Abstract
Introduction
Abnormalities in central hemodynamic functions before and throughout pregnancy may antedate impaired fetal growth. We aimed to assess cardiac output (CO) and total peripheral vascular resistance (TPVR) trajectories throughout singleton pregnancies with and without impaired fetal growth by systematic review and meta‐analysis.
Material and Methods
PubMed and Embase were systematically searched (inception – July 2023), and reference lists were screened. Studies reporting CO and TPVR during singleton pregnancies complicated by impaired fetal growth were included. Studies measuring hemodynamic parameters in women with prepregnancy hypertension and/or cardiac diseases were excluded. Absolute values of hemodynamic parameters were calculated over pregnancy using a random‐effects model, and subgroup analyses differentiated more severe clinical phenotypes of impaired fetal growth. The systematic review was registered in the PROSPERO database (CRD42020172252).
Results
Thirty‐three studies were included, comprising 7816 women. Hemodynamic function in non‐pregnant women did not differ between those who subsequently gave birth to a growth‐restricted neonate or an appropriately grown neonate. Pregnancies complicated by impaired fetal growth were accompanied by elevated second and third‐trimester TPVR and concurrent reduced third‐trimester CO. Second and third‐trimester TPVR was consistently higher when fetal growth restriction was accompanied by abnormal perfusion indices instead of only low birthweight (centile), concurrent maternal hypertensive disorder of pregnancy, and when small for gestational age was accompanied by preterm birth.
Conclusions
Impaired fetal growth is associated with increased vascular resistance and reduced CO from the second trimester onwards. More severe phenotypes, particularly those with attenuated placental perfusion or lower gestational age at birth, exhibit the most vasoconstrictive hemodynamic profile. Future studies could focus on targeted preventive measures to restore hemodynamic function.
Keywords: cardiac output, fetal growth restriction, hemodynamic function, maternal hemodynamics, total peripheral vascular resistance
Maternal cardiovascular adaptation is altered in pregnancies complicated by impaired fetal growth. From the second trimester onwards, lower cardiac output and increased total peripheral vascular resistance emerge, highlighting the need for early hemodynamic monitoring and potential interventions in at‐risk pregnancies.
Abbreviations
- CO
cardiac output
- FGR
fetal growth restriction
- HDP
hypertensive disorder of pregnancy
- SGA
small for gestational age
- TPVR
total peripheral vascular resistance
Key message.
Maternal cardiovascular adaptation is altered in pregnancies complicated by impaired fetal growth. From the second trimester onwards, lower cardiac output and increased total peripheral vascular resistance emerge, highlighting the need for early hemodynamic monitoring and potential interventions in at‐risk pregnancies.
1. INTRODUCTION
Healthy pregnancy is accompanied by major hemodynamic changes that when adaptive, benefit uteroplacental perfusion. A first trimester drop in systemic vascular resistance triggers several compensatory mechanisms to maintain blood pressure and perfusion, among an increase in plasma volume and cardiac output (CO). 1 , 2 Compared with non‐pregnant values, in healthy pregnancy, total peripheral vascular resistance (TPVR) decreases by 24%, and CO increases by 30%, with maximal change being reached in second half of pregnancy. The early increase in maternal CO and reduction in TPVR from preconception toward the second trimester seem to correlate beneficially with the neonate's fetal growth and birthweight (BW). 3
Maternal early‐pregnancy circulatory maladjustments seem to associate with abnormal placental development and function, a process considered uteroplacental vascular maladaptation, ultimately leading to uteroplacental insufficiency and attenuated fetal growth. 4 , 5 , 6 , 7 , 8 Offspring, smaller in size than usual for their gestational age, are referred to as small for gestational age (SGA), often defined as birthweight below the 10th centile for the gestational age. If fetal growth restriction (FGR) is accompanied by arterial flow alterations as measured by Doppler ultrasound, then this is thought to reflect placental‐insufficiency‐attenuating fetal growth, and therefore, considered “true” FGR. 6 Short‐term adverse outcomes associated with SGA and FGR infants include stillbirth, preterm delivery, and increased neonatal mortality and morbidity. 9 , 10 In later life, offspring born SGA and FGR are at increased risk of developing obesity, diabetes mellitus, and cardiovascular disorders. 11 , 12
Therefore, timely detection of women at risk of delivering SGA and FGR infants may be of utmost importance in instituting general preventive measures and opening a window toward tailored correction of maternal hemodynamics to improve fetal development and subsequent health. Therefore, this systematic review and meta‐analysis aimed to assess whether prepregnancy and gestational CO and TPVR trajectories differ between women who give birth to a growth‐restricted neonate compared with pregnancies with normal neonate growth.
