Impaired maternal central hemodynamics precede the onset of vascular disorders of pregnancy at high altitude

Abstract

Hypertensive disorders of pregnancy represent an escalating global health concern with increasing incidence in low- to middle-income countries and high-income countries alike. The current lack of methods to detect the subclinical stages of preeclampsia (PE) and fetal growth restriction (FGR), two common vascular disorders of pregnancy, limits treatment options to minimize acute- and long-term adverse outcomes for both mother and child. To determine whether impaired maternal cardiovascular or uteroplacental vascular function precedes the onset of PE and/or FGR (PE-FGR), we used noninvasive techniques to obtain serial measurements of maternal cardiac output (CO), stroke volume (SV), systemic vascular resistance (SVR), and uterine and fetal arterial resistance at gestational weeks 10–16, 20–24, and 30–34 for 79 maternal-infant pairs in La Paz-El Alto, Bolivia (3,850 m), where the chronic hypoxia of high altitude increases the incidence of PE and FGR. Compared with controls (n = 55), PE-FGR cases (n = 24) had lower SV, higher SVR, and greater uterine artery resistance at 10–16 wk. In addition, fetuses of women with lower SV and higher SVR at 10–16 wk showed evidence of brain sparing at 30–34 wk and had lower birth weights, respectively. Although the trajectory of SV and SVR across pregnancy was similar between groups, PE-FGR cases had a comparatively blunted rise in CO from the first to the third visit. Impaired maternal central hemodynamics and increased uteroplacental resistance precede PE-FGR onset, highlighting the potential use of such measures for identifying high-risk pregnancies at high altitudes.

NEW & NOTEWORTHY In this prospective study of maternal central hemodynamics at high altitude, pregnancies later affected by preeclampsia (PE) and/or fetal growth restriction (FGR) show elevated systemic and uterine vascular resistance and reduced stroke volume as early as 10–16 wk gestation. Maternal hemodynamic assessments could facilitate early detection of high-risk pregnancies, improving resource allocation and reducing adverse outcomes. We propose an integrated model linking maternal cardiovascular performance to placental insufficiency, enhancing the understanding of PE-FGR in high-altitude settings.

INTRODUCTION

Successful pregnancy requires extensive cardiovascular changes to support uteroplacental perfusion and meet increased maternal and fetal metabolic demands across gestation. Such changes begin early in the first trimester of a healthy pregnancy, during which reduced maternal peripheral vascular resistance and arterial pressure permit a rise in cardiac output (CO) (1, 2). Uterine artery (UtA) blood flow also begins to rise early in pregnancy due to increased vessel diameter and, subsequently, blood flow velocity (3, 4). Collectively, these adaptations result in a progressive redistribution of CO to favor the uteroplacental circulation during the third trimester, when fetal growth increases exponentially. Incomplete maternal hemodynamic adaptation to pregnancy is observed in preeclampsia (PE) and fetal growth restriction (FGR) (5–8), each characterized by lower maternal CO and stroke volume (SV) and alongside high systemic and uterine vascular resistance in late gestation but also before diagnosis (5, 6, 8–10). The detection of such abnormalities before clinical evidence of disease suggests that disrupted maternal cardiovascular hemodynamics may be central to the etiology of PE and FGR.

The chronic hypoxia of high-altitude (HA) residence (>2,500 m, 8,250 ft) impairs maternal and uteroplacental vascular adaptation to pregnancy, resembling PE and FGR at sea level. Specifically, compared with low-altitude pregnancy, maternal CO, SV, and UtA blood flow are reduced in healthy, high-altitude pregnancies (11, 12), and the typical decrease in blood pressure during pregnancy is also largely absent (13, 14). In vitro studies of isolated uterine resistance vessels obtained from altitude-exposed women or experimental animals also demonstrate less nitric oxide (NO)-induced vasodilation, as reported in PE and FGR at sea level (15, 16). PE and FGR emerge as critical concerns during high-altitude pregnancy due to their increased incidence (17–19), co-occurrence, and strong association with adverse acute and long-term cardiovascular outcomes across the lifespan for mother and child (20–28).

The public health impact of these hypoxia-associated vascular disorders of pregnancy is magnified in resource-limited countries like Bolivia, where maternal and infant mortality rates are among the highest in the Western Hemisphere (29, 30), and approximately half of the population lives at high altitudes. One major obstacle to lowering maternal-infant mortality and morbidity rates in resource-limiting settings is the absence of noninvasive, easy-to-use tools for the early identification of high-risk pregnancies. Early detection is crucial because it provides the opportunity for increased patient monitoring, strategic timing of delivery, and the targeted distribution of resources needed to mitigate negative outcomes. A recent cross-sectional study of pregnant women living in La Paz or El Alto, Bolivia (3,850 m) reported impaired third-trimester maternal cardiovascular function and higher maternal plasma levels of the antiangiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1) in FGR cases compared with healthy controls (31).

