Birth prevalence of congenital malformations in singleton pregnancies resulting from in vitro fertilization/intracytoplasmic sperm injection worldwide: a systematic review and meta-analysis

We conducted a systematic review and meta-analysis to estimate the worldwide birth prevalence of total congenital malformations (CMs), major CMs, and specific CMs according to organs and systems classification associated with IVF/ICSI singleton pregnancies. Unrestricted searches were conducted, with an end-date parameter of 1 June 2017, of PubMed, Embase, Google Scholar, Cochrane Libraries, and Chinese databases, to identify cohort studies assessing CMs associated with IVF/ICSI singleton pregnancies. The prevalence estimates were summarized and analyzed by meta-analysis. Thirty-four cohort studies comprising 159,021 IVF/ICSI and 6704,405 spontaneously conceived singleton pregnancies met the inclusion criteria. Among IVF/ICSI singleton pregnancies, pooled estimates of total CMs and major CMs (per 10,000) were 484.3 (95% CI 363.8-641.9) and 475.8 (95% CI 304.9-735.2), respectively; for specific CMs, pooled estimates 13.04 (95% CI 9.90-17.18) for cleft lip and/or palate, 17.01 (95% CI 8.01-36.06) for eye, ear, face, and neck malformations, 16.51(95% CI 11.56-23.57) for nervous system malformations, 36.21 (95% CI 26.20-50.02) for chromosomal defects, 8.31 (95% CI 4.21-16.40) for respiratory system malformations, 38.01 (95% CI 24.06-60.00) for digestive system malformations, 110.25 (95% CI 66.92-181.12) for musculoskeletal system malformations, 108.92 (95% CI 68.73-172.21) for urogenital system malformations, and 77.20 (95% CI 53.25-111.80) for circulatory system malformations. The IVF/ICSI singleton pregnancies compared with those conceived naturally experienced higher prevalence of total CMs, major CMs, and most specific CMs. Significant differences across continents, countries, types of assisted conception, and diagnose time of CMs were observed for total CMs birth prevalence among IVF/ICSI singleton pregnancies. The IVF/ICSI singleton pregnancies were significantly associated with high birth prevalence of CMs, representing a major global health burden. Significant differences across continents, countries, types of ART, and diagnose time of CMs were found. However, it remains uncertain whether detected differences represent true or methodological differences. In the future, population wide prospective CMs' registries covering the entire world population are needed to determine the exact birth prevalence.