Vascular Placental Pathology and Cardiac Structure in Stillborn Fetuses

Abstract

Objective Adverse pregnancy outcomes, including preterm birth and preeclampsia, are associated with worse cardiovascular outcomes for offspring. Examination of the placenta is important for understanding how the prenatal period shapes long-term cardiovascular health. We sought to investigate the association between placental vascular malperfusion and fetal cardiac structure.

Study Design Data obtained from the Stillbirth Collaborative Research Network included stillbirths with placental pathology and autopsy. Stillbirths were classified in two ways: based on the severity of placental maternal vascular malperfusion (MVM) and based on the cause of death (MVM, fetal vascular malperfusion [FVM], or acute infection/controls). Organ weight and heart measures were standardized by gestational age (GA) and compared across groups.

Results We included 329 stillbirths in the analysis by MVM severity and 76 in the analysis by cause of death (COD). While z-scores for most organ weights/heart measures were smaller when COD was attributed to MVM as compared with FVM or controls, heart weight and brain weight z-scores did not differ by COD (p > 0.05). In analyses accounting for body size, the difference between heart and body weight z-score was −0.05 (standard deviation [SD]: 0.53) among those with MVM as a COD and −0.20 (SD: 0.95) among those with severe MVM. Right and left ventricle thicknesses and tricuspid, pulmonary, mitral, and aortic valve circumferences were consistently as expected or larger than expected for GA and body weight. In the analysis investigating the severity of MVM, those with the most severe MVM had heart measures that were as expected or larger than expected for body weight while those with only mild to moderate MVM had heart measures that were generally small relative to body weight.

Conclusion When assessed as COD or based on severity, MVM was associated with heart measures that were as expected or larger than expected for GA and body weight, indicating possible heart sparing.

Key Points

• Fetal deaths with MVM show smaller organ weights.

• Heart weight sparing is seen with fetal death attributed to MVM.

• Heart weight sparing is more pronounced with severe MVM.

Keywords

autopsy - maternal vascular malperfusion - fetal vascular malperfusion - heart - weight sparing - placental pathology

Heart disease is the leading cause of death (COD) in the United States, accounting for one in five deaths.[1] Early risk stratification is essential for targeting interventions to reduce the burden of heart disease.[2] [3] Consistent with the developmental origins of the health and disease framework, the prenatal period may be a critical window for shaping the long-term risk of heart disease.[4] Human studies show that adverse birth outcomes, including preterm birth, poor fetal growth, and preeclampsia are associated with long-term offspring cardiovascular morbidity and mortality.[5] [6] [7] [8] [9] [10] [11] [12] [13] Further, these adverse birth outcomes have been linked with cardiac remodeling and dysfunction, as assessed both in early life and adulthood.[14] [15] [16] [17] [18] [19] [20] [21] These cardiac changes may contribute to increased susceptibility for later-life cardiovascular disease (CVD).[21] Understanding the mechanisms underlying the association between adverse birth outcomes and offspring cardiac dysfunction is critical for improving the identification of those at increased risk of CVD and developing interventions to improve cardiovascular health across the life course.

While adverse birth outcomes are multifactorial, there is increasing recognition that abnormal placentation is a significant contributor.[22] [23] Placental lesions indicative of defective deep placentation are grouped as maternal vascular malperfusion (MVM).[22] [24] MVM can be evaluated through placental histologic assessment following delivery and MVM lesions are identified in up to 50% of those born preterm,[25] 96% of those with poor fetal growth,[26] and 95% of those with early-onset preeclampsia.[27] Other chronic placental pathologies that have been shown to contribute to fetal growth restriction and preeclampsia, including chronic inflammation and fetal vascular malperfusion (FVM), might also play a role in cardiac development. FVM is of particular interest because fetal placental vessels are in direct continuity with the developing fetal cardiovascular system, making an anatomically plausible link between fetal vascular disease in the placenta, fetal blood flow alterations, and potential impact on cardiac development and/or function. Thus, assessment of placental MVM and FVM may yield insights into underlying mechanisms of altered cardiac development and improve the identification of those at risk of adverse cardiovascular health across the life course.