Longitudinal assessments of maternal cardiovascular dynamics beginning before the diagnosis of vascular disorders of pregnancy are vital for establishing the temporal relationship between maternal hemodynamics and the onset of PE with or without FGR. We, therefore, conducted prospective studies in 79 high-altitude resident women to test the hypothesis that increased systemic and uteroplacental vascular resistance preceded the onset of PE or FGR and fetal circulatory changes, including Doppler indices of brain sparing. We also measured circulating maternal levels of sFlt-1 and the proangiogenic placental-like growth factor (PLGF) because endothelial dysfunction is recognized as one mechanism contributing to altered maternal systemic hemodynamics in vascular disorders of pregnancy. Such studies are imperative for developing effective early detection strategies and intervention protocols tailored to HA settings.

MATERIALS AND METHODS

Study Population and Design

This prospective study included 87 women receiving prenatal care and scheduled to deliver at Hospital Materno-Infantil, the largest maternal-child hospital serving the high-altitude cities of La Paz and El Alto, Bolivia (3,850 m). Studies were performed from June 2019 through May 2021. Inclusion criteria were maternal age (18–45 yr at enrollment), no significant health history (e.g., diabetes [type I or II], cardiopulmonary disease) or anemia (hemoglobin < 8.5 g/dL), singleton pregnancy, and high-altitude residence for the duration of the current pregnancy. Fetal inclusion criteria were no evidence of fetal aneuploidy, genetic disorders, or structural anomalies. Qualifying women were identified by their prenatal care providers with the aid of study collaborators. Women who contracted COVID-19 infection during the current pregnancy (n = 6) were excluded from analyses given the widespread inflammation and endothelial dysfunction associated with COVID-19 infection and the potential for such effects to confound our results (32). Women with incomplete clinical pregnancy-course information (n = 2) were also excluded, resulting in a cohort of 79 maternal-infant pairs for analysis.

Maternal demographics [age, height, pre-pregnant weight, pre-pregnant body mass index (BMI), altitude of birth and childhood], reproductive history (gravidity, parity), and medical history were collected from medical records or self-administered questionnaires. To ensure accuracy, self-reported medical data from the questionnaires underwent verification with the corresponding health records, and no inconsistencies were observed. Maternal hemodynamics and Doppler ultrasound evaluations of UtA resistance indices, fetal hemodynamics, and embryonic or fetal growth were conducted between 10–16 wk, 20–24 wk, and 30–34 wk of pregnancy. Maternal systolic and diastolic blood pressures were also recorded during these assessments. Newborn and delivery complications, birth weight, gestational age (GA) at delivery, infant sex, anthropometry, and Apgar scores were extracted from hospital records. A study overview is shown in Fig. 1.

Figure 1.

Study design overview. The timing of data collection, sampling, and Doppler ultrasound measurements are shown.

Hemodynamic Study Parameters

Following established protocols, maternal cardiovascular parameters were measured using a noninvasive ultrasound CO monitor (USCOM-1A; USCOM Ltd., Sydney, Australia) following established protocols [Perry et al. (8)]. Briefly, the velocity time integral (VTI) of the ejection flow and heart rate (HR) were measured using a suprasternal insonation window for the aortic valve. SV (mL) was calculated as the product of the aortic valve cross-sectional area and the VTI. Using manually entered systolic and diastolic blood pressure measurements (SBP and DBP, respectively), the mean arterial pressure (MAP, mmHg) was calculated as MAP = DBP + ([SBP − DBP]/3). Using these parameters, CO (SV × HR, L/min) and systemic vascular resistance (SVR = MAP/CO, dyn·s/cm⁵) were calculated. Body surface area (BSA) was estimated using the Du Bois method (33), and BSA-indexed values for CO (cardiac index, L/min/m²), SV (SVI; mL/m²), and SVR (SVRI; dyn·s/cm⁵/m²) were derived accordingly. Continuous-wave Doppler ultrasound estimates of cardiac index using these methods strongly correlate with direct measurements acquired via pulmonary artery catheterization (34, 35).

On the same day, transabdominal Doppler ultrasound was used to measure UtA, umbilical artery (UmbA), and middle cerebral artery (MCA) resistance indices [pulsatility index (PI), resistance index (RI), and systolic/end-diastolic ratio (S/D)], along with fetal biometry, using Medisono P25 equipment with appropriate probes, as previously outlined (12). Standard fetal biometry and estimated fetal weight (EFW) were recorded, with arterial resistance indices obtained bilaterally and reported as the average across both sides. The cerebroplacental ratio (CPR), an index of fetal brain sparing, was calculated as the MCA PI/UmbA PI.

Biochemical Measurements

At the first and second hemodynamic examinations, maternal peripheral blood samples were collected by routine venipuncture from an antecubital vein into ethylenediamine tetraacetic acid-coated collection tubes (Fig. 1). Before centrifugation, maternal hemoglobin concentration was measured in triplicate using the HemoCue Hb 201+ System (HemoCue, Angelholm, Sweden). The remaining sample was processed to obtain plasma for the duplicate measurement of sFlt-1 and PLGF via commercially available enzyme-linked immunosorbent assay kits (R&D Systems, Inc., Minneapolis, MN). Plasma samples were flash-frozen and stored at −80°C until analysis.

