title: Noninvasive fetal RhCE genotyping from maternal blood.
abstract: BACKGROUND
  The successful prevention of RhD disease has brought attention to other red blood cells' antigens causing alloimmunisation including RhC/c and RhE/e. Prenatal diagnosis of fetal Rh genotype from maternal blood is in clinical use in Europe but not in the USA.
  
  
  OBJECTIVE
  To estimate the collective reported diagnostic accuracy of fetal RhCE genotyping from peripheral maternal blood and compare the results of genotyping when fetal cells and free fetal DNA (FfDNA) are used.
  
  
  METHODS
  English-written literature describing fetal RhCE determination from maternal blood using fetal cells or FfDNA was performed using medical subject headings and text words. The sources included Pubmed (1966-2007), Ovid (1966-2007), CINAHL, The Cochrane Library, ACP Journal Club and OCLC. Key words were prenatal diagnosis, fetal RhCE, fetal DNA in maternal blood and alloimmunisation.
  
  
  METHODS
  A study was considered eligible if it described fetal RhCE type determination using maternal peripheral blood reported in the English literature. Abstracts were excluded.
  
  
  METHODS
  From each study, we determined the number of samples tested, fetal RhCE genotype, the source of the fetal DNA, gestational age, presence of alloimmunisation and confirmation of fetal RhCE type. Exclusions and inclusions were noted. We calculated composite estimates of accuracy using a weighted random effects model. We assessed the papers against an international quality, STARD checklist which is standards for reporting studies of diagnostic accuracy.
  
  
  RESULTS
  We identified 20 protocols in six English-written publications reporting fetal RhC/c (seven protocols) and/or E/e (13 protocols) genotyping using DNA obtained from maternal blood for a total of 369 samples. For RhC/c, 176 samples were tested and for RhE/e, 193 samples were tested. Accuracy was determined for each study and for all studies. The combined accuracy of fetal genotype was 96.3% for RhC/c and 98.2% for RhE/e. Only a few samples of the sorted cells were found to be a source for accurate diagnosis, but plasma was consistently the best source of fetal RhCE genotyping in 147/147 (100%) for RhC/c and 168/168 (100%) for RhE/e.
  
  
  CONCLUSIONS
  The combined accuracy of noninvasive fetal RhC/c or RhE/e determination using maternal peripheral blood is 96.3% and 98.2%, respectively. FfDNA in maternal plasma is a better source for genotyping reported to be 100% correct for both RHCE genotypes. Further studies and reports of accuracy from laboratories performing the tests are required before prenatal determination of fetal RhC/c or RhE/e genotypes from maternal blood can safely replace the current methods used in the management of the RhC/c or RhE alloimmunised pregnancies.
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, Temple University School of Medicine, and Department of Obstetrics & Gynecology, Temple University Hospital, Philadelphia, PA 19140, USA. drgeifman@aol.com
authors.forename: O
authors.initials: O
authors.lastname: Geifman-Holtzman
authors.forename: C A
authors.initials: CA
authors.lastname: Grotegut
authors.forename: J P
authors.initials: JP
authors.lastname: Gaughan
authors.forename: E J
authors.initials: EJ
authors.lastname: Holtzman
authors.forename: C
authors.initials: C
authors.lastname: Floro
authors.forename: E
authors.initials: E
authors.lastname: Hernandez
mesh_terms: D004247:DNA / Q000097:blood; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D005838:Genotype; D006801:Humans; D011247:Pregnancy / Q000097:blood; D011296:Prenatal Diagnosis / Q000379:methods*; D012203:Rh Isoimmunization / Q000517:prevention & control; D012204:Rh-Hr Blood-Group System / Q000235:genetics*; D012680:Sensitivity and Specificity
chemical_list: D005819:Genetic Markers; C066468:RHCE protein, human; D012204:Rh-Hr Blood-Group System; D004247:DNA