Studies investigating MVM in relation to offspring cardiovascular disease risk are limited by data availability, particularly the availability of placental assessments. However, one study with routine placental assessment demonstrated that MVM is associated with elevated blood pressure in childhood among those born early preterm (<34 weeks gestation).[28] Further, our recent findings demonstrate that stillborn fetuses with a COD attributed to MVM demonstrated relative sparing of heart weight for gestational age (GA).[29] Building on these findings, the purpose of our analysis was to (1) replicate findings in a different stillbirth cohort and investigate whether similar patterns are observed for FVM and (2) to determine whether the severity of MVM is similarly associated with changes in cardiac structure.

Materials and Methods

Sample Derivation

Data were derived from the Stillbirth Collaborative Research Network (SCRN), a study of stillbirths and livebirths completed at 59 hospitals across five geographic regions in the United States from 2005 to 2009.[30] Institutional Review Boards from each center and Data Coordinating and Analysis Center approved study procedures; for each portion of the study, participants gave written informed consent. Placental and postmortem examinations were standardized across institutions, as described previously.[31] [32] Briefly, placentas were examined fresh, whenever possible, by trained SCRN pathologists, photographed, and weighed after trimming of the umbilical cord and membranes. Representative sections for histological analysis included two sections of the umbilical cord, one section perpendicular to the umbilical cord insertion site, one membrane roll, and four randomly selected sections of placental parenchyma from a center slice. Fetal COD was assigned according to Initial Causes of Fetal Death Evaluation, which assigns stillbirth COD according to a standardized protocol; lesions/pathologies are rated as 1 (present), 2 (possible COD), or 3 (probable COD).[33] Level of maceration was graded and categorized as grade 0 = no maceration, grade I = skin desquamation involving ≤1% of the body surface area, grade II = skin desquamation involving >1 but <5% of the body surface area, grade II = skin desquamation involving ≥5% of the body surface area, grade IV = total brown skin discoloration, and grade V = mummification. In this analysis, severe maceration was considered either grade IV or V.

Participants were included in these analyses if they delivered a singleton stillbirth with a GA of ≥20 weeks and consented to complete placental and postmortem examinations. Participants were excluded if postmortem stillbirth examination revealed evidence of structural heart disease, congenital or metabolic cardiac disease, or multiple or syndromic anomalies.

Analyses of MVM severity in relation to the structural fetal heart measures included all participants meeting eligibility criteria. For analyses based on COD, participants were restricted to those with COD attributable to MVM and/or FVM. For comparison, we included controls with COD due to acute placental infection, as acute processes close to death are unlikely to impact long-term placental function and/or significantly change cardiac structure. Participants were assigned to the following groups according to COD:

1. Compromised maternal circulation: probable (3) COD due to extensive villous (parenchymal) infarcts;

2. Compromised fetal circulation: probable (3) COD due to compromised fetal microcirculation (thromboembolism of umbilical vein or villous fetal capillaries and avascular villi, with evidence of obstruction), umbilical cord entrapment (including nuchal, body, or shoulder cord with evidence of occlusion and fetal hypoxia), or umbilical cord stricture (true knots, torsions, or narrowing with thrombi or other obstruction); and

3. Control: possible (2) or probable (3) COD attributable to placental infection (culture or PCR proven with placental changes) or chorioamnionitis (culture or PCR proven with funisitis) with the absence of other probable (3) COD in any category.

Participants with COD outside of these parameters were excluded from analyses comparing MVM, FVM, and controls.

Weights and Measures

Organ weights and measures were extracted from SCRN autopsy data. GA-adjusted z-scores for each organ were derived from published stillbirth references.[34] [35] [36] Relative organ weight/measure to body weight was calculated by subtracting body weight z-score from organ weight or measure z-score for each fetus.

Lesions of Maternal Vascular Malperfusion

Placental MVM lesions were extracted from SCRN placental pathology data. An established method for scoring the number of MVM lesions present was used, as shown in [Table 1].[37] The total score for MVM lesions was calculated, and groups were defined as scores of 0–1 (no/mild MVM), 2–3 (moderate MVM), or ≥4 (severe MVM).

Table 1 Calculation of maternal vascular malperfusion lesion score

Freedman–Ernst MVM variables	Points	SCRN placental examination
Fibrinoid necrosis/acute atherosis	1	Fibrinoid necrosis or atherosis/foam cells of membranes or basal plate
Muscularization of basal plate arterioles	1	Thick vessel walls (hypertrophy) of decidual vasculature on basal plate
Basal decidual vascular thrombus	1	Thrombosis of decidual vasculature on basal plate
Mural hypertrophy of membrane arterioles	1	Thick vessel walls (hypertrophic) on free membranes
Single infarct	1	Villous parenchymal infarction—focal
Multiple infarcts, <5% of parenchyma	2	Villous parenchymal infarction—multiple foci, patchy, or diffuse
Multiple infarcts, ≥5% of parenchyma	2
Increased syncytial knots	1	Increased syncytial knots of villous parenchyma—multiple foci or diffuse
Villous agglutination	1	Not available
Increased perivillous fibrin deposition	1	Fibrinoid deposition of villous parenchyma or intervillous fibrin deposition—multiple foci or diffuse
Distal villous hypoplasia/small terminal villous diameters	1	Distal villous hypoplasia of villous parenchyma—multiple foci or diffuse
Retroplacental blood/hematoma	1	Hemorrhage/Clot on basal plate
Retroplacental blood/hematoma with hemosiderin or infarct	2	Hemorrhage/Clot on basal plate, with villous infarction
Small for gestational age (SGA) placenta	2	Placental weight <10th percentile for GA (isolated SGA placenta not considered MVM)

Abbreviation: GA, gestational age; MVM, maternal vascular malperfusion; SCRN, Stillbirth Collaborative Research Network.

Statistical Analyses

First, demographic and fetal characteristics were compared across groups (compromised maternal circulation, compromised fetal circulation, control) using Kruskal–Wallis (continuous) and chi-square (categorical) tests; post hoc comparisons between groups were completed using Mann–Whitney (continuous) and chi-square (categorical) tests. Organ z-scores and organ-to-body z-score differences were compared among and between groups using the appropriate tests, as above.

Organ z-scores and organ-to-body z-score differences were compared among and between MVM lesion categories (0–1, 2–3, and ≥4) using the methods detailed above. A Mann–Kendall test of trend was conducted to determine trends in relative z-scores across groups. The relative proportions of MVM lesion categories across our initial groups (compromised maternal circulation, compromised fetal circulation, and control) were compared using a chi-square test.

Statistical analyses were completed using RStudio (version 2022.12.0, R version 4.2.2). A p-value of 0.05 was used to determine statistical significance for primary analyses testing overall differences across groups. A p-value threshold of 0.0167 (0.05/3) was used to determine statistical significance for post hoc analyses, which included three comparisons.

Results

Study Sample

Our final sample comprised 329 participants; of these, 76 met the COD criteria for classification into our three groups (compromised maternal circulation, compromised fetal circulation, and control). Sample derivation is shown in [Fig. 1]. Among the COD sample, participants classified as controls were more likely to identify as a racial minority group (57.9%) in comparison to 19% of those with compromised maternal and 25% of those with compromised fetal circulation ([Table 2]). Those with compromised maternal circulation as a COD had lower birth weights on average (784 g, standard deviation [SD]: 569) in comparison to those with compromised fetal circulation (1,720 g, SD: 1,308) and controls (1,125 g, SD: 1,210). Similarly, 28.6% of those with compromised maternal circulation were small for GA (birth weight <10th percentile for age and sex), though this was not statistically significantly different from those with compromised fetal circulation (11.1%) or controls (5.3%; p = 0.12). There were no statistically significant differences in ethnicity, years of education, or maternal age at delivery.

Fig. 1 This diagram shows the sample selection within the SCRN cohort. MVM, maternal vascular malperfusion; SCRN, Stillbirth Collaborative Research Network.

