Congenital heart defects (CHD) include structural malformations of the heart and/or major vessels present at birth or persisting abnormally after birth; it is the most frequent group of major congenital anomalies with a live prevalence that varies between 4.05 and 10.4 per 1000 live births.1–3 This prevalence is constant worldwide, nevertheless, it is dependent on case definition.4

Despite substantial progress in its diagnosis and management, CHDs remain the major cause of infant mortality due to congenital anomalies, requiring multiple hospitalizations and surgical procedures.5,6 Infant mortality and morbidity associated with preterm birth have also been extensively described.

Congenital heart defects and preterm birth are, therefore, leading causes of infant mortality and morbidity, but the relationship between them remains unclear. Associations between congenital anomalies and preterm birth are known.7–10 However, there are few specific data regarding the relationship of prematurity and CHD and the association between specific categories of CHD and preterm birth. Besides, few studies have been adjusted for maternal covariates related to fetal growth.

The etiology of most non-syndromic CHD and preterm birth is uncertain. Probably it involves complex interactions between multiple environmental exposures and genetic susceptibilities. It is conceivable that both may occur independently but share common risk factors.11–13 Alternatively, preterm birth in neonates with CHD may be caused by abnormal fetal hemodynamic profiles.13 The objective of our study was to investigate the association between preterm birth and CHD while controlling other risk factors for CHD. Since CHDs are a major global health concern, it is important to identify possible risk factors associated with their development and prematurity.

This study showed that preterm and low birth weight neonates (<2500 g birth weight) have more than twice the prevalence of CHD as term neonates, findings similar to previous studies.5,11,13,20,21 The odd ratio for CHD in prematurity was 2.7 (or 2.5 excluding extracardiac malformations) even when considering only the severe CHD group, showing that the excess of CHD among preterm cannot be explained by minor malformations.

The only statistically significant variable between the study groups related to a higher risk for CHD was the presence of extracardiac malformations. However, the exclusion of this variable had no significant impact on the results. Furthermore, 68% of new-borns with CHD born between 2003 and 2017 were identified prenatally. As we do not recommend premature delivery, it is unlikely that prenatal diagnosis had any significant influence on gestational age at delivery. Therefore, the twofold increase in the overall risk of CHD was probably due to spontaneous preterm birth.

The spectrum of CHD among preterm and term neonates is inconsistent between series. Laas et al. and Matthiesen et al. reported that the category of anomalies of the ventricular outflow tract, mainly affecting the right ventricle, had the highest risk of PTB.5,21 Tanner et al. reported that preterms had a higher prevalence of pulmonary atresia with VSD, CAVSD, COA, TOF and PS.11 Our results were similar to those reported by Godfrey et al., a small study of a single neonatal unit, where septal defects were the prevalent anomalies.11

Over the 15 years of study, there were no significant changes in the prevalence of CHD categories, probably because the recent advances in diagnostic methods had more impact in detecting mild CHD, and these kinds of alterations were not included in this study.

Although the study covered many years, the CIs for some rare and more complex CHD were large, indicating the limited precision of some of our estimates, due to relatively small numbers of these lesions.

Surprisingly, there were no statistically significant differences in the neonatal mortality rate between preterm and term neonates with CHD (p=0.799) or severe CHD (p=0.554). A possible explanation for these findings is that the additional effect of CHD on neonatal mortality rates, particularly severe CHD, is more pronounced in term and near term infants, for whom mortality rates are otherwise low, which puts preterm and term neonates on the same severity level. This suggests that, as the severity of CHD increases, the relative effect of preterm birth decreases.11,12 The cause of death in most term neonates with CHD was cardiac, in contrast to the preterm group in which their death was mainly due to complications related to prematurity, highlighting the higher impact of CHD on the outcomes of term neonates.

In the term neonate group, mortality decreased over the years, with 80% of deaths reported between 2003 and 2007; however, mortality did not decrease significantly in the preterm neonate group. Thus, although survival among premature infants has improved, this shows that the technical evolution over the years had more impact in overcoming cardiac lesions than complications related to prematurity.

Previous studies have found that a 1–2 week increase in gestational age increases an infant's odds of survival over time. This is probably due to increased organ maturation, mainly lung maturation, and the increased likelihood of successful surgery to correct the heart defect.11,23–25 However, unlike our analysis, these results did not take into consideration neonatal mortality. In the neonatal period, the CHD factor is probably more significant than the comorbidities associated with prematurity, which will have more weight later in life, contributing to the increase in long-term morbidity and mortality. Nevertheless, prematurity impacted the treatment strategy chosen for low birth weight large VSD and CAVSD, where they underwent a staged correction, but the follow-up was uneventful.

As this is a retrospective study, there are limitations, some related to incomplete medical records. For instance, we adjusted our estimates for several known risks of CHD, however, maternal drug intake could not be completely clarified, as well as other risk factors, such as maternal illnesses and obesity, which can also increase the risk of CHD.15–19

Due to our sample size, we were unable to examine the risk of neonatal mortality for extremely (<28 weeks) preterm infants. In addition, we were unable to assess in detail the extent to which differences in neonatal mortality between the two groups were due to the CHD spectrum.

The data could not be truly representative of the CHD profile in our community, as it was collected in a single tertiary Center. Second, only 40–50% of CHD are diagnosed in the first week and 50–60% in the first month of life.4 As our study included only cases diagnosed during the prenatal and neonatal periods, a significant number of CHD cases could have been lost, especially in term neonates who usually have a shorter hospital stay. In addition, to minimize the ascertainment bias, we excluded mild cardiac defects, however, it may also have been a source of selection bias. Despite the possibility of selection bias, the prevalence of live birth CHD in our study was higher than the average prevalence of live births CHD in Europe.2,3

The excess of CHD among preterm is intriguing, but unclear. One possible explanation is that CHD and preterm births share risk factors or a common cause.5 CHDs have a multifactorial etiology, involving a wide range of genetic and environmental risk factors.15,18 Thus, prematurity may be causally related to the same factor(s) that precipitated CHD.4 Las et al. conjectured that a deterioration in the genetic program of fetal development might cause both CHD and preterm births.

Alternatively, preterm birth in neonates with CHD can be caused by abnormal fetal hemodynamics.13 However, most cardiovascular malformations have little effect on the developing fetus and become hemodynamically significant only after birth. There is also no evidence that CHD is associated with any impairment of placental function that may precipitate premature birth or cause stillbirth.11,21

Max Godfrey et al. speculated that minor septal defects spontaneously close in utero, so fewer defects might be apparent in mature neonates.22 This theory is consistent with our results since abnormalities of the atria/ventricles and the atrial/ventricular septum were the only CHD significantly higher in preterm compared to term neonates. Furthermore, as we demonstrate in Figure 1, septal defects are more prevalent as the prematurity is more marked. Also, as usually seen in term neonates, muscular VSD was the most frequent type, probably because defects in the muscular septum are supposed to close as a result of growth and hypertrophy of the surrounding muscular septum over time, and prematurity does not allow for completion of the embryological process of septal development.26,27 It is also possible that CHD may be independently associated with preterm birth or low birth weight.

Ultimately, the relationship between CHD and preterm neonates can have significant implications on prenatal care, prevention and risk stratification, and also on postnatal care. Following prenatal diagnosis of CHD, women can benefit from more frequent and detailed ultrasounds to follow-up fetal growth and other manifestations conducive to premature labor.13

We found an increased risk of CHD, mainly septal defects, in preterm neonates, although the etiology of prematurity between neonates with CHD is still uncertain. Further research on the association between CHD and preterm birth is needed to identify common pathways and shared risk factors to help prevent these two major contributors to infant morbidity and mortality.

This research received no specific grant from any funding agency, commercial or not-for-profit sectors.

None declared.