflow pressure and CVP; a rise in CVP of 1 mm Hg reduces lymph flow 13%, and flow stops at a CVP of 12 mm Hg. These results are confirmed by other observations of linear decline in lymph flow when CVP exceeds 5 mm Hg and a cessation of flow at CVPs greater than 18 mm Hg.
Also of note is a computer simulation model in which cardiovascular and fluid electrolyte disturbances (eg, severe anemia, lymphatic obstruction, excess fluid and electrolyte loads, elevation in angiotensin levels) and compensating homeostatic mechanisms have been examined. This model demonstrated that "...fetal cardiac failure constituted the strongest stimulus for the formation of fetal edema..."[4] , thus further substantiating the pivotal role of CVP in the development of fetal hydrops.
Many other physiologic disturbances are associated with human fetal hydrops. Elevations in aldosterone, renin, norepinephrine, and angiotensin I levels are likely to be secondary consequences. Although infusion of angiotensin I led to fetal hydrops in nephrectomized sheep, the 4-fold rise in CVP was probably the primary cause of the hydrops. The meaning of increased levels of coenzyme Q10, placental vascular endothelial growth factor, and endothelin and decreased cytokine interleukin-3 levels is unclear at this time.
However, of particular interest is the 3-fold to 5-fold increase in atrial natriuretic peptide (ANP) that accompanies both human fetal hydrops (with cardiac anomaly or isoimmunization) and ovine hydrops (induced by obstruction of venous return, sustained tachycardia, or induced anemia). A return of ANP levels to normal parallels the resolution of hydrops. These observations and the observations that vascular permeation of albumin is enhanced and cardiovascular and renal homeostatic adaptations are influenced by this peptide suggest an important role for ANP in fetal hydrops.
Evidence of low fetal plasma levels of cyclic guanosine monophosphate suggests that reduced nitric oxide production due to injury of fetal vascular endothelial cells may be involved in the development of fetal hydrops. This isolated observation requires confirmation and further study.
Despite numerous case reports, decades of clinical experience, and several research studies regarding the etiology and pathogenesis of hydrops, many questions still remain. Currently, which fetal neural and hormonal mechanisms induce and maintain the redistribution of blood flow, and which mechanisms allow metabolic disorders to cause hydrops, are almost completely unknown.[1]
Epidemiology
Frequency
United States
The precise incidence of hydrops fetalis is difficult to elucidate, because many cases are not detected prior to intrauterine fetal death and some cases may resolve spontaneously in utero. The best estimate for how common hydrops fetalis is in the United States is approximately 1 in 600 to 1 in 4000 pregnancies. The incidence of immune hydrops has significantly decreased with the wide use of passive immunization using Rh immunoglobulin for Rh-negative mothers at 28 weeks' gestation (following suspected fetomaternal hemorrhage) and postpartum (following the delivery of an Rh-positive infant). The efficacy of this program has been demonstrated by a decline in the incidence of Rh hemolytic disease of the fetus or newborn, from 65 in 10,000 births in the United States in 1960 to 10.6 in 10,000 births in 1990.
International
Hydrops fetalis is much more common in Southeast Asia. The best figures come from Thailand, where the expected frequency of hydrops, from homozygous alpha-thalassemia or Bart hydrops alone, is 1 in 500 to 1 in 1500 pregnancies.[5] Accurate figures from the Mediterranean region are not available; however, the commonness of glucose-6-phosphate dehydrogenase (G-6-PD) deficiency and of defects in alpha-chain hemoglobin production in several populations from this region lead to the suspicion that the incidence of hydrops in that region is much higher than it is in the United States.
Mortality/Morbidity
Estimates of mortality vary widely, from nearly zero to virtually 100%. Most case series report 60-90% mortality, although some improvements are notable in more recent reports. Many causes for these variations are recognized, not the least of which include the sophistication of diagnostic methods used and the complexity and costs of treatment. However, the most important single factor is the cause of the hydrops. A significant proportion of these cases are caused or accompanied by multiple and complex congenital malformations of genetic and/or chromosomal origin, which by themselves are fatal at an early age. Many other causes are accompanied by masses or fluid accumulations, which compress the developing fetal lung and preclude its normal development. Thus, the presence or absence and potential prevention of pulmonary hypoplasia are of crucial importance.
Another highly important factor is the very premature delivery of most babies with hydrops consequent to conditions that distend the uterus and provoke early labor or to therapeutic interventions (eg, fetal thoracentesis, paracentesis, complex fetal surgical procedures).
One study showed that mortality rate was highest among neonates with congenital anomalies and lowest among neonates with congenital chylothorax.[6] Infants who died were more likely to be more premature, were sicker after birth (with lower 5-minute Apgar scores), and needed higher levels of support during the first day after birth.
Race
Ethnic influences are related almost entirely to cause. Selected examples include the importance of genetic variations in the alpha-chain structure of hemoglobin in Asian and Mediterranean populations in addition to the more serious nature of the hemolytic disease in the African American fetus affected by maternal ABO-factor isoimmunization.
Sex
Sex influences in incidence or outcome of hydrops fetalis are largely related to the cause of the condition. A significant proportion of hydrops is caused by or associated with chromosomal abnormalities or syndromes. Many of these are X-linked disorders.
Because most individuals with hydrops fetalis are delivered quite prematurely, and because fetal pulmonary maturation takes place earlier in female than in male fetuses, male preterm infants are at greater risk for the pulmonary complications of very preterm delivery. They are also at greater risk for infections (nosocomial or otherwise), which are quite common in the very preterm infant. A striking example of greater male risk is the nearly 13-fold increase in the odds ratio for development of hydrops in the male fetus with Rh D hemolytic disease. Although a single precise risk figure is not available for the heterogenous collection of cases that comprise hydrops fetalis, male fetuses appear to have greater risk for occurrence, morbidity, and mortality.
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