Discussion

Twin gestation has been associated with a higher incidence of congenital malformations, including CHD, in both naturally conceived pregnancies and those conceived using assisted reproductive technologies.Reference Dawson, Tinker and Jamieson^1, Reference Patil, Nguyen, Groff, Wu, Elliott and Gunatilake⁵ Large-scale population studies and meta-analyses have shown that the incidence of CHD in assisted reproductive technologies, including inductive medications and procedures like in vitro fertilisation, is between 1 and 3%, with a slightly larger percentage being affected with both CHD and extracardiac malformations.Reference Patil, Nguyen, Groff, Wu, Elliott and Gunatilake^5, Reference Giorgione, Parazzini and Fesslova⁶ Variability in the incidence of malformations between different methods of assisted reproductive technology, if any, is unknown, and therefore most studies do not differentiate between the technologies utilised.Reference Patil, Nguyen, Groff, Wu, Elliott and Gunatilake^5, Reference Tararbit, Lelong and Thieulin⁷ Among all twin gestations, the incidence of malformations appears to be greater in monozygotic than in dizygotic twins and is more likely to occur in only one twin.Reference Dawson, Tinker and Jamieson^1–Reference Glinianaia, Rankin and Wright⁴ The twins in the present study represent a deviation from this paradigm.

Tetralogy of Fallot is the most common cyanotic CHD, accounting for 7–10% of all CHD.Reference Ross-Hesselink and Johnson⁸ The pathogenesis of Tetralogy of Fallot is complex and has yet to be fully elucidated, but proposed mechanisms include neural crest cell mutations and epigenetic modifications like imprinting.Reference Patil, Nguyen, Groff, Wu, Elliott and Gunatilake^5, Reference Di Felice and Zummo⁹ Like other CHD, potential risk factors include embryonic stress and underlying chromosomal abnormalities.Reference Giorgione, Parazzini and Fesslova^6, Reference Sullivan-Pyke, Senapati, Mainigi and Barnhart¹⁰ Increased levels of embryonic stress associated with assisted reproductive technologies and multiple gestations themselves have been proposed as mechanisms that may induce or unmask previously silent genetic mutations.Reference Dawson, Tinker and Jamieson^1, Reference Patil, Nguyen, Groff, Wu, Elliott and Gunatilake^5–Reference Sullivan-Pyke, Senapati, Mainigi and Barnhart¹⁰ Tetralogy of Fallot has classically been associated with 22q11 deletions (DiGeorge syndrome) and, more recently, has been noted in several specific gene variants, including NKX2.5, GATA4, and TBX5. Interestingly, chromosomal anomalies such as trisomies or inherited syndromes are thought to contribute to less than 15% of Tetralogy of Fallot cases in infants conceived spontaneously and only around 20% of cases in infants conceived using assisted reproductive technology.Reference Tararbit, Lelong and Houyel^3, Reference Giorgione, Parazzini and Fesslova⁶ In the present case, genetic testing beyond amniocentesis for trisomies 13, 18, and 21 was deferred, therefore precluding the possibility of more precisely determining a genetic predisposition.

We consider the most likely etiology of the malformations in this case to be a previously unrecognised genetic abnormality that was unmasked by increased levels of embryonic stress during gestation from potential placental insufficiency secondary to subchorionic haemorrhage, the process of in vitro fertilisation, and the twin gestation itself. The fact that both twins were born with Tetralogy of Fallot and additional congenital malformations suggests that an underlying genetic abnormality was contributory. However, the absence of family history of congenital malformations and the negative amniocentesis results makes a predictable inherited chromosomal anomaly such as trisomy less likely. Teratogenic effects stemming from medication use or an infectious etiology are other well-recognised etiologies of congenital malformations but are also unlikely in this case since that the mother did not report medication or substance use during pregnancy and since her prenatal testing was unremarkable.

This case is unique in that it represents the possible convergence of several causes of congenital malformations discussed in the literature, including genetic abnormalities and stress-induced mutations in assisted reproductive technologies and twin gestations. On the other hand, this case diverges from the norm of congenital mutations occurring most commonly in a single twin and in monozygotic pregnancies. More research is required to more clearly elucidate the mechanisms underlying malformations and CHD in multiple gestations and in infants conceived via assisted reproductive technologies. As previous studies have noted, it is difficult to separate potential confounding factors between subfertility, the use of assisted reproductive technologies, and twin gestations. It is possible that the same factors that lead families to use assisted reproductive technology are also associated with subfertility, congenital malformations, and/or twinning.Reference Dawson, Tinker and Jamieson^1, Reference Patil, Nguyen, Groff, Wu, Elliott and Gunatilake⁵