Discussion

In a novel approach using the Walker cohort, this study investigated the association between parental CHD and offspring birth outcomes. This is the first study including PW measurements and a paternal sample, allowing exploration of associations between offspring PW (and its ratio to BW) and paternal CHD development.

Walker babies from mothers who later developed CHD were born nearly 31g lighter, and this association was independent of whether the father also developed CHD or not. This is in agreement with previous reports of maternal CVD mortality being consistently associated with lower offspring BW. ^{Reference Davey Smith, Hart and Ferrell3,Reference Davey Smith4,Reference Davey Smith, Sterne, Tynelius, Lawlor and Rasmussen7,Reference Li, Chen and Sung9,Reference Shaikh, Kjøllesdal and Naess10,Reference Shaikh, Kjølllesdal, Carslake, Stoltenberg, Davey Smith and Næss14,Reference Vik, Romundstad, Carslake, Davey Smith and Nilsen37} Although we found no difference in offspring BW by whether the fathers subsequently developed CHD or not, using Cox regression we found negative associations between offspring BW and both maternal and paternal CHD risk. This is also supported by the cumulative incidence curves, where the trajectories for parents with offspring in the lowest quartile of BW show increased CHD incidence compared to parents in the highest quartile. Although we identified associations between paternal CHD risk and offspring BW, they are notably of a smaller magnitude than those seen for the mothers, and closer to the 0.05 significance level. The paternal associations suggest that offspring BW is partially genetically determined through the inheritance of CVD-susceptibility variants. The maternal results, however, are consistent with the strong influence of the intrauterine environment and the reflection of maternal health (and subsequent disease risk) over offspring fetal growth, ^{Reference Heaman, Kingston, Chalmers, Sauve, Lee and Young38,Reference Bai, Korfage, Mautner and Raat39} likely obscuring the effect of the maternal genotype. ^{Reference Catov, Wu, Olsen, Sutton-Tyrrell, Li and Nohr40,Reference Cirillo and Cohn41} One might argue that the paternal associations result simply from the shared parental environment and familial deprivation, but the associations between offspring BW and CVD spread across the extended family, ^{Reference Naess, Stoltenberg and Hoff13,Reference Shaikh, Kjølllesdal, Carslake, Stoltenberg, Davey Smith and Næss14} strongly suggesting the transmission of CVD-risk alleles through generations. The determination of BW and adult disease has been characterised as a complex mechanism resulting from the interplay between the environmental influences over maternal health (and therefore over the intrauterine environment), the independent expression of the maternal and fetal genomes, and possibly also epigenetic modifications. ^{Reference Shaikh, Kjølllesdal, Carslake, Stoltenberg, Davey Smith and Næss14,Reference Gluckman, Hanson and Beedle16,Reference Sato, Fudono and Imai27,Reference Vik, Romundstad, Carslake, Davey Smith and Nilsen37,Reference Agha, Hajj and Rifas-Shiman42}

The model including offspring BW and PW showed strong and directionally opposed effect estimates for BW (HR: 0.837) and PW (HR: 1.142), identifying a positive association between the latter and maternal CHD development after accounting for BW. We also found associations between maternal CHD risk and increased offspring PW:BW ratio (HR: 1.144), as a rough reflection of placental inefficiency. This is consistent with the study by Yeung et al. ^{Reference Yeung, Saha and Zhu21} who identified associations between higher offspring PW:BW ratios and increased maternal mortality from several causes such as CVD. Earlier, Davey-Smith et al. ^{Reference Davey Smith, Whitley, Gissler and Hemminki5} failed to find such associations, but their sample size was considerably smaller. These results support a link between placental efficiency, fetal growth, and maternal cardiovascular health. Maternal vascular disorders have been linked to poor placental perfusion, leading to insufficiency, impaired fetal growth, and an enlargement of the placenta. ^{Reference Catov, Newman and Roberts12,Reference Benagiano, Mancuso, Brosens and Benagiano43} Increased PW and PW:BW ratios have been associated with adult CVD risk factors and mortality, ^{Reference Barker, Bull, Osmond and Simmonds17–Reference Barker, Larsen, Osmond, Thornburg, Kajantie and Eriksson20} supporting the role of the placenta as a determinant of fetal outcomes and later disease development. We did not find significant associations between paternal CHD risk and offspring PW or PW:BW ratio, but there are no other studies in the literature for comparison. In contrast to our previous investigation on parental T2D, ^{Reference Sánchez-Soriano, Pearson and Reynolds29} we failed to identify paternal associations with offspring PW which could be explained by the fetal inheritance of a disease susceptibility genotype, leading to adult cardiometabolic disorders. Nonetheless, offspring from fathers who later developed CHD had slightly lighter placentas. Alternatively, fetal CVD-susceptibility variants might not be expressed in the placenta, ^{Reference Herzog, Eggink and Willemsen44} they might be subject to parent-of-origin differential expression, ^{Reference Reik, Constancia and Fowden45} or their action might be outweighed by direct maternal effects.

