Safety and Risks · Birth Defects
Richard M et al., 2025 · Human Reproduction
Abstract Is conception using in vitro fertilization (IVF) associated with the multiple congenital anomaly pattern referred to as VACTERL? Children conceived through IVF were more than twice as likely to develop VACTERL compared to those naturally conceived (OR 2.57, 95% CI 1.93-3.39). VACTERL (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities) is a multiple congenital anomaly pattern with a likely multifactorial origin, as few genetic or non-genetic risk factors have been identified. Some studies have suggested a potential link between IVF and VACTERL, yet this relationship has not been thoroughly investigated while accounting for other maternal characteristics. Given the rarity of VACTERL, large datasets with comprehensive information on fertility treatment parameters, maternal characteristics, and birth outcomes are essential to better understand this association. Study design, size, duration
We performed a population-based study of live births in four U.S. states (Massachusetts, New York, North Carolina, and Texas) between 2004 and 2018, linking birth records and birth defect data to IVF cycles reported in the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS). Naturally conceived births were selected as controls at a 10:1 ratio during the same period as the IVF birth. The study included a total of 1,315,867 live births. Participants/materials, setting, All study children were linked to state birth defect registries, with defects classified using British Pediatric Association codes. VACTERL cases were identified by code 759.890 or the presence of at least three associated anomalies. Children with known chromosomal or other genetic syndromes were excluded. Logistic regression was used to assess the association between IVF conception and VACTERL. Covariates included maternal age, race/ethnicity, education, and state. Main We identified 363 cases of VACTERL - 78 conceived through IVF (0.053%) and 285 naturally conceived (0.024%). Of these, 232 cases were identified using the diagnostic code 759.890, while 131 additional cases were identified by at least three of the six VACTERL associated anomalies. The most frequent VACTERL congenital anomalies were cardiac defects (54%), followed by renal anomalies (50%) and anal atresia (32%). In unadjusted analysis, IVF was significantly associated with an increased prevalence of VACTERL (OR 2.27, 95% CI 1.75-2.89). After adjusting for maternal socio-demographics, the association was further strengthened (OR 2.57, 95% CI 1.93-3.39) and supported in sensitivity analyses restricted to 1,226,080 singletons (OR 2.74, 95% CI 1.92-3.83). Evaluation of specific IVF treatment parameters (n = 141,882) revealed the highest prevalence of VACTERL in 58 of 102,099 births from fresh embryos (0.057% vs. 0.050% from thawed embryos), 41 of 69,765 births from ICSI (0.059% vs. 0.052% without ICSI), and 27 of 48,629 births from male infertility (0.056% vs. 0.055% without male infertility). Refining our multivariable model of IVF, we found that use of ICSI without a diagnosis of male infertility had the strongest association with VACTERL of all IVF groups (OR 3.04, 95% CI 1.90-4.65) compared to natural conceptions. Limitations, We were unable to assess familial clustering and terminations in the prevalence of VACTERL. However, our analyses are representative of live births and we accounted for maternal characteristics associated with both birth defect risks and the use of fertility treatment. The use of IVF is associated with VACTERL in offspring, but the absolute risk for VACTERL in IVF-conceived offspring remains low. The mechanisms underlying this association are unclear, but altered DNA methylation patterns have been implicated in both IVF and VACTERL etiology. No
Safety and Risks · Birth Defects
Bhat P et al., 2025 · Journal of assisted reproduction and genetics
Congenital anomalies (CAs) are a leading cause of perinatal and child mortality. With the increasing use of assisted reproductive technology (ART), there is a growing need for research on the health outcomes of children conceived through ART. This systematic review was performed to assess the incidence of CAs in ART-conceived children compared to those conceived naturally. This review followed the PRISMA 2020 guidelines and was registered with PROSPERO. A total of 113 studies were included in this meta-analysis, comprising 768,929 children in the ART group and 40,709,337 children in the control group which comprised spontaneously conceived (SC) children. The primary findings indicated that ART-conceived children have a marginally higher risk of CAs compared to the control group. Subgroup analyses showed that children conceived via ICSI, Day 3 transfer, and fresh embryo transfer (ET) had a slightly higher risk of CAs than those conceived via IVF, Day 5 transfer, or frozen embryo transfer (FET). The study highlights a slightly increased incidence of CAs among ART-conceived children over SC children, underscoring the importance of improving ART methods and closely monitoring the health of these children to reduce the risk of CAs.