Clinical Birth Outcomes

Controls were defined as a healthy, normotensive pregnancy with an appropriately grown fetus. PE was defined according to the American College of Obstetrics and Gynecology (ACOG) guidelines (36), including elevated blood pressure ≥ 140/90 mmHg on two occasions 4 h apart, after 20 wk of gestation, and either proteinuria (≥300 mg/dL on a 24-h urine protein test, protein to creatinine ratio of ≥0.3 mg/mmol, or urine protein dipstick reading >1 if quantitative analysis is not available) or, in the absence of proteinuria, thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema, or cerebral or visual symptoms. Although we acknowledge that there is no definitive method to differentiate between pathologically growth-restricted and constitutionally small fetuses, we distinguished probable cases of pathological FGR as those with an EFW below the 10th percentile according to the Hadlock C formula and a birth weight below the 10th percentile for gestational age and sex according to the intergrowth-21st standards (37–39). Infants born before 37 wk of gestation were classified as preterm. PE and FGR cases were grouped (PE-FGR) for comparison with healthy controls.

Statistical Analyses

Investigators performing biochemical sample analyses or hemodynamic studies were blinded to control, PE, and/or FGR status. Before analyses, continuous variables were evaluated for normality using Shapiro–Wilk tests. Maternal demographics and pregnancy characteristics were contrasted between controls and adverse outcomes (PE-FGR cases). As appropriate, mean or median values or frequencies were compared using the Student’s t test, Mann–Whitney U test, or the χ² test, respectively. Univariate general linear models were used to generate and compare estimated marginal means between study groups for maternal cardiovascular hemodynamic parameters, UtA resistance indices, fetal hemodynamics, and infant birth weight, adjusting for gestational age at the time of study. Pearson correlation coefficients assessed the association between continuous maternal, fetal, and biochemical variables. Multivariable logistic regression modeling, adjusted for gestational age, evaluated the predictive utility of cardiovascular indices for developing PE-FGR. Linear mixed models were tested for differences in cardiovascular performance trajectories throughout pregnancy between control pregnancies and PE-FGR. Data are expressed as means ± SD for continuous variables or the frequency and 95% confidence interval for proportions. A two-sided P value <0.05 was considered evidence of association or difference in sample means or frequencies. Data analyses were conducted using R software (R for macOS 12, v.2023.12.1 + 402), and graphical representations were generated using GraphPad (v.10.2.2) or BioRender (http://biorender.com/).

Study Approval

Study participants were enrolled after providing written informed consent to study procedures approved by the University of Colorado Multiple Institutional Review Board and its Bolivian equivalents operated by the Caja Nacional de Salud and the Hospital Materno-Infantil.

RESULTS

Demographic and Pregnancy Characteristics

Among the 79 maternal-infant pairs included for analysis, 17 pregnancies were complicated by PE (n = 12 mild PE, n = 5 severe PE), including four cases with overlapping FGR. In addition, seven pregnancies were affected by isolated FGR.

Maternal age was equivalent in controls and PE-FGR cases (Table 1). In both groups, nearly all women were born and raised at high altitudes, had lived at high altitudes for their entire lives, and had completed at least a secondary education. Although some women reported smoking tobacco before conception (controls: 30%, PE-FGR: 32%), only one woman, a PE-FGR case, reported doing so during pregnancy. In both groups, most (54%–56%) self-identified as Andean-European (“Mestiza”) ancestry, with the remainder (43%–46%) identifying as Andean. Prepregnant BMI, gravidity, parity, primiparity, and HR were similar between groups. Two pregnancies were conceived by in vitro fertilization, representing one in each group.

Table 1.

Demographic and pregnancy characteristics stratified by study groups

	Control (n = 55)	PE-FGR (n = 24)	P Value
Maternal Characteristics
Age, yr	32.8 ± 5.8	34.1 ± 4.6	0.200
Altitude at birth, m	3,574 ± 598	3,485 ± 792	0.583
Altitude of childhood, m	3,550 ± 590	3,226 ± 1,198	0.109
Residence > 2,500 m, years	32.4 ± 6.3	31.5 ± 9.0	0.680
Education, yes secondary (n, %)	53 (98.1)	25 (100.0)	1.000
Ancestry			0.771
Andean (n, %)	23 (42.6)	11 (45.8)
Mestizo (n, %)	30 (55.6)	13 (54.2)
Other (n, %)	1 (1.9)	0 (0.0)
BMI, prepregnancy, kg/m2	24.5 [23.0, 27.6]	25.8 [22.7, 27.6]	0.654
Overweight, BMI >25 (n, %)	22 (46.8)	13 (52.0)	0.880
Obesity, BMI >30 (n, %)	6 (12.8)	4 (16.0)	0.511
Gravidity (no.)	2.6 ± 1.5	2.9 ± 1.7	0.756
Parity (no.)	1.0 ± 1.0	1.0 ± 1.0	0.890
Primiparous (n, %)	17 (32.7)	10 (40.0)	0.731
Heart rate, beats/min
10–16 wk	69.9 ± 11.0	71.2 ± 10.4	0.692
20–24 wk	75.1 ± 10.5	76.0 ± 18.4	0.815
30–34 wk	79.3 ± 10.4	85.3 ± 12.9	0.207
Birth outcomes
GA at birth, wk	38+5 [37+6, 39+0]	37+5 [36+3, 38+4]	0.020
Preterm (n, %)	4 (7.7)	6 (25.0)	0.087
Birth weight, g	3,206 ± 402	2,505 ± 752	<0.001
Birth weight, GA adjusted*	3,119 ± 51	2,672 ± 78	<0.001
Fetal sex, Male (n, %)	24 (52.2)	9 (52.9)	0.945
VLBW < 1,500 g (n, %)	0 (0.0)	2 (8.3)	0.086
LBW < 2,500 g (n, %)	2 (3.7)	8 (3.3)	0.008
FGR, <10th percentile (n, %)	0 (0.0)	10 (43.5)	0.003
NICU admission (n, %)	5 (9.1)	6 (25.0)	0.002
Perinatal mortality (n, %)	0 (0.0)	5 (20.8)	0.003

BMI, body mass index; FGR, fetal growth restriction; GA, gestational age; LBW, low birth weight; NICU, neonatal intensive care unit; VLBW, very low birth weight.