Table 2 Demographic characteristics of study sample by cause of death group (n = 76)

Measure	Control (n = 19)	Compromised fetal circulation (n = 36)	Compromised maternal circulation (n = 21)	p-Value
Ethnicity (Hispanic)	4 (21.1)	18 (50.0)	8 (38.1)	0.11
Race (minority)	11 (57.9)	9 (25.0)	4 (19.0)	0.015
Education (y)	12.6 (2.6)	13.9 (2.7)	13.1 (2.6)	0.3
Maternal age at delivery (y)	27.3 (6.6)	27.5 (7.4)	28.7 (5.9)	0.6
Fetus sex (female)	6 (31.6)	18 (50.0)	9 (42.9)	0.4
Fetal weight (g)	1,125 (1,210)	1,720 (1,308)	784 (569)	0.047
Small for gestational age infant	1 (5.3)	4 (11.1)	6 (28.6)	0.12
Gestational age at birth (wk)	27.0 (7.7)	30.9 (6.9)	27.7 (4.5)	0.056
Severe maceration (grades IV–V)	0 (0)	6 (17.1)[a]	5 (23.8)	0.09

Notes: Results are presented as n (%) or mean (standard deviation).

Minority race self-identified as Black, Asian, Native Hawaiian/Pacific Islander, American Indian/Alaskan Native, or other.

^a Maceration grade was missing for one sample.

Among the MVM group, 159 (48.3%) had no/mild MVM, 82 (24.9%) had moderate MVM, and 88 (26.8%) had severe MVM ([Table 3]). The proportion of participants identified as Hispanic differed by MVM severity, with 28.9% identified as Hispanic among the no/mild MVM group, 34.1% among the moderate MVM group, and 46.0% among the severe MVM group (p = 0.027). There were no differences in other demographic characteristics, including race, education, and maternal age. While GA and fetal sex also did not differ across groups, those with severe MVM had the lowest birth weight (1,006 g, SD: 852, p = 0.022).

Table 3 Demographic characteristics of study sample by the severity of maternal vascular malperfusion, n = 329

Measure	Number of MVM lesions			p-Value
	0–1 (n = 159)	2–3 (n = 82)	4+ (n = 88)
Ethnicity (Hispanic)	46 (28.9)	28 (34.1)	40 (46.0)	0.027
Race (minority)	62 (39.0)	27 (32.9)	27 (30.7)	0.4
Education (y)	13.0 (2.7)	13.0 (2.9)	13.1 (3.0)	0.9
Maternal age at delivery (y)	27.6 (6.2)	27.0 (6.5)	27.9 (6.7)	0.8
Fetus sex (female)	72 (45.3)	41 (50.0)	45 (51.1)	0.6
Fetal weight (g)	1,524 (1,237)	1,432 (1,350)	1,006 (852)	0.022
Gestational age at birth (wk)	29.3 (7.0)	28.8 (7.1)	28.3 (5.7)	0.6

Abbreviation: MVM, maternal vascular malperfusion.

Notes: Results are presented as n (%) or mean (standard deviation).

Minority race self-identified as Black, Asian, Native Hawaiian/Pacific Islander, American Indian/Alaskan Native, or Other.

Analysis by Cause of Death

Measures of organ weight z-scores were generally statistically significantly smaller for those with COD related to compromised maternal circulation ([Table 4]). However, there was no statistically significant difference in brain weight z-score or heart weight z-score across the three groups. Heart measure z-scores were generally smaller than expected for GA in the compromised maternal circulation group (mean z-scores <0), whereas heart measures were generally as expected or larger than expected in the compromised fetal circulation and control groups (mean z-scores ≥0). Post hoc analyses comparing those with compromised maternal circulation to controls demonstrated statistically significantly smaller left ventricular thickness, tricuspid valve circumference, mitral valve circumference, and aortic valve circumference.

