PRENATAL DIAGNOSIS Prenat Diagn 2005; 25: 220–224. Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/pd.1110 Lack of correlation between elevated maternal serum hCG during second-trimester biochemical screening and fetal congenital anomaly Claudio Celentano 1 *, Paolo Emilio Guanciali-Franchi 2 , Marco Liberati 1 , Chiara Palka 3 , Donatella Fantasia 2 , Elisena Morizio 2 , Giuseppe Calabrese 2 , Liborio Stuppia 2 and Siegfried Rotmensch 4 1 Department of Obstetrics and Gynecology, University ‘G.d’Annunzio’, Chieti, Italy 2 Department of Medical Genetics, University ‘G.d’Annunzio’, Chieti, Italy 3 Department of Medical Genetics, CSS-Mendel, University ‘La Sapienza’, Rome, Italy 4 Department of Obstetrics and Gynecology, The Edith Wolfson Medical Center, Holon, affiliated to Tel Aviv University Medical School, Tel Aviv, Israel Objective Isolated elevations in midtrimester maternal serum human chorionic gonadotrophin concentrations (MShCG) have been reported to be associated with a substantially increased likelihood of fetal congenital malformations. The reported malformations included a wide range of organ systems, originating at different embryologic developmental stages. The purpose of our study was to determine the significance of an isolated elevated MShCG (>2.5 MoM) in midtrimester for the detection of fetal structural anomalies in a large population. Methods Among 10 144 women who underwent a biochemical triple screen at 15 to 18 weeks’ gestation, 463 patients, who had an elevated MShCG, but normal α-fetoprotein (AFP) and unconjugated estriol (uE 3 ) levels, were identified. Patients with an integrated calculated Down syndrome risk above 1 : 250 were excluded. Only nonsmokers, at ages <35 years, without a history of prior fetal anomalies were included. The control group consisted of 463 patients with normal serum analyte concentrations and Down syndrome risks below 1 : 250, who were matched for maternal age and date of biochemical screen. All patients underwent a detailed genetic sonogram in which an anatomic survey and multiple ‘soft markers’ for aneuploidy were looked for. Newborns were examined by a senior pediatrician trained in dysmorphology. Results MShCG levels were 3.18 ± 0.72 versus 0.99 ± 0.43 MoM (p < 0.0001) in study and control groups respectively. Sonography revealed 8 versus 6 cases of major congenital anomalies among the 463 patients of their respective groups, and 39 versus 36 sonographic ‘soft markers’ for aneuploidy. Fetal karyotyping and neonatal examination for dysmorphology revealed 6 chromosomal anomalies (4 Down syndrome; 2 Turner syndrome) among the 8 major malformations in the study group, but none in the controls (p < 0.0001). Three of the 39 fetuses with ‘soft markers’ and elevated MShCG were found to have trisomy 21. Conclusion Isolated elevation of MShCG does not confer an increased risk of fetal congenital anomalies other than chromosomal abnormalities. However, elevated MShCG levels in combination with sonographic ‘soft markers’ for aneuploidy were associated with a high incidence of chromosomal anomalies, despite a normal biochemical triple screen risk estimate. Copyright  2005 John Wiley & Sons, Ltd. KEY WORDS: elevated serum hCG; congenital anomaly risk INTRODUCTION Maternal serum human chorionic gonadotrophin (MShCG) is the most sensitive single biochemical screening marker for the detection of Down syndrome in midtrimester of pregnancy (Muller et al., 1993; Crossley et al., 1991). Since the original description of elevated MShCG levels in Down syndrome pregnancies (Bogart et al., 1987), additional associations with adverse out- comes have been described. Preterm labor, intrauterine growth restriction, preeclampsia, and fetal death were found to be more frequent among patients with ele- vated hCG (Chandra et al., 2003; van Rijn et al., 1999; Onderoglu and Kabulcu, 1997). *Correspondence to: Claudio Celentano, 5 Umbria St., 65016 Montesilvano (PE), Italy. E-mail: ccelen@tin.it Multiple authors (Barnes et al., 1992; Schmidt et al., 1993; Fejgin et al.,1997) reported an increased incidence of structural fetal anomalies in the presence of ele- vated midtrimester MShCG concentrations, even in the absence of chromosomal anomalies. Fejgin et al. (1997) suggested a targeted fetal sonogram for patients with elevated MShCG who had an otherwise normal triple screen, based on a 9.51 fold increase in fetal malforma- tions unrelated to chromosomal abnormalities in their sample of 298 patients. The pathophysiologic mech- anism linking elevated MShCG levels and congenital anomalies remained unclear. Furthermore, the finding of a wide range of anomalies in multiple fetal organ systems originating in different developmental stages in the Fejgin study was somewhat puzzling, and was not shared by our clinical experience. The purpose of our study was to determine the significance of an elevated MShCG (>2.5 MoM) as an Copyright  2005 John Wiley & Sons, Ltd. Received: 27 August 2004 Revised: 21 November 2004 Accepted: 21 November 2004