For adjusted variables values are shown as the *Adjusted for GA and sex. For the adjusted birth weight data are shown as the estimated marginal means ± SE. All other data are shown as the mean ± SD, median [IQR] or as frequency (%).

Compared with controls, PE-FGR cases delivered infants of lower birth weight, even after correction for infant sex and earlier GA at birth (702 g less after adjustment). Low birth weight (<2,500 g), very low birth weight (<1,500 g), and FGR were, by definition, more common in cases than controls. Eleven infants were admitted to the neonatal intensive care unit. Five perinatal deaths, including three stillbirths, were recorded in the PE-FGR group.

Maternal Cardiovascular Function, UtA Resistance Indices, and Fetal Hemodynamics

Maternal hemodynamic and uteroplacental parameters for controls and cases were measured at 13.2 ± 1.4 and 12.9 ± 1.5 gestational weeks, 20.8 ± 1.4 and 20.6 ± 1.5 gestational weeks, and 34.1 ± 1.5 at 33.5 ± 0.9 wk, respectively.

Across pregnancy, maternal CO and HR gradually increased from the 10 to 16 wk visit onward among all women, whereas SV, SVR, and SVRI remained relatively constant (Fig. 2, Table 1). Correlation analyses showed significant relationships among these hemodynamic parameters within all three visits, such that lower CO at the first, second, or third visit corresponded with decreased SV (r = 0.74, 0.79, and 0.88, respectively; all P < 0.001), increased SVR (r = −0.83, −0.84, −0.57, respectively; all P < 0.001) or SVRI (r = −0.69, r = −0.79, r = −0.54, respectively; all P < 0.001).

Figure 2.

Prospective measures of maternal cardiovascular performance and uterine artery resistance index at 10–16 wk, 20–24 wk, and 30–34 wk of pregnancy. Cardiac output (A), stroke volume (B), systemic vascular resistance (SVR) (C), SVR index (SVRI) (D), and uterine artery pulsatility index (UtA PI; E) are compared between healthy controls (yellow circles, white bar) and preeclampsia (PE)-fetal growth restriction (FGR) cases (black circles, gray bar). Significance values for comparisons of PE-FGR and controls are shown within each plot and were adjusted for gestational week of measurement. Sample sizes are indicated in the figure.

Compared with controls, PE-FGR cases had lower SV at each visit and higher SVR—but not SVRI—at 10–16 wk (Fig. 2, B–D). There was no significant difference in MAP between controls and cases throughout pregnancy (e.g., 10–16 wk: 81.8 ± 8.6 mmHg and 82.3 ± 9.2 mmHg, respectively). Similarly, there was no significant difference in cardiac index between controls and PE-FGR across pregnancy (e.g., 10–16 wk: 2.6 ± 0.5 L/min/m² and 2.5 ± 0.7 L/min/m², respectively). Maternal UtA PI was higher in PE-FGR than controls at 10–16 wk and 20–24 wk (Fig. 2E). UmbA PI also tended to be higher for PE-FGR cases at the second and third visit, whereas the MCA PI (Fig. 3) and CPR were similar (1.12 vs. 1.07 and 1.98 vs. 2.04 for the second and third visit, respectively).

Figure 3.

Umbilical (A) and middle cerebral (B) artery pulsatility indices at 20–24 wk and 30–34 wk of pregnancy. Mean umbilical and middle cerebral artery pulsatility indices (UmbA and MCA PI) values between controls (yellow circles, white bar) and preeclampsia (PE)-fetal growth restriction (FGR) cases (black circles, gray bar) did not differ by case-control status. Significance values are shown within each panel and sample sizes are indicated in the figure.

Logistic regression modeling showed higher SV at 10–16 wk lowered the risk of developing PE-FGR [OR: 0.93, 95% confidence interval (CI) 0.87–0.99, P = 0.025], whereas greater SVR raised the risk of PE-FGR (OR: 1.24, 95% CI 1.03–1.55, P = 0.039) (Table 2). Linear mixed modeling revealed no significant differences in the SV, SVR, or SVR index trajectory between control and PE-FGR cases. However, PE-FGR cases showed a blunted rise in CO from the first to the third visit compared with controls (β = −0.59, 95% CI −1.14; −0.03, P = 0.026) (Table 3).

Table 2.