2. MATERIAL AND METHODS
2.1. Data sources and search strategy
This article follows the previously designed series of meta‐analyses on maternal cardiovascular and cardiometabolic adaptation during pregnancy, reported in accordance with the Preferred Reporting Guidelines for Systematic Reviews and Meta‐Analyses (PRISMA). 1 , 2 , 13 , 14 , 15 , 16 , 17 The current study was registered in the PROSPERO database (CRD42020172252).
We searched in MEDLINE (PubMed) and Embase (Ovid) for studies evaluating CO and TPVR in pregnancies complicated by impaired fetal growth between inception (1946 in PubMed and 1974 in Embase) and July 2023 (Table S1). Reference lists of included studies were checked for additional eligible articles.
2.2. Eligibility criteria and study selection
Studies were selected by two independent investigators (LJ and EM). Initial screening was based on title/abstract, followed by full‐text assessment of potentially eligible studies according to inclusion and exclusion criteria. Discrepancies were resolved by mutual agreement. Original study articles reporting numerical values of hemodynamic parameters during human singleton pregnancies (mean with standard deviation [SD], standard error [SE], or 95% confidence interval [CI], or median with interquartile range [IQR] or range) were included. Requests were made to retrieve additional information wherever applicable. Conference abstracts, articles in languages other than English and Dutch, case reports, and reviews were excluded. Studies that measured hemodynamic parameters in women with prepregnancy cardiac disease and/or chronic hypertension were also excluded.
2.3. Data extraction
The following information was collected using a standardized form: study characteristics (study design, measurement method, and definition of impaired fetal growth) and participant characteristics (age, maternal hypertensive disorder of pregnancy (HDP), and gestational age at delivery). Central hemodynamic parameters of interest were CO (in L min−1) and TPVR (in dyne sec cm−5). In intervention studies, only baseline values before the intervention's start were extracted. If the exact gestational age of the measurements was not mentioned, it was included as 7 weeks gestational age for the first trimester, 21 weeks for the second trimester, and 34 weeks for the third trimester.
2.4. Risk of bias assessment
The quality of the included studies was assessed using a modified list of items described in the Quality in Prognosis Studies (QUIPS) tool. Studies were scored plus or minus in six domains, including study participation, study attrition, prognostic factor measurements, data reporting, study confounding, and study design. Unreported or inapplicable items received a negative score. Cross‐sectional studies scored negative for study attrition because loss‐to‐follow‐up reporting is not applicable to this study design. Studies were classified as high (>80%), moderate (40%–80%), or low quality (<40%).
2.5. Data synthesis
Hemodynamic parameters were categorized into first trimester (<14 weeks), second trimester (15–28 weeks), third trimester (29–41 weeks), and a non‐pregnant state. The primary outcome was the pooled estimate of absolute CO and TPVR values with a 95% CI in pregnancies complicated by impaired fetal growth, irrespective of its definition.
Subgroup analyses were performed to provide in‐depth insight into clinical phenotypes of impaired fetal growth. First, differences in hemodynamic parameters per trimester were analyzed between impaired fetal growth defined by fetal or neonatal (birth)weight (centile) and by weight and additional criteria suggestive of placental dysfunction (e.g., deviant Doppler measurement of the uterine/umbilical artery, deviant cerebral‐placental ratio, and/or oligohydramnios). Second, differences in hemodynamic parameters per trimester were analyzed in women with impaired fetal growth with and without concurrent HDP. Third, hemodynamic parameters were related to gestational age at delivery. Studies were divided into three groups (<32 weeks, 32–37 weeks, ≥37 weeks of gestational age at delivery), with gestational age entered as a continuous variable when assessing the effect on hemodynamic values.
To account for methodological heterogeneity, we performed modality‐specific subgroup analyses stratified by the most frequently used techniques (echocardiography, USCOM, and NICOM). Other measurement methods were reported too infrequently and heterogeneously to allow separate pooling.
