Abstract
Objective:
Determine the association of placental vascular abnormality with neurodevelopment (ND) in toddlers with congenital heart disease (CHD) requiring intervention with cardiopulmonary bypass (CPB) in the first year of life.
Study design:
This single center retrospective cohort study included 69 singleton, term-born infants with prenatally diagnosed CHD requiring CPB in infancy who had placental pathology data and underwent ND follow-up assessment with the Bayley Scales of Infant and Toddler Development (Bayley). Infants with a clinically diagnosed genetic abnormality were included. Placental vascular abnormality was defined as maternal vascular malperfusion, fetal vascular malperfusion, or delayed villous maturation. Multivariable regression models were used to assess the association between placental vascular abnormality and Bayley scores.
Results:
Placental vascular abnormality was present in 43 % (30/69) of the cohort and was associated with lower Bayley language and motor scores on univariate analysis. A significant interaction was identified between placental vascular abnormality and genetic abnormality, which occurred in 26 % (18/69) of the cohort. In multivariable models, compared to infants with genetic abnormality alone, infants with placental vascular abnormality and genetic abnormality had lower cognitive (group difference −18.4, 95 % CI −30.7, −6.1), language (group difference −27.5, 95 % CI −41.2, −13.9), and motor (group difference −27.6, 95 % CI −40.9, −14.2) composite scores. There was no association of placental vascular abnormality with ND scores for infants without genetic abnormality in multivariable models.
Conclusion:
Placental vascular abnormalities are associated with worse ND outcomes in infants with CHD when a genetic abnormality is also present.
Keywords: Congenital heart disease, Placenta, Neurodevelopmental outcomes
1. Introduction
Progress in surgical approaches and intensive care management for infants with congenital heart disease (CHD) have reduced mortality for this population and have contributed to a growing number of adults living with even the most severe forms of CHD [1]. As survival has increased, long-term morbidities have emerged. Neurodevelopmental (ND) and psychosocial impairments are now recognized as being among the most common and enduring morbidities that infants with CHD experience. Approximately 50 % of children with CHD display impairments across one or more ND domains [2,3] and up to two-thirds will receive interventional services by adolescence [4]. Many medical and surgical factors contribute to ND outcomes but, in total, postnatal factors only account for a small portion of the variance [2,5]. Furthermore, evolving data suggest that ND risk begins before infant birth [6].
Prenatal contributors to adverse ND outcomes in CHD remain poorly understood, but the role of the placenta has become an increasing area of focus. The placenta is an essential organ within the prenatal environment that contributes to long-term health of the fetus. It not only provides a physical maternofetal barrier but also acts as a site of exchange for gases, immunological factors, and nutrients and is responsible for production of hormones and growth factors that promote fetal growth [7–9]. Growing evidence has linked placental maldevelopment/dysfunction with neuropsychiatric risk in offspring [10]. In pregnancies with fetal CHD, there is higher frequency of placental pathology [11,12], including vascular changes such as maternal vascular malperfusion, fetal vascular malperfusion, delayed villous maturation, and chorangiosis [13–16]. Importantly, placental pathology has recently been associated with smaller neonatal brain volumes [17,18]. These data suggest that placental vascular abnormalities may be important for adverse ND outcome in CHD but preliminary data have been mixed [18,19].
To address this critical knowledge gap, we aimed to determine whether placental vascular lesions (including maternal vascular malperfusion, fetal vascular malperfusion, and delayed villous maturation) are associated with worse ND outcome in toddlers with CHD. We hypothesized that infants with CHD affected by placental vascular abnormalities would have lower ND scores than infants without these placental changes.
2. Methods
2.1. Study design and population
A single center retrospective cohort study was performed to identify mother-infant dyads with a prenatal fetal diagnosis of CHD. Infants born between March 2013 and July 2019 who were greater than or equal to 37 weeks’ gestation at birth, underwent cardiac operations with cardiopulmonary bypass (CPB) within the first year of life, and completed a toddler ND evaluation were included. Exclusion criteria were incomplete placental pathology data, unknown gestational age at birth, and multi-gestation pregnancy. Infants with known genetic syndromes, molecular genetic abnormalities deemed pathogenic, and non-cardiac associated anomalies were included.