Relationship between maternal central hemodynamic parameters across pregnancy and the risk of developing PE-FGR compared to control pregnancies

Dependent Variable: PE-FGR (yes/no)
Reference Group: Controls
Independent Variable	Beta	OR (95% CI)	P Value
CO 1, L/min	−0.615	0.541 (0.218; 1.184)	0.147
CO 2, L/min	−0.572	0.564 (0.292; 0.988)	0.064
CO 3, L/min	−0.392	0.676 (0.285; 1.354)	0.311
SV 1, cm3	−0.069	0.933 (0.871; 0.986)	0.025*
SV 2, cm3	−0.049	0.952 (0.906; 0.995)	0.041*
SV 3, cm3	−0.087	0.087 (0. 819; 0.991)	0.060
SVR 1, dyn·s/cm5/100	0.211	1.235 (1.026; 1.552)	0.039*
SVR 2, dyn·s/cm5/100	0.088	1.092 (0.988; 1.217)	0.085
SVR 3, dyn·s/cm5/100	0.006	1.006 (0.878; 1.105)	0.897
SVRI 1, dyn·s/cm5/m2/100	0.072	1.074 (0.981; 1.189)	0.131
SVRI 2, dyn·s/cm5/m2/100	0.037	1.038 (0.978; 1.104)	0.210
SVRI 3, dyn·s/cm5/m2/100	−0.008	0.992 (0.895; 1.049)	0.813

Effect estimates of logistic regression model outcomes are compared using controls as the reference group. Models were adjusted for gestational age at the time of measurement. *Statistically significant P Values (<0.05) are shown in bold. CO, cardiac output; SV, stroke volume; SVR, systemic vascular resistance; SVRI, systemic vascular resistance index.

Table 3.

Associations between controls, PE-FGR pregnancies, and longitudinal trajectories of cardiac outcome measurements at 10–16, 20–24, and 30–34 gestational weeks

Linear Mixed Model of USCOM-1A Data
Reference Group: Controls
Variable	Beta (95% CI)	P Value
CO, L/min	−0.586 (−1.138; −0.033)	0.026*
SV, cm3	−15.118 (−38.074; 7.838)	0.193
SVR, dyn·s/cm5	−14.253 (−36.232; 7.725)	0.200
SVRI, dyn·s/cm5/m2	−14.485 (−36.161; 7.192)	0.187

Shown are effect estimates of the generalized linear mixed model for the associations between controls and pregnancies complicated by preeclampsia (PE) and/or fetal growth restriction (FGR) and cardiac output (CO), stroke volume (SV), systemic vascular resistance (SVR), and SVR index (SVRI) measured by the cardiac monitor USCOM-1A at 10–16 wk, 20–24 wk, and 30–34 wk. The model is adjusted for the gestational age of measurement. *Statistically significant P Values (<0.05) are shown in bold. CI, confidence interval.

Relationship between Maternal CO, SV, SVR, UtA Resistance, and Fetal Hemodynamics

Women with higher CO at 10–16 wk had a lower UtA S/D ratio (r = −0.35, P = 0.035), whereas those with higher SVR and SVRI also showed higher UtA PI (Fig. 4) and UtA S/D ratio (r = 0.59, P < 0.001). At 10–16 wk, maternal SV, but not SVR or SVRI, also positively correlated with fetal MCA PI, whereas there were no such relationships with UmbA PI (Fig. 5). Third trimester CPR values were positively associated with higher maternal CO (r = 0.40, P = 0.042), SV (r = 0.59, P = 0.002), and SVI (r = 0.51, P = 0.009) at 10–16 wk, with a negative trend observed for SVR (r = −0.385, P = 0.052). Furthermore, maternal SVR at 10–16 wk was significantly associated with lower birth weight (r = −0.29, P = 0.035, β = −0.42, 95% CI −0.82; −0.03); however, after adjusting for gestational age and fetal sex, only a trend was observed (r = −0.26, P = 0.09, β = −0.28, 95% CI −0.606; 0.054, P = 0.098).

Figure 4.

Correlations between maternal cardiac output (A), stroke volume (B), systemic vascular resistance index (SVRI; C), and uterine artery (UtA) pulsatility index (PI) at 10–16 gestational weeks. Pearson correlation coefficients and significance values for all pregnancies, controls (yellow circle, dashed line), and preeclampsia (PE)-fetal growth restriction (FGR) cases (black circles, solid line) are shown. Sample sizes are controls (n = 29) and PE-FGR (n = 13–14).

Figure 5.

Correlations between maternal stroke volume and systemic vascular resistance index (SVRI) at 10–16 gestational weeks and third-trimester umbilical (UmbA) and middle cerebral artery (MCA) pulsatility index (PI). Maternal stroke volume versus UmbA and MCA PI are shown in (A) and (B), respectively. Maternal SVRI versus UmbA and MCA PI are shown in (C) and (D), respectively. Pearson correlation coefficients and significance values for all pregnancies, controls (yellow circles, dashed line), and preeclampsia (PE)-fetal growth restriction (FGR) cases (black circles, solid line) are shown. Sample sizes are: controls (n = 20–22) and PE-FGR (n = 5–7).