Table 4 Organ and heart measure z-scores by cause of death (n = 76)

Measure Mean z-score ± SD	Cause of death			Overall p-value
	Control (n = 19)	Compromised fetal circulation (n = 36)	Compromised maternal circulation (n = 21)
Body weight	0.11 ± 0.96	0.29 ± 1.20	−0.86 ± 0.90[b] [c]	<0.001
Placental weight	−0.16 ± 1.90	−0.85 ± 3.62	−2.57 ± 1.44[b] [c]	<0.001
Heart weight	−0.07 ± 1.10	−0.39 ± 0.82	−0.71 ± 0.82	0.1
Liver weight	0.62 ± 1.15	−0.20 ± 1.17[a]	−0.94 ± 0.66[b] [c]	<0.001
Brain weight	0.06 ± 0.92	−0.10 ± 1.49	−0.50 ± 1.10	0.5
Lung weight	0.55 ± 1.32	0.44 ± 1.31	−0.70 ± 0.88[b] [c]	<0.001
Thymus weight	1.62 ± 3.83	0.16 ± 1.14	−0.26 ± 3.13[b] [c]	<0.001
Spleen weight	0.55 ± 1.37	−0.05 ± 0.98	−0.81 ± 0.95[b] [c]	<0.001
Kidney weight	0.05 ± 1.12	−0.27 ± 1.23	−1.11 ± 1.01[b] [c]	0.004
Adrenal weight	0.68 ± 0.97	0.51 ± 2.35	−0.86 ± 0.75[b] [c]	<0.001
Right ventricle thickness	0.45 ± 1.35	0.08 ± 1.06	−0.49 ± 0.94	0.024
Left ventricle thickness	0.90 ± 1.99	−0.26 ± 1.31	−0.42 ± 1.23[b]	0.011
Tricuspid valve circumference	0.71 ± 1.32	0.16 ± 1.50	−0.53 ± 1.15[b]	0.007
Pulmonary valve circumference	0.31 ± 1.20	0.26 ± 1.69	−0.58 ± 1.14	0.054
Mitral valve circumference	0.64 ± 1.04	0.29 ± 1.27	−0.11 ± 0.96[b]	0.038
Aortic valve circumference	0.44 ± 1.26	0.37 ± 2.19	−0.70 ± 1.02[b]	0.024

Abbreviation: SD, standard deviation.

^a p-Value <0.0167 for post hoc comparison of compromised fetal circulation versus control.

^b p-Value <0.0167 for post hoc comparison of compromised maternal circulation versus control.

^c p-Value <0.0167 for post hoc comparison of compromised fetal circulation versus compromised maternal circulation.

In analyses accounting for body size (difference between organ weight or measure z-score and body weight z-score), heart weight was as expected for body size in those with compromised maternal circulation (mean difference in z-score: −0.04, SD: 0.53), which was not significantly different from the control group (mean: −0.18, SD: 0.88; [Table 5]). In contrast, those with compromised fetal circulation had heart weights that were small relative to body weight (mean: −0.68, SD: 0.76, p < 0.01). This trend was also observed for brain weight relative to body weight, where those with compromised maternal circulation and controls had brain weights as expected for body weight (compromised maternal: 0.07, SD: 1.05; control: −0.03, SD: 0.60), and those with compromised fetal circulation had small brain weights relative to body weight (−0.45, SD: 1.47). However, the difference in brain weight z-score was not statistically significant across groups (p = 0.20). Other heart measures relative to body size generally did not differ across COD groups.

Table 5 Difference between organ or heart measure z-score and body weight z-score by cause of death (n = 76)

Measure Mean difference in z-score ± SD	Cause of death			Overall p-value
	Control (n = 19)	Compromised fetal circulation (n = 36)	Compromised maternal circulation (n = 21)
Placental weight	−0.27 ± 1.81	−1.14 ± 3.50[a]	−1.76 ± 1.51[b]	0.009
Heart weight	−0.18 ± 0.88	−0.68 ± 0.76	−0.04 ± 0.53[c]	0.006
Liver weight	0.51 ± 0.94	−0.62 ± 0.86[a]	−0.18 ± 0.37[b] [c]	<0.001
Brain weight	−0.03 ± 0.59	−0.45 ± 1.47	0.07 ± 1.05	0.2
Right ventricle thickness	0.34 ± 1.54	−0.13 ± 1.56	0.37 ± 1.22	0.3
Left ventricle thickness	0.79 ± 2.21	−0.44 ± 1.55	0.44 ± 1.60	0.038
Tricuspid valve circumference	0.60 ± 1.24	−0.13 ± 1.50	0.34 ± 1.27	0.2
Pulmonary valve circumference	0.20 ± 1.04	−0.03 ± 1.41	0.28 ± 1.08	0.6
Mitral valve circumference	0.56 ± 1.06	0.00 ± 1.41	0.76 ± 1.19	0.2
Aortic valve circumference	0.36 ± 1.14	0.08 ± 1.98	0.16 ± 0.81	0.4

Abbreviation: SD, standard deviation.

