More than 2 million children are conceived annually using assisted reproductive technologies (ARTs).¹ Although previous studies have shown that children born from ART have a higher risk for congenital anomalies (CAs), whether this observed risk is attributable to underlying parental infertility or the ART treatment itself remains unclear.^1,2 According to a recent Australian population-based cohort study published in the Annals of Internal Medicine, ART-conceived children had slightly higher risks for CAs compared to naturally-conceived (NC) children.¹ Importantly, this increased risk was mitigated when compared to children conceived naturally to parents who had a history of infertility, suggesting that parental infertility may be a contributing factor in the increased risk of CAs in ART-conceived infants.¹

Since the first successful in vitro fertilization (IVF) treatment in 1978, ART technology has developed rapidly and is now used extensively worldwide.³ Previous studies have shown that ART is associated with an increased risk of birth defects including cardiovascular, musculoskeletal, urogenital, central nervous system, and orofacial defects.³ Rapid adoption of new ART techniques, such as the cryopreservation of eggs and embryos and intracytoplasmic sperm injection (ICSI), which are used in approximately 80% of embryo transfers today may incur further risks for CAs.¹ As such, researchers from the University of New South Wales, Australia sought to investigate the role of underlying parental infertility and fertility treatment on CA risks in the first 2 years of life by studying a contemporary longitudinal cohort of over 850,000 infants conceived naturally or via ART in Australia between 2009 and 2016.¹

The population-based longitudinal cohort study enrolled a total of 851,984 children who were born in New South Wales between 2009 and 2017, of which 97.2% and 2.8% were singleton and plural infants respectively.¹ Among these singleton infants (n=828,099), 2.0% were ART-ICSI-conceived, 1.7% were ART-IVF-conceived, 4.4% were NC from parents with a history of infertility (NC-infertile control infant), and 90.2% were NC from fertile parents (NC-fertile infants). As for the plural infants (n=23,885), 14.4% were ART-conceived and 79.7% were NC.¹ Baseline characteristics and crude prevalence of CA outcomes were compared between the groups, as well as the use of a propensity score-weighted method to estimate the adjusted risk differences (aRDs) for CAs between the cohorts.¹

The findings of the study found that ART-conceived infants had a higher risk of any major CA compared to NC-fertile control infants (aRD=41.3 per 10,000 births; 95% CI: 7.4-75.2].¹ When classified by organ system, ART-conceived infants were more susceptible to major genitourinary (aRD=19.0 per 10,000 births; 95% CI: 2.3-35.6), cardiovascular (aRD=14.5 per 10,000 births; 95% CI: 0.2-28.7), and urinary (aRD=14.4 per 10,000 births; 95% CI: 1.8-26.9) CAs when compared to NC-fertile control infants.¹ The magnitude of risk difference in any major CAs was reduced and was no longer significant when the ART-conceived infants were compared to NC-infertile  control infants (aRD=28.1 per 10,000 births; 95% CI: -8.7 to 64.9), suggesting that the increased CAs risk seen in ART-conceived children may be partly attributable to underlying parental infertility.¹

After accounting for parental infertility, ART-IVF-conceived infants were found to have an elevated risk of any major CA when compared to NC-infertile control infants (aRD=52.4 per 10,000 births; 95% CI: 3.5-101.3).¹ Despite only possessing a modest increased risk for any major CAs when compared to NC-infertile controls (aRD=21.3 per 10,000 births; 95% CI: -24.2 to 66.8), ART-ICSI-conceived infants exhibited an increased risk of major genitourinary CAs (aRD=31.8 per 10,000 births; 95% CI: 9.5-54.2) when compared to NC-infertile controls.¹ This adjusted risk difference was further divided in the comparison between ART-ICSI-conceived and NC-infertile controls when only accounting for female parental infertility (aRD=47.8 per 10,000 births; 95% CI: 12.6-83.1).¹ Furthermore, a direct comparison of IVF- vs. ICSI-conceived infants revealed that the latter had a higher risk for major genital CAs (aRD=20.1 per 10,000 births; 95% CI: 1.7-38.4), reinforcing that ICSI represents an independent risk factor for genitourinary CAs, and should be reserved for patients with male factor infertility.¹

In conclusion, the results of this study indicated the possibility of parental infertility being a contributing factor to the increased risk of major CAs seen in ART-conceived infants.¹ Between the 2 ART treatments, ICSI and IVF, IVF contributed to a greater risk of developing major CAs among infants with infertile parents.¹ Nevertheless, ICSI was observed to be related to an elevated risk of genitourinary CAs, especially among ART-conceived infants with infertile mothers.¹ As such, couples should be counseled on the elevated risk of genitourinary abnormalities with ART conceptions, particularly with ICSI, which should be avoided in couples without issues of male infertility.¹