Relationship between Maternal sFlt-1/PLGF and Hemodynamic Indices

At 10–16 wk, maternal plasma sFlt-1, PLGF, and sFlt-1/PLGF were similar in controls and PE-FGR (data not shown). At 20–24 wk, maternal plasma sFlt-1 levels were lower in controls than PE-FGR (1,578.8 ± 925.7 pg/mL vs. 3,167.4 ± 2,702.1 pg/mL, P = 0.016), whereas PLGF and sFlt-1/PLGF did not differ between groups. Among healthy women, a higher circulating sFlt-1/PLGF ratio at 10–16 wk had lower CO and SV and a trend toward greater SVRI; however, this was not the case for PE-FGR or all women combined (Fig. 6). Women with higher circulating sFlt-1 levels at 10–16 or 20–24 wk of pregnancy had higher SVRI at 20–24 wk (r = 0.64, P < 0.001 and r = 0.61, P < 0.001, respectively). Greater sFlt-1 at 10–16 wk was also linked to lower CO at the second visit (r = −0.37, P = 0.045), whereas a higher sFlt-1/PLGF ratio was associated with reduced SV between 20 and 24 wk (r = −0.52, P = 0.02). There were no significant associations between the sFlt-1/PLGF ratio and MCA or UmbA PI, CPR, or UtA resistance indices (PI, RI, or S/D) at any visit.

Figure 6.

Correlations between maternal soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PLGF) ratio, maternal cardiac output (A), stroke volume (B), systemic vascular resistance index (SVRI) (C), and uterine artery (UtA) pulsatility index (PI) (D) at 10–16 gestational weeks. Pearson correlation coefficients and significance values for all pregnancies, controls (yellow circles, dashed line), and preeclampsia (PE)-fetal growth restriction (FGR) cases (black circles, solid line) are shown. Sample sizes are: controls (n = 13–15) and PE-FGR (n = 11–13).

DISCUSSION

In this prospective study of high-altitude resident women, impaired maternal central hemodynamic responses to pregnancy were evident in the subclinical stages of PE or FGR, two prominent vascular disorders of pregnancy associated with acute and long-term adverse health outcomes for mother and child. Specifically, pregnant women living in La Paz or El Alto, Bolivia (3,850 m) who later developed PE-FGR were characterized by a low SV, high SVR phenotype at 10–16 wk of pregnancy, alongside greater uterine vascular resistance. Our data also showed an inverse relationship between maternal CO and SV at 10–16 gestational weeks and the development of PE-FGR and fetal brain sparing later in pregnancy. In addition, women with higher SVR at 10–16 gestational weeks also had greater UtA resistance and delivered infants of lower birth weight. These findings emphasize the importance of maternal central and uteroplacental vascular responses early in pregnancy and highlight the potential for such measures to detect high-risk pregnancies before disease onset.

Comparing maternal cardiovascular parameters across pregnancy in our cohort of healthy, high-altitude women to published sea-level values reveals slightly different patterns between altitudes. In healthy, low-altitude pregnancies, maternal SVR decreases as early as 6 wk postconception (40), followed by a gradual increase in CO that can rise by up to 45% from nonpregnant levels (41). The sharpest increase in CO occurs early in the first trimester due to increased SV (42) and compensates for profound peripheral vasodilation and a ∼35%–40% reduction in SVR (43). Consistent with findings in uncomplicated pregnancies at low altitudes, maternal CO gradually increased in our healthy, high-altitude cohort from the first visit (10–16 wk) onward. Examining the relationship of hemodynamic parameters within individuals across all three visits showed that women with lower CO tended to have reduced SV and higher SVR, as expected based on previous literature. However, unlike low-altitude pregnancies, we found relatively stable SV and SVR values throughout pregnancy in healthy controls. This phenomenon may be attributed to a relative contraction of plasma volume (lower preload) or diminished left ventricle compliance or arterial compliance (increased afterload) in high-altitude pregnancies compared with those at lower altitudes.

Since this report is the first to measure maternal central hemodynamics in the late-first trimester of pregnancy at high altitudes, no highland reference values for early pregnancy were available for comparison. However, comparing our data to studies of lowland-resident populations revealed that altitudinal differences in maternal central hemodynamics were apparent as early as 10–16 gestational weeks. Healthy highlanders in the present cohort had 20% lower CO, 13%–25% lower SV, and 30% higher SVR than healthy lowland-resident women studied in the first trimester (44, 45). Further supporting the impact of altitude on CO and SVR among pregnant women, Kametas et al. (11) showed reduced maternal CO in the second trimester at high altitudes in Peru [Cerro de Pasco (4,370 m)] compared with sea level [Lima (154 m)]. These altitudinal effects may be partially driven by reduced intravascular space, as suggested by lower CO, left atrial diameter, and end-diastolic diameter (11), and the lesser rise in blood and plasma volume during pregnancy that has been reported in some (46), but not in other studies (47).