Maternal, fetal, and infant data were obtained through electronic medical record review. Maternal sociodemographic characteristics included age, race, ethnicity, and zip code and insurance type at the time of delivery. Zip code was used to calculate the Area Deprivation Index, a neighborhood-level measure of social deprivation [20]. Substance exposures, including tobacco, alcohol, or other recreational drugs, that were reported by the mother before or during pregnancy were also recorded. Medical information included body mass index, hypertensive disorders (chronic hypertension, pregnancy-induced hypertension, or pre-eclampsia), diabetic disorders (gestational or pre-existing/chronic type 1 or type 2 diabetes mellitus), gravidity, parity, and pregnancy complications.
Fetal/infant characteristics included sex, race, gestational age at birth, birth weight, genetic abnormalities and cardiac-specific data. Genetic abnormality was defined as a clinical diagnosis of a syndrome or identification of a pathogenic variant on clinical testing. Acquisition, and type, of genetic testing was at the discretion of the clinician but standard practice at our institution during the study period was generally to obtain chromosomal microarray analysis in infants with CHD. Based on advances in genetic testing over time, whole exome sequencing was more commonly utilized later in the cohort. Specific targeted testing varied depending on the degree of clinical suspicion. For cardiac-specific data, fetal echocardiograms were reviewed to determine CHD diagnosis, which was then confirmed postnatally. Cardiac surgical variables included age at primary surgical repair, procedure type, CPB time, and cross clamp time. Procedures were categorized based on the updated Society of Thoracic Surgeons – European Association for Cardio-Thoracic Surgery Congenital Heart Surgery (STAT) Mortality Categories, which ranges from 1 to 5 and categorizes patients based on least to most complex (i.e., highest mortality) operations [21,22]. Infant medical complications prior to ND testing included post-operative length of stay for the initial CPB operation, cardiac arrest, need for mechanical circulatory support (extracorporeal membrane oxygenation or ventricular assist device), need for cardiac transplantation, culture proven sepsis, seizures, and stroke. The number of operations prior to ND testing were recorded as an overall assessment of major anesthetic exposures and included cardiac catheterizations, cardiac surgical operations, and other non-cardiac surgeries.
2.2. Placental pathology data
Placental pathology data were obtained through maternal chart review and included both gross and histopathologic data, which were reviewed and categorized similar to that previously described [13]. Briefly, all data were reviewed and categorized by two raters (K.M. and C.B.O.) and discrepancies were reviewed by a pediatric pathologist for final categorization (M.H.). Placental vascular abnormalities were considered the primary predictor and were classified as maternal vascular malperfusion, fetal vascular malperfusion, or delayed villous maturation using the Amsterdam criteria [23]. These three abnormalities were grouped together as one “placental vascular abnormality” variable for the purposes of analysis, due to sample size and because we hypothesized that all would cause placental dysfunction that could affect fetal brain development and thus ND outcome. Additional data collected from gross and histologic assessment included placental weight, birth weight to placental weight ratio, and inflammation (acute and chronic) as defined by the Amsterdam Criteria [23].
2.3. Neurodevelopmental data
The Bayley Scales of Infant and Toddler Development (Bayley) was used as the ND outcome measure [24,25]. Testing for the cohort occurred from August 2014 through October 2020 and was administered by trained psychologists or psychometricians through a multidisciplinary follow up clinic designed for patients with CHD. Cognitive, language, and motor composite scores were recorded as the primary outcomes. Receptive language, expressive language, fine motor, and gross motor subscale scores were secondary outcomes. The majority of patients (n = 50) were tested using the Third Edition of the Bayley (Bayley-III), and a smaller number (n = 19) were tested with the Fourth Edition (Bayley-4). For patients with multiple Bayley assessments, the latest assessment was used in analysis.
2.4. Statistical analysis
Statistical software IBM SPSS version 28 and SAS version 9.4 were used for analysis. Statistical significance was defined as a p < 0.05. Demographic, socioeconomic, surgical, and medical data were compared between individuals with and without placental vascular abnormality using parametric and nonparametric methods, as appropriate. A univariate general linear model was used to evaluate the association of placental vascular abnormality with Bayley scores. Potential covariates were examined in a similar fashion and were considered for inclusion in the multivariable models if the univariate association had a p ≤ 0.1. Variables that met this threshold and were included in model selection were maternal age at time of delivery, substance exposure (tobacco, alcohol, and other drugs), infant sex, genetic abnormality, single ventricle cardiac physiology, post operative length of stay after primary CPB procedure, and number of infant cardiac operations (not including catheterizations) prior to Bayley testing. Although cardiac arrest, cardiac transplantation, and stroke met criteria for inclusion based on univariate association, they were not considered in model selection based on the small sample size of patients with these complications.
An interaction between placental vascular abnormality and genetic abnormality was identified, therefore the final multivariable linear regression models assessed the heterogeneous effect of placental vascular abnormality between genetic abnormality groups while controlling for potential covariates. The final models included covariates selected via a forward selection procedure, allowing potential confounders with p ≤ 0.1 to enter the model, while forcing placental vascular abnormality, genetic abnormality, and the interaction between placental vascular abnormality and genetic abnormality in the model. Bayley version was also forced into the model to account for systematic variation in Bayley scoring, which prevents direct comparison.
3. Results
3.1. Study population
Sixty-nine maternal-fetal dyads met inclusion criteria for the study (Fig. 1). Placental vascular abnormality was seen in 43 % (30/69) of patients, the majority of which was maternal vascular malperfusion (38 %, 26/69). Fetal vascular malperfusion was present in 10 % (7/69) and delayed villous maturation in 10 % (7/69). More than one placental vascular abnormality was seen in 14 % (10/69). There were no significant differences in demographic, socioeconomic, surgical, and medical characteristics between those with and without placental vascular abnormality (Table 1). The ages at Bayley testing ranged from 12.4 to 40.2 months. The median age at testing was similar for those with and without placental vascular abnormality (Table 1).
Fig. 1.
Patient inclusion and exclusion.
Table 1.
Cohort characteristics.
| Placental vascular abnormality (n = 30) | No placental vascular abnormality (n = 39) | P-value | |
|---|---|---|---|
| Maternal characteristics | |||
| Age at delivery, years | 27.4 ± 6.3 | 29.0 ± 5.3 | 0.25 |
| Hypertensive disorder | 2 (6.7) | 9 (23.1) | 0.10* |
| Diabetic disorder | 6 (20.0) | 3 (7.7) | 0.16* |
| Substance exposure | 10 (33.3) | 16 (41.0) | 0.51 |
| Polyhydramnios | 1 (3.3) | 4 (10.3) | 0.38* |
| Placental characteristics | |||
| Placental weight, grams | 455 ± 120 | 469 ± 93 | 0.60 |
| Birth weight: | |||
| placental weight ratio | 7.3 ± 1.5 | 7.1 ± 1.5 | 0.69 |
| Placental inflammation | 7 (23.3) | 7 (17.9) | 0.76* |
| Infant characteristics | |||
| Sex, male | 16 (53.3) | 21 (53.8) | 0.97 |
| Race | 0.48* | ||
| American Indian/Alaskan native | 1 (3.3) | 0 (0.0) | |
| Black/African American | 3 (10.0) | 4 (10.3) | |
| White | 25 (83.3) | 35 (89.7) | |
| Unknown | 1 (3.3) | 0 (0.0) | |
| Gestational age at birth, weeks | 39.0 (38.0, 39.2) | 39.0 (38.4, 39.1) | 0.76** |
| Birth weight, grams | 3185 ± 484 | 3239 ± 444 | 0.63 |
| Genetic abnormality | 9 (30.0) | 9 (23.1) | 0.52 |
| Single ventricle physiology | 15 (50.0) | 22 (56.4) | 0.60 |
| Age at primary surgery, days | 8 (3, 37 | 6 (4, 8) | 0.08** |
| CPB time, minutes | 123.8 ± 54.1 | 144.3 ± 54.0 | 0.17 |
| Cross clamp time, minutes | 58.9 ± 41.3 | 62.4 ± 43.5 | 0.76 |
| Post operative LOS, days | 22 (9, 34) | 15 (9, 28) | 0.70** |
| Cardiac arrest | 3 (10.0) | 1 (2.6) | 0.31* |
| Mechanical circulatory support | 2 (6.7) | 3 (7.7) | >0.99* |
| Cardiac transplant | 1 (3.3) | 2 (5.1) | >0.99* |
| Culture proven sepsis | 3 (10.0) | 1 (2.6) | 0.31* |
| Seizures | 3 (10.0) | 1 (2.6) | 0.31* |
| Stroke | 3 (10.0) | 2 (5.1) | 0.65* |
| Number of cardiac operations | 0.37* | ||
| 1 | 14 (46.7) | 20 (51.3) | |
| 2 | 12 (40.0) | 18 (46.2) | |
| 3 or more | 4 (13.3) | 1 (2.6) | |
| Number of cardiac catheterizations | 0.09* | ||
| 0 | 8 (26.7) | 7 (17.9) | |
| 1 | 5 (16.7) | 17 (43.6) | |
| 2 | 7 (23.3) | 9 (23.1) | |
| 3 or more | 10 (33.3) | 6 (15.3) | |
| Number of non-cardiac surgeries | 0.41* | ||
| 0 | 10 (33.3) | 21 (53.8) | |
| 1 | 13 (43.3) | 11 (28.2) | |
| 2 or more | 7 (23.3) | 7 (17.9) | |
| Age at Bayley, months | 21.3 ± 5 | 22.4 ± 6.3 | 0.43 |
| National ADI at Bayley | 65.4 ± 22.4 | 57.9 ± 24.9 | 0.20 |
Data are reported as mean ± standard deviation, median (interquartile range) and number (percentage) as appropriate. Hypertensive disorder was defined as chronic hypertension, pregnancy-induced hypertension, or pre-eclampsia. Diabetic disorder was defined as gestational or pre-existing/chronic type 1 or type 2 diabetes mellitus. Substance use included tobacco, alcohol, and other drugs. Placental inflammation included both chronic and acute inflammation as defined by the Amsterdam Criteria [23]. Postoperative LOS was for the initial CPB operation. Mechanical circulatory support included extracorporeal membrane oxygenation and/or ventricular assist device.
ADI = Area deprivation index; CPB = cardiopulmonary bypass; LOS = length of stay.
P-value associated with Fisher’s exact test. Other p-values were from Chi-square test for categorical variables.
P-value associated with Wilcoxon’s test. Other p-values were from t-test for continuous variables.
The distribution of STAT Mortality Categories for the cohort were as follows: 13 % (n = 9) were Category 1, 25 % (n = 17) were Category 2, 17 % (n = 12) were Category 3, 12 % (n = 8) were Category 4, and 33 % (n = 23) were Category 5. Genetic abnormality was present in 26 % (18/69) of the cohort. Table 2 shows the genetic diagnosis/pathogenic variant, associated non-cardiac anomalies, and presence/absence (and type) of placental vascular abnormality for each infant categorized as having a genetic abnormality. There was no difference in frequency of genetic diagnoses for those with and without placental vascular abnormality (Table 1). Due to sample size, STAT categories were grouped into lower surgical complexity [1–3] versus higher surgical complexity [4,5] to examine the association of STAT category with presence of genetic abnormality. The frequency of genetic abnormality did not differ for lower versus higher surgical complexity (21 % vs. 32 %, p = 0.29). Infants with and without genetic abnormality had a median postoperative length of stay of 24 days and 15 days, respectively; however, there was not a group difference on Mann-Whitney U test (p = 0.27).
Table 2.
Genetic diagnosis, non-cardiac anomalies, and placental vascular abnormality for each patient with a genetic abnormality.
| Genetic diagnosis and/or pathogenic variant | Non-cardiac anomalies present in individual | Placental vascular abnormality |
|---|---|---|
| Alagille Syndrome | Intrahepatic biliary duct agenesis | No |
| Heterotaxy syndrome with c.985C > T (p.Arg329Cys) mutation in exon 10 of CRELD1 gene | Congenital asplenia | No |
| Heterotaxy syndrome without an identified pathogenic variant | Congenital asplenia, Intestinal malrotation | No |
| Heterotaxy syndrome without an identified pathogenic variant | None | No |
| Heterotaxy syndrome without an identified pathogenic variant | None | Yes (maternal vascular malperfusion) |
| Jacobsen Syndrome | Left renal agenesis, Moderate right renal hydronephrosis | No |
| Kabuki Syndrome | Duplex left kidney | Yes (maternal and fetal vascular malperfusion) |
| Trisomy 21 with mosaic Turner’s syndrome and Wolff Parkinson White syndrome without identified genetic variant | None | Yes (maternal vascular malperfusion) |
| 4p16.1-p15.33 deletion; 4q31.1-q35.2 duplication, 4q21q22.3 deletion | Laryngomalacia, Bilateral congenital hip subluxation, Intestinal malrotation | Yes (fetal vascular malperfusion) |
| 6p23p22.3 deletion | External auditory canal atresia bilaterally, Hypospadias, Thumb hypoplasia | No |
| 7p22.2p22.3 duplication | Pulmonary lymphangiectasia | Yes (maternal vascular malperfusion) |
| 14q11.2 deletion (includes MYH6 and MYH7 genes) | None | Yes (maternal vascular malperfusion and delayed villous maturation) |
| 22q11.2 deletion syndrome | Laryngeal cleft, Cervical vertebra anomaly | Yes (delayed villous maturation) |
| Opitz Syndrome | None | Yes (maternal vascular malperfusion) |
| 22q11.2 deletion syndrome | Cleft palate | Yes (maternal vascular malperfusion and delayed villous maturation) |
| Heterotaxy syndrome | Intestinal malrotation, Congenital hypothyroidism | No |
| Turner Syndrome | Congenital hypothyroidism | No |
| 12p13.2 deletion | None | Yes (maternal vascular malperfusion) |
3.2. Association of placental vascular abnormality with Bayley scores
Univariate analyses of the association between placental vascular abnormality and Bayley scores are displayed in Table 3. The presence of placental vascular abnormality was associated with lower language composite scores (mean 81.7 vs 93.9; p < 0.01), as well as lower receptive (mean 7.1 vs 8.9; p = 0.02) and expressive (mean 6.8 vs 9.1; p < 0.01) language scaled scores. Placental vascular abnormality was also associated with lower motor composite scores (mean 81.2 vs 92.1; p = 0.01), as well as lower gross motor scaled scores (mean 5.8 vs 7.8; p < 0.01). Other developmental domains had a similar directionality, but the associations were not significant.
Table 3.
Bayley scores for infants with and without placental vascular abnormality.
| Placental vascular abnormality (n = 30) | No placental vascular abnormality (n = 39) | P-value | |
|---|---|---|---|
| Cognitive composite | 87.4 ± 16.8 | 92.4 ± 14.8 | 0.20 |
| Language composite | 81.7 ± 17.1 | 93.9 ± 17.4 | <0.01 |
| Receptive language subscale | 7.1 ± 3.2 | 8.9 ± 2.9 | 0.02 |
| Expressive language subscale | 6.8 ± 3.1 | 9.1 ± 3.4 | <0.01 |
| Motor composite score | 81.2 ± 18.5 | 92.1 ± 15.5 | 0.01 |
| Fine motor subscale | 8.1 ± 3.6 | 9.6 ± 2.9 | 0.06 |
| Gross motor subscale | 5.8 ± 3.1 | 7.8 ± 2.6 | <0.01 |
Data are reported as mean ± standard deviation.