Our capacity to find a significant negative association between paternal CHD and offspring PW might have been restricted by our late study start point or by the reduced sample with PW available, limiting the statistical power. Through power calculations, we estimated that we had around 50% probability of finding real associations between PW adjusted for BW or PW:BW ratio and paternal CHD of a magnitude similar to those seen in the maternal analyses with the same confidence level (0.001), but around 90% probability of finding them under a 0.05 confidence level. However, these calculations ^{Reference Qiu, Chavarro, Lazarus, Rosner and Ma36} did not incorporate the adjustments performed to comply with the proportional hazards assumption. Recent studies have shown that the association between low BW and the adult development of cardiometabolic disease is governed by a fetal-only effect, being confounded by the maternal effect on the intrauterine environment. ^{Reference Warrington, Beaumont and Horikoshi26,Reference Moen, Brumpton and Willer46,Reference Chen, Bacelis and Sole-Navais47} Following this logic and due to the additional evidence hinting at an effect similar to BW, it is likely that our restricted power among other study limitations described below prevented us from finding associations between paternal CHD and offspring PW.

For this investigation we have used the Walker cohort, ^{Reference Libby, Smith and McEwan28} which includes accurate records for three quarters of the total births in the region during its time, and enabling linkage to health records from the parents, which by now have experienced remarkable disease morbidity. However, there are inevitable limitations of such an epidemiological cohort that need to be considered when interpreting our results. In contrast with other reports using a wider cardiovascular mortality outcome definition including a more variable array of conditions, which might be diversely associated with offspring growth, we have focused on CHD hospitalisations and mortality, for which over 90% were categorised as ischaemic heart diseases. Focusing on CHD only might have limited our sample size. In addition, the hospital admissions data only started being collected after 1980, thirty years after the delivery of the oldest children in the cohort. This carries the possibility of some CHD cases being introduced into the model with a delay or being missed completely due to death or no subsequent admissions during the observable period. This is especially problematic for the paternal analyses due to their earlier onset of CHD. Additionally, the possibility of death before developing CHD should also be considered. The Fine-Gray regression was performed to investigate the associations for CHD risk accounting for the competing risk of death, but the death records lacked cause of death until 1989, which pushed the study start point further back, increasing the CHD cases missed and therefore being relegated to supplementary material. Any explanatory variables violating the proportional hazards assumption for the Cox and Fine-Gray models were adjusted by adding an interaction term of said covariates with the logarithm of follow-up time. This was considered necessary to prevent proportional hazards violations, albeit increasing the risk of overfitting the model and complicating the interpretation of the results, since the estimated effect of these variables should also consider the time-dependent effect as quantified by the interaction term. The survival regression analyses could not be adjusted for parental weight, height, or smoking and alcohol consumption since these were mostly unavailable for Walker, variables which might act as confounders for offspring outcomes and parental CHD risk. The analyses were adjusted by deprivation index (HBSIMD) from 2019 as a proxy for socio-economic class, which was also missing from Walker. This data resulted highly correlated with a social class categorisation ⁴⁸ of the parental occupation data available from Walker (analyses not shown). We did not adjust for multiple testing as our separate analyses for BW, PW, and BW:PW as predictors of parental CHD each offered different perspectives on the analyses and were conducted in different subsets of the dataset. Finally, since PW measurements were only collected for the latter half of the cohort, our ability to identify significant associations with offspring PW might have been limited by the analyses being restricted to a younger and smaller parental sample, with lower CHD morbidity. The differences between the entire parental datasets and the subset of individuals for which offspring PW was available are described in Supplementary Table 5.

In conclusion, we have provided additional evidence for independent and directionally opposed effects of maternal CHD risk on offspring BW and PW. Maternal CHD risk was also positively associated with offspring PW to BW ratio, highlighting the importance of placental development and efficiency for fetal growth and its relationship with adult disease. Further analyses with a more comprehensive cohort are required to provide additional insights regarding any association of paternal CHD with offspring PW, and future efforts should focus on unravelling how fetal CVD-susceptibility variants might be influencing not just BW, but placental growth and function.