We performed a systematic review of the literature to evaluate the incidence and types of lysosomal storage disorders (LSDs) in case series of nonimmune hydrops (NIH). PubMed and Ovid were reviewed for case series evaluating the workup of NIH diagnosed in utero or in the neonatal period in human subjects. Search terms were as follows: nonimmune hydrops, non immune hydrops, metabolic genetic disorders, and lysosomal storage disorders. The time period searched was 1979 through January 2014. Retrospective case series with at least 5 cases of fetal and/or neonatal NIH with its workup mentioned were identified. Idiopathic NIH was defined as NIH without an apparent cause after an initial workup. Exclusion criteria included studies published in languages other than English and review articles. The 3 authors screened all abstracts and manuscripts independently. Metaanalysis of Observational Studies in Epidemiology guidelines were followed. Fifty-four case series with 678 total cases of NIH were identified. The overall incidence of LSD was 5.2% (35 of 678) in all NIH cases that tested for any LSD and 17.4% (35 of 201) in idiopathic NIH cases. The 3 most common LSDs identified in cases of NIH, in order of decreasing incidence, were Mucopolysaccharidosis type VII, Gaucher’s disease, and GM1-gangliosidosis. LSDs occur in 5.2% of all NIH cases and in 17.4% of idiopathic NIH cases and so should be screened for in this clinical scenario. Additionally, if a comprehensive LSD workup is completed on idiopathic cases, 29.6% of those would be reclassified as LSD. LSD testing does not only allow diagnosis but also ensures better counseling, appropriate management, and planning for possible early intervention. Moreover, their detection may aid in a prenatal diagnosis in subsequent pregnancies.
Hydrops fetalis is a life-threatening fetal state that is defined by the pathologically increased fluid accumulation in fetal soft tissues and body cavities. Specifically, hydrops fetalis is diagnosed by the presence of 2 or more abnormal fluid collections in the fetus including ascites, pleural effusions, pericardial effusions, and skin edema. This condition is diagnosed by prenatal ultrasound. A subset of hydrops fetalis that is classified as nonimmune hydrops fetalis (NIH) is comprised of cases that are not caused by red blood cell alloimmunization. NIH accounts for almost 90% of cases of hydrops, with an incidence of 1 in 1700-3000 pregnancies.
NIH is the end-stage manifestation of several disorders. The differential diagnosis is extensive ( Table 1 ), and the success in identifying a cause depends on the extent of the workup. Table 2 represents an example of a basic pre- and postnatal workup for NIH. Although older studies report many cases as idiopathic, recent larger series and a recent systematic review report that a cause can be found in up to 85% of cases. Some of the most common causes of NIH are cardiac disorders (both structural malformations and arrhythmias), other structural malformations, chromosomal anomalies, infections, and hematological abnormalities.
| Conditions associated with NIH | Approximate percentage of NIH associated with condition |
|---|---|
| Cardiovascular | 30% |
| Fetal arrhythmias | |
| Structural | |
| Cardiac/thoracic mass | |
| High cardiac output failure | |
| Vascular disorders | |
| Extracardiac anomalies | 20% |
| Thorax | |
| Urinary | |
| Gastrointestinal | |
| Skeletal dysplasias | |
| Chromosomal abnormalities | 20% |
| 45x (or mosaic 45X/46XX) trisomy 21, trisomy 18, trisomy 13, triploidy | |
| Infections | 10% |
| Hematologic | 5-10% |
| Red cells loss | |
| Underproduction | |
| Monochorionic twin pregnancy | 5% |
| Metabolic/genetic syndromes | 2-6% |
| Step 1: prenatal | Step 1: neonatal a |
|---|---|
| Maternal work up | Blood |
| CBC (MCV in particular), hemoglobin electrophoresis, RPR, Kleinhaur-Betke, serology for parvovirus, CMV, toxoplasmosis, rubella | Urea, electrolytes, creatinine, protein, albumin, protein electrophoresis, liver function tests, bilirubin, osmolality, CBC, hemoglobin electrophoresis, serology for parvovirus, CMV, toxoplasmosis, rubella, karyotype, microarray |
| Urine | |
| Albumin–exclude congenital nephrotic syndrome | |
| Fetal workup | Ascitic fluid/pleural fluid |
| Detailed anatomy ultrasound, including MCA PSV; fetal echocardiography, microarray | Protein, albumin, lipid analysis to check for chylous secretion, micro, virology, microarray |
| Other | |
| Chest X-ray, electrocardiogram, ultrasound of heart, kidney, brain, autopsy |
| Step 2: prenatal | Step 2: neonatal a |
|---|---|
| LSD testing | LSD testing |
Materials and methods
Lysosomal storage disorders (LSDs) have been reported to account for about 1-15% of the causes of NIH cases, yet in clinical practice, these LSDs are often not evaluated. Our objective was to evaluate, by review of the literature, the significance of LSDs as the underlying etiology of NIH and whether evaluating for LSDs would be clinically useful in the workup of NIH.