An interaction was identified for placental vascular abnormality and genetic abnormality in relation to Bayley scores, such that the association of placental vascular abnormality with ND outcome varied by presence/absence of genetic abnormality. Composite scores for those with and without placental abnormality by genetic group are shown in Fig. 2.
Fig. 2.
Neurodevelopmental outcomes by placental abnormality group for infants with and without genetic abnormality.
The final multivariable regression models for each Bayley outcome are displayed in Table 4. The interaction between placental vascular abnormality and genetic abnormality remained significant across all developmental domains. Compared to infants with genetic abnormality but no placental vascular abnormality, infants with genetic abnormality who also had placental vascular abnormality had lower cognitive (group difference − 18.4, 95 % CI −30.7, −6.1), language (group difference −27.5, 95 % CI −41.2, −13.9), and motor (group difference −27.6, 95 % CI −40.9, −14.2) composite scores. When a genetic abnormality was not present, placental vascular abnormality was not significant. Similar findings were seen for the language and motor subscales (Table 4). As described in the methods, maternal age at time of delivery, substance exposure (tobacco, alcohol, and other drugs), infant sex, genetic abnormality, single ventricle cardiac physiology, post operative length of stay after primary CPB procedure, and number of infant cardiac operations (not including catheterizations) prior to Bayley testing met criteria for consideration as covariates in the multivariable models. However, postoperative length of stay for the initial CPB operation, number of cardiac operations, and infant sex were the only variables that met the threshold to be retained in final models. For the primary outcomes of Bayley composite scores, longer postoperative length of stay was associated with lower scores across all three composites, whereas infant sex was only associated with the language composite. No other covariates met the threshold for retention in final models.
Table 4.
Multivariable regression models for bayley scores by placental vascular abnormality group.
| Group difference (95 % CI) | P value | Adjusted R2 | |
|---|---|---|---|
| Cognitive composite | 0.38 | ||
| No genetic abnormality | 1.7 (−5.8, 9.2) | 0.65 | |
| Genetic abnormality | −18.4 (−30.7, −6.1) | <0.01 | |
| Placental vascular abnormality × genetic abnormality interaction | 20.1 (5.6, 34.6) | <0.01 | |
| Language composite | 0.45 | ||
| No genetic abnormality | −5.5(−13.7, 2.6) | 0.18 | |
| Genetic abnormality | −27.5(−41.2, −13.9) | <0.001 | |
| Placental vascular abnormality × genetic abnormality interaction | 22.0 (5.9, 38.0) | <0.01 | |
| Motor composite | 0.42 | ||
| No genetic abnormality | −3.6 (−11.7, 4.5) | 0.38 | |
| Genetic abnormality | −27.6 (−40.9, −14.2) | <0.001 | |
| Placental vascular abnormality × genetic abnormality interaction | 23.9 (8.2, 39.7) | <0.01 | |
| Receptive language subscale | 0.37 | ||
| No genetic abnormality | −0.6 (−2.2, 0.9) | 0.41 | |
| Genetic abnormality | −4.4 (−6.9, −2.0) | <0.001 | |
| Placental vascular abnormality × genetic abnormality interaction | 3.8 (0.9, 6.7) | 0.01 | |
| Expressive language subscale | 0.40 | ||
| No genetic abnormality | −1.1 (−2.8, 0.5) | 0.17 | |
| Genetic abnormality | −4.8 (−7.4, −2.1) | <0.001 | |
| Placental vascular abnormality × genetic abnormality interaction | 3.6 (0.5, 6.8) | 0.03 | |
| Fine motor subscale | 0.38 | ||
| No genetic abnormality | −0.4 (−2.0, 1.2) | 0.63 | |
| Genetic abnormality | −4.9 (−7.5, −2.3) | <0.001 | |
| Placental vascular abnormality × genetic abnormality interaction | 4.5 (1.5, 7.6) | <0.01 | |
| Gross motor subscale | 0.43 | ||
| No genetic abnormality | −0.9 (−2.3, 0.5) | 0.20 | |
| Genetic abnormality | −4.5 (−6.8, −2.3) | <0.001 | |
| Placental vascular abnormality × genetic abnormality interaction | 3.6 (1.0, 6.3) | <0.01 |
The group difference is the difference between infants with placental vascular abnormality (n = 30) minus those without placental vascular abnormality (n = 39). A total of 18 infants had a genetic abnormality. Covariates that met the threshold of p ≤ 0.1 were retained in the final models, with the exception of Bayley version, which was adjusted for in all models. Covariates retained for each final model: cognitive composite included postoperative length of stay; language composite included postoperative length of stay and infant sex; motor composite included postoperative length of stay; receptive language subscale included infant sex; expressive language subscale included postoperative length of stay and infant sex; fine motor subscale included postoperative length of stay and number of cardiac operations; gross motor subscale included postoperative length of stay.
