Male subfertility and the risk of major birth defects in children born after in vitro fertilization and intracytoplasmic sperm injection: a retrospective cohort study.

BACKGROUND: Children born after intracytoplasmic sperm injection (ICSI) are at increased risk of specific major birth defects compared with children born after in vitro fertilization (IVF). However, whether this risk is due to the treatment itself (i.e., IVF or ICSI) or underlying male subfertility is unknown. This study investigated the associations between male subfertility and the risk of major birth defects in children born after IVF and ICSI. METHODS: We conducted a retrospective cohort study using data from the Japanese assisted reproductive technology registry between 2007 and 2014. Fresh embryo transfer cycles registered from 2007 to 2014 that resulted in singleton live births, still births, or selective terminations were included (n = 59,971). Major birth defects were defined by the US Centers for Disease Control and Prevention guidelines, excluding chromosomal abnormalities. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using generalized estimating equations adjusting for potential confounders. RESULTS: Major birth defects were reported in 626/59,971 (1.04%) cases. Among IVF cycles, male subfertility was associated with significantly greater risks of hypospadias (3/3163 [0.09%] vs 4/28,671 [0.01%], adjusted OR = 6.85, 95% CI 2.05-22.9, P = 0.002) and atrial septal defects (4/3163 [0.13%] vs 9/28,671 [0.03%], adjusted OR = 3.98, 95% CI 1.12-14.1, P = 0.03) compared with fertile men. Subgroup analysis using sperm parameters showed that oligozoospermia (i.e., sperm concentrations < 15 million/mL) was significantly associated with a greater risk of ventricular septal defects compared with normal sperm concentrations in IVF pregnancies (5/868 [0.58%] vs 60/28,090 [0.21%], adjusted OR = 2.68, 95% CI 1.15-6.27, P = 0.02), and severe oligozoospermia (i.e., sperm concentrations < 5 million/mL) was significantly associated with an increased risk of hypospadias compared with normal sperm concentrations in ICSI pregnancies (5/3136 [0.16%] vs 5/16,865 [0.03%], adjusted OR = 3.88, 95% CI 1.14-13.2, P = 0.03). CONCLUSIONS: The results of this exploratory study suggest that underlying male subfertility may play a role in the risk of major birth defects related to ICSI and IVF. Further research, including systematic reviews adjusting for confounders, is required to confirm the associations between male subfertility and major cardiac and urogenital birth defects.

Risk of major congenital anomalies after assisted hatching: analysis of three-year data from the national assisted reproduction registry in Japan.

OBJECTIVE: To assess perinatal risk of major congenital anomalies in children born after embryo transfer with assisted hatching (AH). DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): Cycles registered from 2010 to 2012 and conceived via single-embryo transfer were included for the analysis. Live births, still births after 22 weeks of gestation, and selectively terminated cases because of congenital anomalies were included. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Major congenital anomaly. RESULT(S): AH was performed in 35,488 cycles among 72,125 included cycles (49.2%). A total of 1,046 major congenital anomalies (1.4%) were identified (1.36% in AH group vs. 1.50% in non-AH group). Overall risks for major congenital anomalies were not significantly different between AH and non-AH groups adjusting for maternal age, calendar year, fetal sex, embryo stage at transfer, and status of cryopreservation. There were 1,009 cases of twins (1.5%) and 10 cases of triplets (0.015%) among all included cycles. No specific organ system demonstrated significant association between AH and non-AH groups. Subgroup analysis demonstrated no significant association between AH and non-AH groups in intracytoplasmic sperm injection cycles or in vitro fertilization in fresh cycles. Similar nonsignificant association was observed between early-cleavage or blastocyst stage at transfer in frozen-thawed cycles. CONCLUSION(S): Our results suggest that AH alone does not increase the risk of major congenital anomaly.