2.6. Data analyses
According to the Cochrane Handbook for Systematic Reviews of Interventions, SE or 95% CI values were converted to SD. Data reported as median with IQR or median and range were used to estimate SD, either by dividing the difference of the 25th and the 75th percentile by 1.35 or using the appropriate formula based on sample size. 18 , 19 If multiple measurements were reported for the same women at one gestational age interval, the mean and SD were pooled into one measurement. Pooled CO and TPVR values per trimester were calculated using a random‐effects model, allowing inter‐study variation. 20 Subgroup and trend analyses were used to explore overall patterns across clinically relevant categories. These analyses were exploratory and descriptive and should not be interpreted as evidence of causality or independent effects. Egger's regression test for funnel plot asymmetry evaluated publication bias for each interval, and the trim‐and‐fill method corrected for bias if present. 21 , 22 The ratio between total heterogeneity and total variability (I‐squared statistic (I 2)) is presented as a measure of heterogeneity. I 2 can distinguish true heterogeneity from sampling variance and is expressed as a percentage. 23 All analyses were conducted in R (version 4.0.4) with the meta‐package (version 5.2‐0). 24 , 25
3. RESULTS
3.1. Study selection and characteristics
Full‐text screening of 125 articles revealed that 90 studies did not meet the inclusion and exclusion criteria (Figure 1). Among the 35 eligible articles, data overlap between two studies was confirmed, 26 , 27 , 28 and the most comprehensive and appropriate analysis was included. 28 Three contacted authors provided additional data not presented in the original publication. 29 , 30 , 31 In total, 33 studies were included in the meta‐analyses, comprising data from 7816 women. A summary of the included studies and their study populations is presented in Table S2.
FIGURE 1.
Flow diagram summarizing selection of included studies.
Most studies used transthoracic echocardiography to assess maternal hemodynamic parameters (n = 13). Other used techniques were USCOM (n = 11), NICOM(MO) (n = 6), Portapress (n = 1), impedance cardiography (n = 1), and dye dilution technique (n = 1).
3.2. Risk of bias of included studies
Of the 33 included studies, 10 (30%) were scored as high quality, 22 (67%) as moderate quality, and 1 (3%) as low quality (Table S3).
3.3. Absolute hemodynamic values
Table 1 and Figure S1 depict absolute CO values during pregnancies complicated by impaired fetal growth. In the third trimester, absolute CO is significantly lower in pregnancies with impaired fetal growth compared with pregnancies with normal fetal growth (5.56 L min−1 vs. 6.68 L min−1, p‐value < 0.001). In the second trimester, a similar trend was observed (5.74 L min−1 vs. 7.07 L min−1, p‐value = 0.062), although this difference was not statistically significant, potentially due to limited power. No significant differences were observed in the first trimester (5.82 L min−1 vs. 6.34 L min−1, p‐value = 0.515) or the non‐pregnant state (5.48 L min−1 vs. 5.66 L min−1, p‐value = 0.664). These findings suggest that hemodynamic changes arise during pregnancy, as prepregnancy CO did not differ significantly. Publication bias was present in all trimesters; corrected values are presented in Table 1.
TABLE 1.
Absolute values of hemodynamic parameters during pregnancies with impaired fetal growth compared with pregnancies with normal growth.
| Hemodynamic parameter | First trimester | Second trimester | Third trimester | Non‐pregnant | |
|---|---|---|---|---|---|
| Cardiac output (L min−1) |
Abs value IFG pregnancies (95% CI) (number of study groups) |
5.82 (5.13–6.52) (n = 9) a 6.62 (5.97–7.26) |
5.74 (4.95–6.53) (n = 16) a 7.06 (6.27–7.85) |
5.65 (5.29–6.01) (n = 30) a 6.39 (6.02–6.76) |
5.48 (5.27 to 5.69) (n = 4) |
|
Abs value normal growth pregnancies (95% CI) (number of study groups) |
6.34 (5.08–7.60) (n = 5) |
7.07 (6.18–7.95) (n = 5) |
6.68 (6.19–7.17) (n = 14) |
5.66 (4.93–6.40) (n = 3) |
|
| p‐value | 0.515 | 0.062 | 0.001 | 0.664 | |
| Total peripheral vascular resistance (dyne sec cm−5) |
Abs value IFG pregnancies (95% CI) (number of study groups) |
1171 (1083–1260) (n = 9) |
1370 (1174–1567) (n = 16) a 1001 (807–1195) |
1372 (1305–1439) (n = 28) a 1147 (1075–1218) |
1092 (792–1392) (n = 4) |
|
Abs value normal growth pregnancies (95% CI) (number of study groups) |
1076 (922–1230) (n = 5) |
973 (827–1120) (n = 5) |
1030 (971–1090) (n = 14) |
1187 (655–1719) (n = 3) |
|
| p‐value | 0.275 | 0.004 | <0.001 | 0.762 | |
Abbreviations: Abs, absolute; CI, confidence interval; IFG, impaired fetal growth.
Values corrected for publication bias are also presented for intervals with statistically significant funnel plot asymmetry.