4. Discussion
This study aimed to define the association between placental vascular abnormalities and ND outcomes in prenatally diagnosed infants with CHD. We identified a significant interaction between placental vascular abnormality and genetic abnormality. In multivariable models, the presence of placental vascular abnormality was associated with lower Bayley scores for infants who had genetic abnormality but not for those without genetic abnormality. The combination of placental vascular abnormality and genetic abnormality resulted in a reduction of 18.4–27.6 points (approximately 1.5 to 2 standard deviations of population norms) across cognitive, language, and motor composite scores. These findings highlight the complex relationships between placenta, genetics, and ND for the CHD population and underscore the importance of considering genetic factors for ND outcome studies, particularly as genetic technology continues to advance.
Neuroplacentology has emerged as a growing field linking the placenta with brain development and ND for offspring [10,27–29]. Placental abnormalities have been associated with abnormal neurologic outcomes in several different infant populations. Specifically, fetal vascular malperfusion has been associated with impaired ND at two years of age in infants with intrauterine growth restriction [30]. Fetal vascular malperfusion has also been linked with worse electronic fetal monitoring tracings for neonates presenting with encephalopathy [31]. In preterm infants, placental lesions, notably when multiple, are associated with an increased incidence of ND impairment [32]. As the field has evolved, it has been proposed that placental dysfunction may contribute to poor brain growth and impaired ND for infants with CHD as well [33,34]. In support of this, increased severity of placental pathology has been associated with smaller brain volumes in neonates with CHD [17,18]. Our study expands these findings by focusing on later outcomes (toddler ND) and including infants with genetic abnormalities, which allowed us to identify a differential impact of placental vascular abnormality on ND outcome based on the infants’ underlying genetics. The results of the current study are in line with a retrospective cohort study that, on univariate analysis, showed lower Bayley-III scores for infants with dextro-transposition of the great arteries and single ventricle physiology who also had placental abnormalities [19]. Their results did not remain significant in multivariable models, although an interaction between placental abnormality and genetics was not examined [19].
Our finding that infants with both placental vascular abnormality and genetic abnormality are at higher risk for ND impairment, regardless of other ND risk factors, underscores the potential for shared genetic pathways in the placenta-heart-brain axis. Placental histopathologic abnormalities are not well described for syndromic patients with CHD, which were the patients included in the current study. However, recent literature supports that disruption in molecular pathways common to placental and cardiac development may be important for CHD [35]. For example, 328 genes have been identified that are commonly expressed in both placental and first trimester heart cells [36]. Specific genes that have been implicated in CHD and placental dysfunction include the neurogenic locus notch homolog protein 1 (NOTCH1) [36–39], as well as the Wnt signaling pathway [40,41] and transcription factors in the GATA family [36,42]. Epigenetic changes from a hypoxic intrauterine environment, including angiogenic dysregulation, may also be important [43–45]. Endothelial nitric oxide synthase [46,47], placental growth factor [48], pregnancy-associated plasma protein A [49], and soluble Fms-like tyrosine kinase-1 [50] have all been shown to be altered with CHD. Future studies investigating genetic and epigenetic influences across the placenta-heart-brain axis would be valuable for understanding pathophysiology and risk stratification of patients.