Methods for review
PubMed and Ovid were reviewed for case series evaluating the workup of NIH diagnosed in utero or in the neonatal period in human subjects. Search terms were as follows: nonimmune hydrops, non immune hydrops, metabolic genetic disorders, and lysosomal storage disorders. The time period searched was 1979 through January 2014. Exclusion criteria were studies published in languages other than English, abstracts, unpublished studies, and review articles. Hand searching was also done using reference lists of obtained articles. The literature search was done by 2 investigators (A.C.G. and V.B.).
Retrospective studies and case series with cases of NIH with its workup described were identified. We included manuscripts with at least 5 cases of NIH to minimize publication bias. The criteria for the diagnosis of NIH were recorded. Three reviewers (A.C.G., V.B., and P.L.) screened all abstracts and manuscripts independently. Articles were screened for comparability of cases, and large studies were reviewed for overlapping cases. References for included articles are provided in the Reference section, and references excluded from the article are available from the authors upon request.
In each article reporting the workup of NIH, the details of the workup (eg, ultrasound, karyotype, etc) were recorded, including any metabolic tests, such as LSD. Pre- vs postnatal workups were recorded. If no diagnosis was identified as the probable cause for the NIH after the initial workup, the case was defined as idiopathic.
Each case series with 5 or more cases of NIH was evaluated for testing for LSD. LSD was defined as a category of metabolic disorders caused by defects in the lysosomal function, resulting in the accumulation of undegraded materials that triggers a cascade of pathological outcomes. The Methods section of each article was evaluated to see which LSDs were screened and how many of the cases of NIH received this LSD screening ( Table 3 ). Only cases of LSD confirmed by enzymatic or genetic tests were included. Which LSDs were the most commonly tested for was evaluated.
| Author/year (oldest to newest) | Location | Cases of NIH | Criteria for diagnosis of NIH | NIH initial workup | List of metabolic diseases tested for | Prenatal vs postnatal workup | Comments |
|---|---|---|---|---|---|---|---|
| Mahony et al, 1984 | United States | 27 | Generalized skin thickening… and/or ≥2 of the following: placental enlargement, pericardial effusion, pleural effusion, and ascites | Ultrasound, other workup not specified | Not specified | Prenatal | |
| Im et al, 1984 | Canada | 20 | By ultrasound: a double fetal abdominal or scalp contour and fetal ascites. Postmortem generalized edema, accumulation of fluid in fetal serous compartments, and edema throughout placenta | Ultrasound, other workup not specified | Not specified | Both | |
| McFadden and Taylor, 1989 | Canada | 90 | NIH listed as a diagnosis (from autopsy) or with criteria for the diagnosis of NIH | Autopsy | Not specified | Postnatal | |
| McCoy et al, 1995 | United States | 82 | Presence of excess fluid in ≥2 sites | Thoracentesis, paracentesis, autopsy, karyotype, detailed ultrasound | Not specified | Both | 51% diagnosed before autopsy; karyotypes were available for 14/18 idiopathic cases |
| Rejjal et al, 1996 | Saudi Arabia | 17 | Presence of ≥2 of the following features by prenatal ultrasound: generalized gross subcutaneous edema, ascites, pleural effusion, pericardial effusion, plus the absence of antibodies to red blood cell antigens | Ultrasound, maternal antibody screen, echocardiogram, CBC, chromosomal analysis, TORCH, and parvovirus B19 testing | Not specified | Both | |
| Groener et al, 1999 | The Netherlands | 17 | Excessive fluid accumulation within fetal extravascular compartments and body cavities in cases not caused by red cell alloimmunization | Fetal blood samples | GM1-gangliosidosis Gaucher’s disease Mucopolysaccharidosis IVa Mucopolysaccharidosis VII | Prenatal | |