Table 1 and Figure S2 depict absolute TPVR values during pregnancies complicated by impaired fetal growth. In the second and third trimester, absolute TPVR was significantly higher in pregnancies with impaired fetal growth compared with pregnancies with normal fetal growth (second trimester: 1370 dyne sec cm−5 vs. 973 dyne sec cm−5, p‐value = 0.004; third trimester: 1372 dyne sec cm−5 vs. 1030 dyne sec cm−5, p‐value < 0.001). No significant differences were observed in the non‐pregnant state, suggesting that hemodynamic changes develop during pregnancy rather than prepregnancy. Publication bias was present in the second and third‐trimester intervals; corrected values are presented in Table 1.
The reference curves of absolute CO and TPVR values over the course of pregnancies complicated by impaired fetal growth and in the postpartum period are presented in Figures 2 and 3, respectively.
FIGURE 2.
Absolute CO values in pregnancies with impaired fetal growth over the course of pregnancy and in the postpartum period, with mean (solid line) and 5th and 95th percentiles (dashed lines) weighted by study sample size. Size of individual plots indicates sample size of point estimate, and their color indicates study quality: Red, low quality; green, moderate quality; blue, high quality. Studies with multiple measurements during pregnancy are plotted per measurement.
FIGURE 3.
Absolute TPVR values in pregnancies with impaired fetal growth over the course of pregnancy and in the postpartum period, with mean (solid line) and 5th and 95th percentiles (dashed lines) weighted by study sample size. Size of individual plots indicates sample size of point estimate, the green color indicates moderate study quality, and the blue color indicates high quality of the study. Studies with multiple measurements during pregnancy are plotted per measurement.
The results of the subgroup analyses stratified by measurement modality were comparable to the overall pooled finding (Table S4, Figures S3–, S8). For echocardiography, CO was lower in pregnancies with impaired fetal growth from the second trimester onwards (second trimester: 4.93 L min−1 vs. 6.08 L min−1, p‐value = <0.01; third trimester: 5.10 L min−1 vs. 6.11 L min−1, p‐value = 0.01). TPVR measured by echocardiography was higher in the second and third trimester (second trimester: 1644 dyne sec cm−5 vs. 1264 dyne sec cm−5, p‐value = 0.03; third trimester: 1531 dyne sec cm−5 vs. 1054 dyne sec cm−5, p‐value = <0.01). In the USCOM subgroup, CO was lower in the second and third trimester (second trimester: 5.93 L min−1 vs. 7.08, p‐value = <0.01; third trimester: 5.66 vs. 6.55, p‐value = <0.01), and TPVR was higher in both trimesters (second trimester: 1340 dyne sec cm−5 vs. 1013 dyne sec cm−5, p‐value = 0.02; third trimester: 1371 dyne sec cm−5 vs. 1064 dyne sec cm−5, p‐value = <0.01). Analyses using NICOM indicated similar patterns, although most comparisons did not reach statistical significance (third trimester CO: 6.70 L min−1 vs. 7.54 L min−1, p‐value = 0.23). In the non‐pregnant state, echocardiography‐based CO was significantly higher in women with impaired fetal growth compared with controls (5.47 L min−1 vs. 4.85 L min−1, p‐value = <0.01), while no significant differences were observed using NICOM. TPVR measured by echocardiography was significantly lower in women with impaired fetal growth compared with controls (1305 dyne sec cm−5 vs. 1567 dyne sec cm−5, p < 0.01). In contrast, for NICOM, no significant differences were seen. These findings suggest that modality‐specific estimates largely align with the overall pooled results, with minor inconsistencies in the non‐pregnant state likely reflecting the limited number of studies available.
3.4. Subgroup analyses of hemodynamic function
Deeper insight into maternal central hemodynamic function was obtained by various subgroup analyses (Table 2). First, absolute values of CO and TPVR were compared between studies that only used fetal or neonatal weight or centile to define impaired fetal growth and studies that used additional criteria (including Doppler measurements). CO in the third trimester was significantly lower (5.24 L min−1 vs. 5.98 L min−1, p‐value = 0.022), and TPVR in the second and third trimesters was significantly higher (second trimester: 1638 dyne sec cm−5 vs. 1161 dyne sec cm−5, p‐value = 0.001; third trimester: 1499 dyne sec cm−5 vs. 1266 dyne sec cm−5, p‐value < 0.001) in study populations that used additional criteria to define impaired fetal growth. Second, we analyzed absolute values of CO and TPVR in women with solely impaired fetal growth compared with women with impaired fetal growth and coexistent HDP. In the second and third trimesters, the TPVR of women with impaired fetal growth and coexistent HDP was markedly higher compared with women with solely impaired fetal growth (second trimester: 1656 dyne sec cm−5 vs. 1196 dyne sec cm−5, p‐value = 0.009; third trimester: 1583 dyne sec cm−5 vs. 1213 dyne sec cm−5, p‐value <0.001). