Anemia of Prematurity - Portal Neonatal

Massive edema of the newborn infant has been recognized for at least 3 centuries. While fetal
hydrops was considered idiopathic a century ago, a causal relationship with maternal-fetal blood
group incompatibilities was recognized soon after red cell antigens were identified. During the mid
years of this past century, fetal hydrops was considered to be primarily the consequence of severe
maternal isoimmunization to fetal blood group antigens foreign to the mother, most commonly those
in the Rhesus (Rh) family. 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 isoimz.
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. This conquest was quickly followed by
recognition that the nonimmune causes of hydrops were, in fact, more common than had been
suspected. Arbitrarily classifying fetal hydrops into these categories is probably no longer clinically
useful since so few current cases are immune, so many are nonimmune, and so many causes for
nonimmune hydrops are currently recognized.
Pathophysiology: Until recently, many speculations but few facts existed about the
pathophysiologic events leading to fetal hydrops. The bewildering heterogeneity of conditions
causing or associated with the syndrome added to the confusion. Studies in sheep, most of which
occurred in the past decade, provide a much clearer picture of fetal hydrops. 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, normal concentrations of serum proteins are found in a sizable proportion of human
hydrops. A closer look at the animal studies provides the clues necessary to piece together the
puzzle of 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. 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 elevated markedly, 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.
Placement of an inflatable tissue expander in the right chest, designed to mimic the effects of a
space-occupying chest mass, has been demonstrated to produce hydrops in fetal sheep. Of
particular note is the 400% rise in CVP, which accompanied both inflation of the expander and
development of fetal hydrops, as well as the parallel decline in CVP and resolution of hydrops when
the expander was deflated. Just how sensitive the fetus can be to obstruction of venous return is
demonstrated in another study in which fetal hydrops was induced by cannulation of 1 carotid artery
and 1 jugular vein or by catheter placement in a single jugular vein in the midgestation ovine fetus.