| Recep, 2001 | Turkey | 30 | Edema with effusion in at least 1 body cavity and skin edema or serous effusion in >1 body space | Ultrasound, maternal type and screen, TORCH titers, parvovirus B19 testing, karyotype, autopsy, echocardiography, and metabolic testing | Investigation for metabolic syndromes in selected cases | Both | |
| Mascaretti et al, 2003 | Brazil | 29 | One or more clinical signs, such as anasarca, peripheral edema, ascites, pericardial and/or pleural effusions, anemia, congestive heart failure, and hypoalbuminemia | Autopsy, ultrasound, echocardiography, karyotype, infectious workup, CBC, maternal type, and screen | Not specified | Both | |
| Burin et al, 2004 | Brazil | 33 | Not specified | Specific enzymatic analysis for lysosomal storage disorders by amniocentesis, autopsy, karyotype, viral studies, TORCH titers, parvovirus testing, coxsackie testing, fetal echocardiography, hemoglobin electrophoresis CBC, maternal type and screen, detailed ultrasound | Gaucher’s disease GM1-gangliosidosis Mucopolysaccharidosis I Mucopolysaccharidosis II Mucopolysaccharidosis IVa Mucopolysaccharidosis VII Niemann-Pick A/B Mucolipidosis II Sialic acid storage disease Sialidosis | Both | Reference center for LSDs |
| Favre et al, 2004 | France | 79 | Fetal ascites | Detailed ultrasound, fetal echocardiography, maternal type and screen, TORCH titers, parvovirus B19 testing, karyotype, amniocentesis for cytomegalovirus, parvovirus, toxoplasmosis, cystic fibrosis screening, autopsy | Not specified | Postnatal | This study looked at both fetal hydrops and isolated ascites |
| Rodriguez et al, 2005 | United States | 32 | Generalized soft tissue edema and presence of fluid in at least 1 of the pericardial, pleural, and peritoneal cavities | Ultrasound, CBC, maternal type and screen, rapid plasma reagin, blood cultures, autopsy, infectious workup | Tested enzyme levels on autopsy | Postnatal | One of the idiopathic fetuses had “histologic features of a lysosomal storage disease … but specific enzymatic defect could not be proved” |
| Kooper et al, 2006 | The Netherlands | 75 | Presence of excessive fluid in >1 body cavity | Not specified | GM1-gangliosidosis Gaucher’s disease Niemann-Pick A/B Mucopolysaccharidosis I Mucopolysaccharidosis VII Sialidosis | Postnatal | Four definite cases and 2 probable cases of LSDs. This is a study evaluating reference values of lysosomal enzymes in NIH. |
| Gort et al, 2012 | Spain | 30 | Excessive fluid accumulation in >1 fetal compartments and body cavities | LSDs were investigated in all, amniocentesis | Gaucher’s disease GM1-gangliosidosis Mucopolysaccharidosis VII | Prenatal | Reference center for LSDs |
| Moreno et al, 2013 | Brazil | 53 | All patients with NIH referred to their center | Detailed ultrasound, fetal echocardiography, karyotype, TORCH titers, CBC, hemoglobin electrophoresis, inborn errors of metabolism testing, autopsy | GM1-Gangliosidosis Gaucher’s disease Mucopolysaccharidosis I Mucopolysaccharidosis II Mucopolysaccharidosis IVa Mucopolysaccharidosis VII Mucolipidosis II Niemann-Pick A/B Sialidosis Sialic acid storage disorders | Both | Reference center for LSD |
| Hasnani-Samnani et al, 2013 | Qatar | 64 | Signs suggesting NIH | CBC, thalassemia screening, Kleinhauer-Betke, TORCH titers, parvovirus B19 testing, karyotype, echocardiography, MCA Dopplers, detailed ultrasound | Metabolic investigation… was done for only a few cases and was negative | Both | |
| Total cases | 678 |
Our primary outcome was the incidence of any LSD in the studies of NIH in which LSDs were tested. The Metaanalysis of Observational Studies in Epidemiology guidelines were followed for systematic review of observational studies. This study was exempt from institutional review board approval.
Results
The Figure reports the data extraction. Of the 54 case series reporting a workup for NIH, 15 (27.8%) reported testing for LSD. In these 15 series, a diagnosis as probable etiology for NIH was detected in 512 of 678 cases (75.5%) ( Tables 3 and 4 ). One study reported genetic diagnoses but did not define what was included in that category. Another series had 10 cases of LSDs, but not all were NIH and we were unable to find out which cases were associated with NIH and which ones were not correlated.