Existing observations about maternal CO and its determinants in PE and FGR are sparse and not internally consistent. Longitudinal studies published by Easterling et al. (48) more than 30 years ago reported higher maternal CO in PE versus healthy pregnancy, an effect presumed due to exaggerated sympathetic activity or overcompensation for the profound reduction in SVR during the first trimester. More recent work indicated that early-onset PE or PE with coexisting FGR was characterized by a low maternal CO and high vascular resistance phenotype, potentially present before conception and persisting throughout pregnancy (5, 9, 10). Recent literature addressing the disparate maternal central hemodynamic phenotypes typifying PE suggests such differences depend upon disease severity as reflected by the timing of onset and the presence or absence of FGR (9, 49). Specifically, Masini et al. (49) propose that PE complicated by FGR is distinguished by elevated SVR before and throughout pregnancy, paralleled by an insufficient rise in CO across gestation and excess extracellular fluid accumulation (49–52). Whereas women who develop PE late in pregnancy have been reported to present with high CO and low SVR early in pregnancy that either 1) converts to a low CO-high SVR state in the third trimester due to intravascular overload or 2) remains a high-CO circulation through all stages of pregnancy (53) (Fig. 7). It should be noted, however, that the persistently high CO phenotype reported by Easterling et al. (48) was derived from a cohort of mostly obese women, which may have affected venous return or vascular parameters in ways that influenced central hemodynamics.

Figure 7.

Trajectory of maternal cardiac output and systemic vascular resistance across healthy and hypertensive pregnancy at low and high altitude. Comparing literature regarding maternal central hemodynamics typifying healthy and preeclamptic pregnancy in lowland-resident women to data presented herein suggests that unique patterns exist in healthy high-altitude pregnancy and those complicated by preeclampsia and/or fetal growth restriction (PE-FGR). In healthy, low-altitude pregnancy (NORM, thick black line), cardiac output (CO) gradually increases across pregnancy, and is coupled with a profound reduction in systemic vascular resistance (SVR) that begins in the first trimester and continues into the second trimester. As described by Masini et al. (49) early-onset PE or PE with overlapping FGR (E-PE; light gray line) is distinguished by a hypodynamic maternal circulation marked by an insufficient rise in CO and a high SVR across gestation (49–52). Late-onset PE (L-PE) has been characterized in two ways: a persistently high CO state (L-PE HI OUTPUT; dashed gray line) or a high CO, low SVR phenotype early in pregnancy that converts to a low CO, high SVR state due to intravascular overload near term (L-PE CROSS; narrow black line) (53, 54). In healthy, high-altitude pregnancy (HI-CON; narrow, dashed black line), maternal CO rises across pregnancy, whereas the relative magnitude of this change is blunted in PE-FGR (HI-PE/FGR; bold, dashed black line). In healthy and PE-FGR pregnancies at high altitudes, the fall in maternal SVR observed in uncomplicated pregnancies at low altitudes does not occur, resembling E-PE at low altitudes albeit less pronounced. Figure adapted with permission from Gyselaers (55). This figure was created in BioRender.com. Julian, C. (2024) BioRender.com/z21c131.

In high-altitude PE-FGR, we observed a comparatively hypodynamic circulation characterized by a low SV, a high SVR, a minimal SVR decline, and a blunted rise in CO across pregnancy. This trajectory mirrors early-onset PE or PE complicated by FGR at low altitudes, albeit less severe (Fig. 7). Notably, in the present cohort, women with uncomplicated pregnancy also showed no SVR reduction between 10–16 and 20–24 wk. Our findings add to the current literature by suggesting that chronic maternal exposure to hypoxia alters central hemodynamic responses to pregnancy in general and that these abnormalities are magnified in the subclinical and clinical stages of PE-FGR. Among several potential mechanisms tipping the scale toward PE-FGR in some but not all high-altitude pregnancies are interindividual differences in sensitivity to NO-induced vasorelaxation (15, 16), redox status at the level of the endothelium or vascular smooth muscle (56–58), hypoxia-induced activation or genetic variation regulating other pathways [e.g., adenosine monophosphate kinase (59–62)] that affect vascular function, or differences in the production, release, or bioavailability of circulating factors, including hormones, that regulate vascular function.

The widespread peripheral vasodilation during pregnancy is partly due to increased NO production and reduced circulating levels of the potent vasoconstrictor endothelin-1 (63). Maternal vascular homeostasis also relies on the balance between the levels of the antiangiogenic factor sFlt-1 and those of angiogenic factors. Circulating sFlt-1 exerts antiangiogenic effects by sequestering the vascular endothelial and placental growth factors, thereby preventing cognate receptors’ activation and disrupting vascular homeostasis (64). The vascular endothelial dysfunction hallmark of PE has been associated with excess placental sFlt-1 secretion into the maternal circulation (65). In this study, circulating sFlt-1 levels at 10–16 gestational weeks were similar between healthy pregnancies and pregnancies later complicated by PE-FGR, but greater in PE-FGR cases by 20–24 wk of pregnancy; our observations align with foundational studies showing that excess sFlt-1 is not detected until 21–24 wk of gestation in women who go on to develop PE (66). Given that distinct maternal central hemodynamic patterns appear before 20 wk in PE-FGR, we consider elevated sFlt-1 may be a cause and consequence of abnormal maternal vascular responses to pregnancy.

Uteroplacental blood flow increases due to a rise in maternal CO, reduced SVR, increased blood volume, and an even greater reduction in uteroplacental vascular resistance that causes most of the rise in CO to be directed to the uteroplacental circulation by late gestation (67). FGR at high altitudes and many human and most experimental animal models of hypertensive disorders of pregnancy at low altitudes are characterized by a blunted expansion of uteroplacental blood flow and a higher uteroplacental vascular resistance (12, 63). Our observations of low CO and high SVR at 10–16 wk alongside increased uteroplacental vascular resistance indices and reduced birth weight are consistent with such low-altitude literature and suggest that the low-CO, high-SVR phenotype we observed in PE-FGR at high altitude likely precedes placental hypoperfusion and directly contributes to fetoplacental hypoxia and restricted fetal growth. We, therefore, propose that an integrated model of maternal hemodynamics and placental function, which considers insufficient maternal cardiovascular performance as a primary contributor to placental insufficiency, may provide a better understanding of PE and FGR at high altitudes and, as others have suggested (8, 49, 68), at low altitude as well.

