title: Neonatal outcome and congenital malformations in children born after ICSI with testicular or epididymal sperm: a controlled national cohort study.
abstract: OBJECTIVE
  Does neonatal outcome including congenital malformations in children born after ICSI with epididymal and testicular sperm [testicular sperm extraction (TESE)/percutaneous epididymal sperm aspiration (PESA)/testicular sperm aspiration (TESA) (TPT)] differ from neonatal outcome in children born after ICSI with ejaculated sperm, IVF and natural conception (NC)?
  
  
  CONCLUSIONS
  Children born after TPT have similar neonatal outcome, including total malformation rates, as have children born after ICSI and IVF with ejaculated sperm. Testing for variance over the four groups may indicate smaller differences in specific malformation rates with TPT as the highest risk group.
  
  
  BACKGROUND
  Regarding neonatal outcome as well as congenital malformations in children born after TPT, studies are few, with limited sample size, heterogeneous and often performed without relevant control groups.
  
  
  METHODS
  Population-based cohort study including all Danish children born after TPT and fresh embryo transfer in Denmark from 1995 to 2009. Children born after transfer of frozen-thawed embryos were excluded. Control groups of children conceived by ICSI with ejaculated sperm, IVF and NC were identified by cross-linkage of the Danish IVF Register, Medical Birth Register (MBR) and National Hospital Discharge Register (HDR).
  The study group consisted of 466 children born after TPT, while the control groups consisted of 8967 (ICSI with ejaculated sperm), 17 592 (IVF) and 63 854 (NC) children. Neonatal outcomes and congenital malformations were analysed for singletons and twins separately. Risk estimates for low birthweight (LBW, <2500 g) and preterm birth (PTB, <37 gestational weeks) were adjusted for maternal age, parity, child gender and year of childbirth. The study group was identified from the Danish national database on children born after TPT. Control groups were obtained from the IVF register and the MBR. All information included in the study was retrieved from the national registers.
  
  
  RESULTS
  Considering singletons and twins as one group, the sex ratio (♂/♀) was significantly lower for children born after TPT (0.89) compared with conventional IVF (1.11; P = 0.017) but did not differ significantly when compared with ICSI with ejaculated sperm (0.94) and NC (1.05). The mean birthweight (BW) for singletons did not differ significantly between groups when including only first-born children. The mean gestational age (GA) in the TPT singletons (279 ± 12 days) was significantly higher compared with IVF (276 ± 18 days; P = 0.02), but similar to ICSI with ejaculated sperm and NC singletons when including only first-born children (277 ± 16 days and 279 ± 14 days, respectively). Rate of stillbirths, perinatal and neonatal mortality in the group of TPT singletons did not differ significantly from any of the control groups. Comparable results were found for the TPT twin group, except for perinatal mortality, which was significantly lower in the TPT group compared with naturally conceived twins. The adjusted risk of LBW was significantly higher for TPT versus NC singletons [adjusted odds ratio (AOR) = 0.67 (0.48-0.93)]; however AOR for PTB was similar in the two groups. Regarding twins, similar adjusted risks were observed for PTB and LBW between the TPT and all three control groups. Significantly more Caesarean sections were performed after IVF (27.3% for singletons) and ICSI (25.1% for singletons) with ejaculated sperm compared with the TPT group (16.4% for singletons). The total rate of congenital malformations in the TPT group was 7.7% and did not differ significantly from any of the control groups. However, singleton TPT boys showed an increased rate of cardiac malformations (3.6%) compared with singleton boys after IVF (1.4%; P = 0.04) and NC (1.1%; P = 0.02). Considering the level of male infertility as a continuum over the four groups, tests for variance in the rate of cardiac malformations in singleton boys, and undescended testicles for singleton as well as twin boys were each significantly increased from NC to IVF to ICSI to TPT (P < 0.001). The rate of hypospadias showed the same pattern, but the TPT group did not differ significantly compared with the control groups.
  
  
  CONCLUSIONS
  One of the limitations is that the TPT group could not be classified according to testicular or epididymal sperm, as these data were not available in the IVF register. Another limitation is that registry-based studies are encumbered with the risk of reporting or coding errors or missing data due to insufficient coding. However, the quality of data on congenital malformations in HDR has, in other studies, been validated and found acceptable for epidemiological research, and furthermore, recordings on study and control groups are performed similarly.
  
  
  CONCLUSIONS
  Accumulating data show that TPT treatment is equally safe as conventional ICSI and IVF treatment and as NC with regard to neonatal outcome including congenital malformation.
  
  
  BACKGROUND
  This study is supported by Laboratory of Reproductive Biology, Scientific Unit, Horsens Hospital. No competing interests declared.
authors.affiliation: Laboratory of Reproductive Biology, Scientific Unit, Horsens Hospital, Horsens, Denmark. fedder@dadlnet.dk
authors.forename: J
authors.initials: J
authors.lastname: Fedder
authors.forename: A
authors.initials: A
authors.lastname: Loft
authors.forename: E T
authors.initials: ET
authors.lastname: Parner
authors.forename: S
authors.initials: S
authors.lastname: Rasmussen
authors.forename: A
authors.initials: A
authors.lastname: Pinborg
mesh_terms: D015331:Cohort Studies; D000013:Congenital Abnormalities / Q000453:epidemiology / Q000209:etiology* / Q000401:mortality; D003718:Denmark / Q000453:epidemiology; D004624:Embryo Transfer / Q000009:adverse effects; D004822:Epididymis / Q000166:cytology / Q000473:pathology*; D005260:Female; D005307:Fertilization in Vitro / Q000009:adverse effects; D005315:Fetal Diseases / Q000453:epidemiology / Q000209:etiology* / Q000401:mortality; D006801:Humans; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000453:epidemiology / Q000209:etiology* / Q000401:mortality; D007248:Infertility, Male / Q000473:pathology; D008297:Male; D011247:Pregnancy; D011256:Pregnancy Outcome; D059285:Pregnancy, Twin; D012042:Registries; D012306:Risk; D020554:Sperm Injections, Intracytoplasmic / Q000009:adverse effects*; D053625:Sperm Retrieval / Q000009:adverse effects*; D013737:Testis / Q000166:cytology / Q000473:pathology*