Discussion
This is the first study to investigate IVF and infertility diagnoses in any CHD, and the first nationwide study to examine pregnancy and fetal outcome in mothers with ASD. Our cohort study showed that women with an ASD diagnosis had an increased risk and a higher prevalence of IVF treatment, and also had more multiple births. Additionally, it confirmed that pre-eclampsia occurred more frequently in patients with ASD during pregnancy. Infants from mothers with ASD were found to have perinatal outcomes comparable to those of infants from the general population despite a slightly lower birth weight.
A substantial proportion of women with ASDs needed help to conceive, a number well above the need found in the reference cohort. Whereas the increased number of multiple births among women with ASD is likely explained by the increased levels of IVF, our data do not provide an explanation for the IVF usage itself. In this regard, it can only be speculated if patients with a an ASD diagnosis who experience difficulties conceiving would be referred to IVF treatment at an earlier stage than patients without a diagnosis, or if this outcome may reasonably be attributed to the late consequences of the haemodynamic effects of the ASD. Despite being a common clinical problem, and an issue that might be concerning to many women, most questions regarding infertility and fertility treatment in patients with CHD remain unanswered. Indeed, these aspects and outcome hereof are only described in a few subtypes of congenital lesions and in small study samples. In women with the Fontan circulation, the outcome of pregnancy showed increased risk of miscarriage, preterm birth and poor fetal growth.12 In contrast, other studies on women with Tetralogy of Fallot and Ebstein’s anomaly showed that the fertility in these patients was not affected, perhaps suggesting that infertility issues may be related to specific lesions and, therefore, affects the CHD population differently. However, the small sample sizes found in both studies might undermine their reliability as both hold a significant risk of being underpowered. Whether our findings are related to differentiated algorithms for referral to IVF treatment, alternated haemodynamics or simple genetics is not known, and, consequently, the pathophysiological basis of this unexpected finding deserves further investigation.
The increased prevalence of pre-eclampsia in women with ASD has been described previously in smaller cohorts from Dutch and Belgian registries, reporting almost identical results as ours. Interestingly, similar findings have been found in healthy women with children with ASD.13 14 Indeed, ASDs in children were strongly associated with maternal early preterm pre-eclampsia (OR 12.0, 95% CI 8.96 to 16.1) and late perm pre-eclampsia.13 These associations indicate that the same pathophysiological mechanisms might be involved in the pathogenesis in both pre-eclampsia and ASD. Several studies have already suggested angiogenetic imbalance as a key component contributing to the pathogenesis in both congenital heart defects in general and preterm pre-eclampsia.15–17 While speculative, abnormal heart development could be caused by an angiogenetic imbalance in the fetus with ensuring anti-angiogenesis at the trophoblast stage, and a maternal anti-angiogenic state might cause the following cascade of events: reduced trophoblast invasion of the spiral arteries, hypoxia in the placenta, hypoxia in the fetus, overproduction of anti-angiogenic factors in the fetus and abnormal heart formation. No matter what the cause, the strong associations demonstrated between pre-eclampsia and ASD lends further support to the notion that there are unforeseen challenges to having an ASD that cannot be explained by the contemporary haemodynamic effects.
Finally, it has been suggested that reduced placental perfusion may cause pre-eclampsia, however, we do not expect diminished cardiac output and, subsequently, reduced blood flow through the placenta in women with ASD.18
Given the adverse events, including higher rates of IVF treatment and a higher prevalence of pre-eclampsia during pregnancy, it was reassuring that fetal outcome in offspring of women with ASDs were comparable to the reference cohort. Nonetheless, our findings did suggest that the birth weight in these infants is lower than normal. This is in accordance with the findings by Yap et al, demonstrating significantly lower birth weight and higher risk of being small for gestational age in offspring of mothers with ASDs.7 Interestingly, these results were associated with the corrective status of the defect, as only offspring of women with an unrepaired ASD experienced these adverse outcomes. This association adds to the conclusion of a novel study characterising the natural history of unrepaired ASD, describing how a defect ‘that is considered insignificant and not warranting closure in early life cannot be considered to be a benign lesion’.19 The demonstrated fetal outcome also reflects that of infants born with ASD from healthy parents, as lower birth weight, normal head circumference and normal placental weight have been demonstrated in these infants.20 21
Limitations
Our data did not suggest an explanation for the higher usage of IVF treatment among women with ASD. Whether higher awareness among obstetricians when confronted with a mother with a CHD, including ASD, results in earlier referral for IVF treatment is unknown. Additionally, it is unknown if any ASDs were diagnosed during the workup prior to IVF treatment, causing an over-representation.
We did not address the potential effects of social skewness. People from lower social groups conceive earlier, and recent unpublished studies show a higher proportion of patients with ASD in these social groups. It might be that patients with ASD try to conceive at a younger age, thereby, identifying fertility issues earlier than an age-matched reference group and, consequently, receive IVF treatment at a younger age.
Finally, interpreting register-based data inherently has some limitations as the validity of the diagnoses in the registries depend of the physicians generating the data. However, all ASD diagnoses given in the DNPR had been manually validated leaving very little error for potential misreporting and under-reporting or over-reporting.22 23 Diagnoses for IVF treatment and infertility have not been formally validated, but some diagnoses such as PCOS appear to be substantially under-reported in the DNPR.