The major strengths of our study stemmed from its prospective design, which permitted the measurement of maternal central hemodynamics, indices of uterine, UmbA, and MCA resistance, and circulating markers of endothelial damage before the onset of disease. This is the first longitudinal study of maternal central hemodynamics at high altitudes in uncomplicated or complicated pregnancies. Our study design enabled the integrated analysis of maternal cardiovascular parameters, uteroplacental resistance indices, fetal hemodynamics, and circulating anti- and proangiogenic factors in the same women; these paired studies enhance data interpretability. Another strength of our study was that the noninvasive maternal systemic and uteroplacental Doppler ultrasound measurements included here were conducted by Bolivian clinicians and scientists using local instruments. Therefore, although we recognize that limited-resource communities face challenges in accessing advanced healthcare and diagnostic laboratory testing, our study and focus on building local research capacity highlight the potential feasibility of using these methods for clinical purposes in limited-resource settings similar to La Paz, Bolivia.

Our study also had limitations. One issue was the absence of nonpregnant or preconception reference measurements to determine preexisting abnormalities in maternal central hemodynamics. There is a strong rationale for initiating prospective assessments before conception and continuing throughout pregnancy in future work as low altitude studies indicate that, compared with healthy controls, women who subsequently developed PE-FGR had lower preconception CO and cardiac index, alongside higher MAP and total peripheral vascular resistance (5). Although postpartum measurements would also be valuable for determining whether abnormal maternal hemodynamic patterns resolve after delivery and, if so, the time course of resolution, it remains important to measure cardiovascular and uteroplacental vascular parameters early in pregnancy for predicting PE-FGR risk. A second consideration is the heterogeneity of adverse outcomes assessed. We grouped PE with or without FGR, and FGR alone into a single “adverse outcome” for our analyses, as has been done in prior related studies (2, 69, 70). Although the diagnostic criteria for PE and FGR are distinct, these disorders often occur in tandem and have common pathophysiological features, including shallow trophoblast invasion of the maternal spiral arteries, placental hypoxia, uteroplacental hypoperfusion, and vascular endothelial dysfunction (71–74). Although our PE-FGR cohort recognizes the clinical reality of this phenotypic overlap and the frequency of co-occurrence, our sample sizes did not permit the detection of differences in key outcome measures between controls, isolated PE, PE with overlapping FGR, and FGR alone. Therefore, larger prospective studies examining the several kinds of hypertensive disease, as defined using ACOG (36), International Society for the Study of Hypertension in Pregnancy (75), or World Health Organization (76) criteria, with or without FGR and FGR alone as distinct entities are required to identify subtle differences in maternal central hemodynamic trajectories across pregnancy and their relationship to disease onset. Finally, because our study did not include a lowland cohort, our assessment of altitudinal effects on maternal cardiovascular performance across pregnancy was limited to comparisons against existing literature for low-altitude cohorts.

Our findings suggest that blunted maternal cardiovascular and uteroplacental responses in high-altitude pregnancy compromise maternal circulatory and placental function, thereby triggering PE-FGR. Furthermore, the noninvasive methods used here demonstrate their potential utility for the early detection of high-risk pregnancies, which would be beneficial for refining the allocation of healthcare resources and patient surveillance to minimize adverse outcomes in resource-limited settings, such as those found at high altitudes in Bolivia. Larger, prospective studies of maternal central hemodynamics at high altitudes, beginning before conception and continuing postpartum, will be vital to determine the role of preexisting abnormalities in maternal central hemodynamics, define cut-points for the early detection of high-risk pregnancy, and the time course of resolution.

DATA AVAILABILITY

Deidentified human subject data for subjects consenting to future data use is available from the corresponding author upon request.

GRANTS

This work was supported by the National Institutes of Health Grants R21 TW010797, R01 HL138181, R01 HD088590, R21 HD111905, and R21 HD111908; the Division of Reproductive Sciences in the Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus; and the University of Colorado Department of Medicine Research and Equity in Academic Medicine (DREAM) Program.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

L.T.-J. and C.G.J. conceived and designed research; C.C.-T., R.G., S.G.-C., A.L., L.L.-V., and L.T.-J. performed experiments; R.E.W., C.C.-T., S.G.-C., J.A.H., and C.G.J. analyzed data; K.B., S.G., and C.G.J. interpreted results of experiments; R.E.W. and C.G.J. prepared figures; R.E.W., J.P., and C.G.J. drafted manuscript; R.E.W., K.B., L.G.M., L.T.-J., and C.G.J., edited and revised manuscript; R.E.W., C.C.-T., R.G., S.G.-C., J.A.H., A.L., L.L.-V., L.G.M., J.P., L.T.-J., and C.G.J. approved final version of manuscript.