Nonimmune Hydrops Fetalis in the Stillborn

Abstract

To the Editor, I read with interest the excellent article by Taweevisit and Thorner that was recently published online [1]. The article describes a series of 78 stillborn fetuses with hydrops fetalis (HF) from the Central Region of Thailand. The purposes of the study were to analyze the etiology of HF by performing autopsy investigations and to identify the various causes of nonimmune HF (NIHF) occurring in Thailand. All cases were diagnosed as NIHF. The authors established that the most common cause of NIHF in their series was homozygous alphathalassemia, compatible with the geographic origin of the series. Among other results, the authors state that 9 cases (11.5%) had no identifiable etiology and that 2 cases (2.6%) presented a phenotype indicating a chromosomal or genetic disorder. A systematic review of the etiology of NIHF was recently published [2]. All 5437 reviewed cases were categorized using 14 classification groups. Among these 14 groups, the chromosomal group comprised chromosomal abnormalities and the syndromic group included syndromes defined as clusters of structural malformations, while the idiopathic group comprised undiagnosed cases. The link between a cause and the mechanism that may trigger generalized edema of the fetus is not always clear. Although most of the 14 NIHF categories were assigned to a defined pathophysiological pathway that led to congestive heart failure, obstructed lymphatic flow, low-plasma colloid osmotic pressure, or, lastly, a combination of the above, it was not possible to reliably classify patients who had previously been assigned to the chromosomal or syndromic disorders groups. In this systematic review, the authors concluded that a definitive pathophysiological mechanism could not be identified in 33.6% of cases, including chromosomal (13.4%), syndromic (4.4%), and idiopathic (15.8%) groups. Although chromosomal or syndromic entities make up a great deal of reported causes of NIHF, I feel that these disorders are not NIHF causes per se. In an attempt to reduce the unacceptably high number of ‘‘nondiagnosed’’ (or only apparently diagnosed) cases, autopsy examination is strongly recommended. The usefulness of immunohistochemical staining techniques in the etiologic diagnosis of NIHF was recently described [3]. Seventy-nine fetuses with a diagnosis of NIHF (out of a total of 1098 fetuses) were studied using antibodies that specifically stain blood and lymph vessels (CD31, CD34, smooth muscle actin antibody, D2-40). This study demonstrated that applying a standard autopsy protocol, very similar indeed to Taweevisit and Thorner’s methods, allowed for the identification of an etiologic diagnosis in only 42 of 79 cases. Adding immunohistochemical methods and reevaluating all cases, a specific pathogenetic mechanism leading to NIHF was able to be identified in an additional 17 fetuses (59/79). The difference was statistically significant (chi-square test; P 5 0.005). This study underlined that a pathogenetic mechanism of NIHF (ie, lymph-vessel dysfunction linked to congenital dysplasia), although rarely recognized and only speculated, in fact should seriously be taken into consideration. Although immunohistochemical staining methods to detect lymphatic dysplasia are widely available, they are not usually included in the standard protocol for fetal autopsy studies. The article [3] concluded that specific immunohistochemical techniques should be mandatory in the autopsies for fetuses with NIHF.