^a p-Value <0.0167 for post hoc comparison of compromised fetal circulation versus control.

^b p-Value <0.0167 for post hoc comparison of compromised maternal circulation versus control.

^c p-Value <0.0167 for post hoc comparison of compromised fetal circulation versus compromised maternal circulation.

Analysis by Maternal Vascular Malperfusion Severity

Body weight and organ-weight z-scores for GA differed by MVM severity in a dose-dependent fashion, with the most severe MVM (score ≥4) having the smallest organ weights for GA (z-scores generally <0), those with moderate MVM (score 2–3) having organ weights that were generally slightly smaller than expected or as expected for GA, and those with no or mild MVM (score 0–1) generally having organ weights that were as expected or larger than expected for GA ([Fig. 2]). Tests of trend for all organ weights were statistically significant (p < 0.05). Heart measures displayed similar patterns, with the smallest z-scores observed among the severe MVM group and the largest z-scores observed among the no/mild MVM group. Similarly, all tests for trends were statistically significant.

Fig. 2 Organ and heart measure z-score by severity of maternal vascular malperfusion (MVM), n = 329. Error bars reflect a 95% confidence interval. circ, circumference; LV, left ventricle; RV, right ventricle.

In analyses comparing organ weights or heart measure z-score relative to body weight z-score, heart weight did not differ by MVM severity, though the smallest difference was observed for those with severe MVM (mean difference between heart weight and body weight z-score: −0.20, SD: 0.95) as compared to those with moderate MVM (−0.78, SD: 3.57) or no/mild MVM (−0.23, SD: 0.85; [Table 6]). In comparison, brain weight was slightly large relative to body size in those with the most severe MVM (0.16, SD: 0.84). In general, those with the most severe MVM had heart measures that were as expected or larger than expected relative to body weight and those with moderate MVM had heart measures that were generally smaller than expected relative to body weight.

Table 6 Difference between organ or heart measure z-score and body weight z-score by the severity of maternal vascular malperfusion, n = 329

Measure Mean difference in z-score ± SD	Number of MVM lesions			Overall p-value
	0–1 (n = 159)	2–3 (n = 82)	4+ (n = 88)
Placental weight	−0.68 ± 3.48[a]	−2.14 ± 3.72[a]	−1.93 ± 1.34[b]	<0.001
Heart weight	−0.23 ± 0.85	−0.78 ± 3.57	−0.20 ± 0.95	0.6
Liver weight	−0.16 ± 1.38	−0.73 ± 3.62	−0.11 ± 0.48	0.3
Brain weight	−0.15 ± 1.21	−0.78 ± 3.95	0.16 ± 0.84	0.1
Right ventricle thickness	0.05 ± 1.61	−0.47 ± 3.74	0.22 ± 1.37	0.7
Left ventricle thickness	0.00 ± 1.69	−0.51 ± 3.87	0.23 ± 1.39	0.3
Tricuspid valve circumference	−0.13 ± 1.45	−0.67 ± 3.63	0.01 ± 1.29	0.7
Pulmonary valve circumference	−0.28 ± 1.34	−1.01 ± 3.62	0.00 ± 1.29[c]	0.023
Mitral valve circumference	0.05 ± 1.39	−0.54 ± 3.83	0.33 ± 1.23	0.1
Aortic valve circumference	−0.25 ± 1.60	−0.76 ± 2.95	0.12 ± 1.14[c]	0.04

Abbreviations: MVM, maternal vascular malperfusion; SD, standard deviation.