We recognize our study has several limitations. The most salient is that this was a retrospective study and therefore was reliant on clinically acquired placental and ND data. Placental evaluation is considered routine care for infants with CHD at our institution, but it was not available for out-born infants or those postnatally diagnosed. Additionally, survivors in our cohort only had a ~ 33 % follow up rate for Bayley testing, which significantly limited the sample size. This prevented subgroup analysis for specific placental vascular lesions, specific genetic syndromes, and primary cardiac physiology. This likely also contributed to the limited number of covariates that remained in the multivariable models. Thus, while our results are of interest, the models should be interpreted with caution and confirmed with future, larger cohorts. Other CHD populations, specifically those born preterm (an exclusion criterion for our study), should also be considered in future cohorts. The reason for lack of ND follow-up was not readily available upon chart review. However, our data are comparable to the 29 % average attendance rate for ND evaluation across 16 major cardiac surgical centers [47]. Nonetheless, low ND attendance could still place our study at risk for attrition bias. Our previously published placental histopathology data from our center had similar demographic and clinical characteristics as those reported here [13]. The only difference is a slightly higher proportion of infants with single ventricle physiology in the current analysis, which likely reflects that our cardiac ND clinic initially focused on those patients. The otherwise comparable characteristics between the two cohorts suggest that, despite low ND follow-up rates, infants who did and did not undergo an ND evaluation were likely similar. The retrospective nature of the study also means that we did not have a control group for comparison. However, this was not the aim of the study and the Bayley has published normative data that permits understanding of our cohort’s scores relative to the general population. Another potential limitation to our study is that the placentas were classified according to the Amsterdam criteria [23]. While this is the current standard for placental pathology evaluation, there may still be discrepancy between raters due to the qualitative nature of the criteria [51]. Newer studies [17,52] have attempted to establish a scoring system for placental pathology severity rather than relying on qualitative assessment of individual components of the placenta. Our hypothesis was specific to vascular abnormalities therefore we did not apply this scoring system, as it spans multiple types of pathologic lesions.
5. Conclusion
Placental vascular abnormality is associated with ND outcome for infants with CHD when a clinically diagnosed genetic abnormality is also present. Future longitudinal studies with larger sample sizes, comprehensive genetic testing, and quantitative assessment of placental size, structure, and function will likely improve our understanding of the placenta-heart-brain axis and the specific risk factors that place these infants at particularly heightened risk for adverse ND outcomes.
Acknowledgements
We acknowledge our institutional data collection teams that facilitated identification of eligible patients.
Sources of funding
This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute (K23HL141602), the Eunice Kennedy Shriver National Institute Of Child Health & Human Development of the National Institutes of Health under Award Number U54 HD087011 to the Intellectual and Developmental Disabilities Research Center at Washington University, and the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital. The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
Disclosure of prior presentation(s)
This study data was presented via poster presentations at the 8th World Congress of Pediatric Cardiology and Cardiac Surgery 2023 Conference in Washington D.C., as well as at the Pediatric Academic Societies 2023 Annual Meeting in Washington D.C. It was also presented via oral presentation at the AAP 2024 105th Perinatal & Developmental Medicine Symposium in Bonita Springs, Florida.
CRediT authorship contribution statement
Kelly L. Meyer: Writing – original draft, Visualization, Validation, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Clare O’Hare: Writing – review & editing, Investigation, Data curation. Mai He: Writing – review & editing, Data curation. Gillian Mayersohn: Writing – review & editing, Conceptualization. Avihu Z. Gazit: Writing – review & editing, Conceptualization. Anthony Odibo: Writing – review & editing, Conceptualization. Jinli Wang: Visualization, Validation, Formal analysis. Cynthia M. Ortinau: Writing – review & editing, Visualization, Validation, Supervision, Project administration, Methodology, Investigation, Funding acquisition, Data curation, Conceptualization.
Declaration of competing interest
None declared.
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