title: Maternal first trimester serum levels of free-beta human chorionic gonadotrophin and male genital anomalies.
abstract: Are maternal first trimester levels of serum free-beta hCG associated with the development of hypospadias or undescended testis (UDT) in boys?
  
  
  
  Overall, first trimester maternal levels of serum free-beta hCG are not associated with hypospadias or UDT. However, elevated levels were found in severe phenotypes (proximal hypospadias and bilateral UDT) suggesting an altered pathway of hormonal release in early pregnancy.
  
  
  
  Human chorionic gonadotrophin peaks in first trimester of pregnancy stimulating fetal testosterone production, which is key to normal male genital development. Endocrine-disrupting insults early in pregnancy have been associated with increased risk of common genital anomalies in males such as hypospadias and UDT. One plausible etiological pathway is altered release of hCG.
  
  
  
  We conducted a record-linkage study of two separate populations of women attending first trimester aneuploidy screening in two Australian states, New South Wales (NSW) and Western Australia (WA), in 2006-2009 and 2001-2003, respectively.
  
  
  
  Included were women who gave birth to a singleton live born male infant. There were 12 099 boys from NSW and 10 518 from WA included, of whom 90 and 77 had hypospadias; and 107 and 109 UDT, respectively. Serum levels of free-beta hCG were ascertained from laboratory databases and combined with relevant birth outcomes and congenital anomalies via record linkage of laboratory, birth, congenital anomalies and hospital data. Median and quartile levels of gestational age specific free-beta hCG multiple of the median (MoM) were compared between affected and unaffected boys. Logistic regression was used to evaluate the association between levels of free-beta hCG MoM and hypospadias or UDT, stratified by suspected placental dysfunction and co-existing anomalies. Where relevant, pooled analysis was conducted.
  
  
  
  There was no difference in median hCG levels amongst women with an infant with hypospadias (NSW = 0.88 MoM, P = 0.83; WA = 0.84 MoM, P = 0.76) or UDT (NSW = 0.89 MoM, P = 0.54; WA = 0.95 MoM, P = 0.95), compared with women with an unaffected boy (NSW = 0.92 MoM; WA = 0.88 MoM). Low (<25th centile) or high (>75th centile) hCG levels were not associated with hypospadias or UDT, nor when stratifying by suspected placental dysfunction and co-existing anomalies. However, there was a tendency towards high levels for severe types, although confidence intervals were wide. When combining NSW and WA results, high hCG MoM levels (>75th centile) were associated with increased risk of proximal hypospadias (odds ratio (OR) 4.34; 95% CI: 1.08-17.4) and bilateral UDT (OR 2.86; 95% CI: 1.02-8.03).
  
  
  
  There were only small numbers of proximal hypospadias and bilateral UDT in both cohorts and although we conducted pooled analyses, results reported on these should be interpreted with caution. Gestational age by ultrasound may have been inaccurately estimated in small and large for gestational age fetuses affecting hCG MoM calculation in those pregnancies. Despite the reliability of our datasets in identifying adverse pregnancy outcomes, we did not have pathology information to confirm tissue lesions in the placenta and therefore our composite outcome should be considered as a proxy for placental dysfunction.
  
  
  
  This is one of the largest population-based studies examining the association between maternal first trimester serum levels of free-beta hCG and genital anomalies-hypospadias and UDT; and the first to compare specific phenotypes by severity. Overall, our findings does not support the hypothesis that alteration in maternal hCG levels is associated with the development of male genital anomalies; however, high hCG free-beta levels found in severe types suggest different underlying etiology involving higher production and secretion of hCG. These findings require further exploration and replication.
  
  
  
  This work was funded by the National Health and Medical Research Council (NHMRC) grant APP1047263. N.N. is supported by a NHMRC Career Development Fellowship APP1067066. C.B. was supported by a NHMRC Principal Research Fellowship #634341. The funding agencies had no role in the design, analysis, interpretation or reporting of the findings. There are no competing interests.
  
  
  
  Not applicable.
authors: Menzies Centre for Health Policy, School of Public Health, University of Sydney, Sydney, NSW 2006, Australia francisco.schneuer@sydney.edu.au joseph.majzoub@childrens.harvard.edu.
authors: F J
authors: FJ
authors: Schneuer
authors: Telethon Kids Institute, The University of Western Australia, Crawley, Western Australia 6009, Australia.
authors: C
authors: C
authors: Bower
authors: Discipline of Paediatrics and Child Health, The Children's Hospital at Westmead, Sydney Medical School, University of Sydney, Sydney, NSW 2145, Australia.
authors: A J A
authors: AJ
authors: Holland
authors: Pathology North, NSW Health Pathology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
authors: V
authors: V
authors: Tasevski
authors: Telethon Kids Institute, The University of Western Australia, Crawley, Western Australia 6009, Australia.
authors: S E
authors: SE
authors: Jamieson
authors: Department of Paediatric Surgery, Princess Margaret Hospital for Children, Subiaco, Western Australia 6008, Australia.
authors: A
authors: A
authors: Barker
authors: Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors: L
authors: L
authors: Lee
authors: Division of Endocrinology, Boston Children's Hospital, and Harvard Medical School, CLSB 16028, 300 Longwood Avenue, Boston, MA 02115, USA francisco.schneuer@sydney.edu.au joseph.majzoub@childrens.harvard.edu.
authors: J A
authors: JA
authors: Majzoub
authors: Menzies Centre for Health Policy, School of Public Health, University of Sydney, Sydney, NSW 2006, Australia.
authors: N
authors: N
authors: Nassar
mesh_terms: D000328:Adult; D001315:Australia; D015415:Biomarkers / Q000097:blood; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000097:blood*; D003456:Cryptorchidism / Q000175:diagnosis*; D005260:Female; D006801:Humans; D007021:Hypospadias / Q000175:diagnosis*; D008297:Male; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000097:blood*; D011296:Prenatal Diagnosis; D055815:Young Adult
chemical_list: D015415:Biomarkers; D018997:Chorionic Gonadotropin, beta Subunit, Human
keywords: cryptorchidism; first trimester pregnancy; first trimester screening; hCG; human chorionic gonadotrophin; hypospadias; male genital anomalies; undescended testis