^a p-Value <0.0167 for post hoc comparison of 2–3 versus 0–1.

^b p-Value <0.0167 for post hoc comparison of 4+ versus 0–1.

^c p-Value <0.0167 for post hoc comparison of 2–3 versus 4 + .

Discussion

Fetal heart weight sparing may occur in the setting of MVM when evaluated either as a COD (compromised maternal circulation) or based on severity (≥4 MVM lesions). Stillbirths with COD attributed to compromised maternal circulation generally had smaller organ weights and heart measures relative to GA. However, after accounting for fetal body weight, those with compromised maternal circulation generally had organ weights and heart measures that were as expected or larger than expected relative to body size. Similar patterns were observed with MVM severity; those with the most severe MVM generally had smaller organ weight and heart measures than expected for their GA. Though in analyses accounting for body size, those in the severe MVM group generally had organ weights and heart measures that were as expected or larger than expected relative to body size. These consistent findings are potentially indicative of heart sparing in MVM. In contrast, heart weight was small relative to GA among those with compromised fetal circulation.

Our findings are consistent with our previous work in a stillbirth sample, where we demonstrated that stillbirths with COD attributed to MVM generally had smaller organ weights and heart measures for GA but also had relative sparing of heart weight and heart measures when analysis accounted for body size.[29] In prior work, we observed that MVM stillbirths had heart weight z-scores that were 0.3 SDs larger than expected for body weight. In the present analysis, we found that heart weights were as expected for body weight among stillbirths with COD attributed to compromised maternal circulation. Similar patterns were observed for brain weight in the COD analysis, with large brain weights relative to body weight observed in prior work and brain weights as expected for body weight observed in the present analysis. These results also build on our previous findings by demonstrating that with increasing severity of MVM, heart weight/measure sparing was generally increased. After accounting for body size, we observed that for the most severe cases of MVM, heart measures were as expected or larger than expected relative to body size.

Findings of generally small organ weights and heart measures among those with severe MVM are consistent with changes observed in fetal growth restriction, a common consequence of severe MVM.[24] Brain weight sparing is also a known feature of growth restriction, and our finding that brain weights are larger relative to body weight in severe MVM as compared to no or mild MVM is consistent.[38] [39] Similarly, growth restriction is associated with changes in cardiac structure and function, including increased wall thickness, hypertrophy, and a more globular shape, as assessed in infancy and childhood.[14] [19] [39] [40] [41] [42] [43] [44] [45] These changes likely contribute to increased CVD risk in adulthood.[10] [18] [45] [46] [47] [48] Findings that stillbirths attributed to compromised fetal circulation have smaller organ measures relative to body size and are also consistent with reported associations between fetal vascular malperfusion and growth restriction.[49] [50]

Strengths and Limitations

Strengths of the analysis include the use of a multisite study with a large sample of stillbirths. Standardized autopsy and placental pathology methods and reporting tools were used across study sites. COD was also evaluated consistently across study sites. Analyses also used measures standardized by GA to account for differences in the GA distributions across groups. Limitations include the inability to determine directionality; placental pathology and fetal measures were both assessed following delivery. Our results do not indicate whether MVM leads to alterations in fetal cardiac development or whether abnormal cardiac development contributes to the development of MVM. Our findings in a stillbirth sample also may not be generalizable to live births with MVM.

Conclusion

Our findings suggest that MVM, both assessed as a COD and based on placental lesion severity, is associated with alterations in cardiac structure, with as expected or larger heart measures observed relative to body size in comparison to those with COD unrelated to MVM or less severe placental MVM burden. Additional research is needed to understand the underlying mechanisms and establish directionality. Future studies should also include measures of neonatal cardiac structure and function to investigate whether findings are consistent in a live birth sample. Consistent findings in a live birth sample may have important implications for cardiovascular health across the life course and may help explain observed associations between adverse birth outcomes and long-term risk of cardiovascular disease.

Conflict of Interest

None declared.

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Publication History

Received: 30 January 2024

Accepted: 25 August 2024

Accepted Manuscript online:
29 August 2024

Article published online:
19 September 2024