Safety and Risks · Birth Defects
Sargisian N et al., 2024 · European heart journal
Children born after assisted reproductive technology (ART) have worse perinatal outcomes compared with spontaneously conceived children. This study investigates whether children conceived after ART have a higher risk of congenital heart defects (CHDs) compared with children born after spontaneous conception (SC). All 7 747 637 liveborn children in Denmark (1994-2014), Finland (1990-2014), Norway (1984-2015), and Sweden (1987-2015), where 171 735 children were conceived after ART, were included. National ART and medical birth registry data were cross-linked with data from other health and population registries. Outcomes were major CHDs, severe CHDs, 6 hierarchical CHD lesion groups, and 10 selected major CHDs, diagnosed prenatally or up to 1 year of age (Denmark, Finland, and Sweden) and prenatally or at birth (Norway). The association between ART and CHDs was assessed with multivariable logistic regression analysis, with adjustment for available confounders. Major CHDs were detected in 3159 children born after ART (1.84%) and in 86 824 children born after SC [1.15%; adjusted odds ratio (AOR) 1.36; 95% confidence interval (CI) 1.31-1.41]. Risk was highest in multiples, regardless of conception method. Severe CHDs were detected in 594 children born after ART (0.35%) and in 19 375 children born after SC (0.26%; AOR 1.30; 95% CI 1.20-1.42). Risk was similar between ICSI and IVF and between frozen and fresh embryo transfer. Assisted reproductive technology-conceived children have a higher prevalence of major CHDs, being rare, but severe conditions. The absolute risks are, however, modest and partly associated with multiple pregnancies, more prevalent in ART.
Safety and Risks · Birth Defects
Henningsen AA et al., 2023 · Fertility and sterility
To investigate whether the risk of major congenital malformations is higher in live-born singletons conceived with intracytoplasmic sperm injection (ICSI) compared with in vitro fertilization (IVF)? Nordic register-based cohort study. Cross-linked data from Medical Birth Registers and National ART and Patient Registers in Denmark, Norway and Sweden. Data were included from the year the first child conceived using ICSI was born: Sweden, 1992; Denmark, 1994; and Norway, 1996. Data were included until 2014 for Denmark and 2015 for Norway and Sweden. All live-born singletons conceived using fresh ICSI (n = 32,484); fresh IVF (n = 47,178); without medical assistance (n = 4,804,844); and cryo-ICSI (n = 7,200) during the study period. Different in vitro conception methods, and cryopreservation of embryos. Risk of major congenital malformations on the basis of International Classification of Diseases codes. The European Concerted Action on Congenital Anomalies and Twins was used to differentiate between major and minor malformations. Among singletons conceived using fresh ICSI, 6.0% had a major malformation, compared with 5.3% of children conceived using fresh IVF; 4.2% of children conceived without medical assistance; and 4.9% of children conceived using cryo-ICSI; adjusted odds ratio (AOR) 1.07 (95% confidence interval [CI] 1.01-1.14) in ICSI vs. IVF; and AOR 1.28 (95% CI, 1.23-1.35) in ICSI vs. no medical assistance; and AOR 1.11 (95% CI, 0.99-1.26) in ICSI fresh vs. cryo-ICSI. When malformations were grouped by different organ systems, children conceived using ICSI had a higher risk of respiratory and chromosomal malformations compared with children conceived using IVF, but there were very few cases in each group. When categorizing children conceived using ICSI according to treatment indication (male factor infertility only vs. other indications), we found a higher risk of hypospadias when ICSI was performed because of male factor infertility only (AOR 1.85 [95% CI 1.03-332]). The indications for ICSI changed over time, as male factor infertility did not remain the primary indication for ICSI throughout the study period. In this large cohort study, we found the risk of major malformations in live-born singletons to be slightly higher after fresh ICSI compared with fresh IVF. These findings should be considered when choosing the assisted reproductive technology method for couples without male factor infertility.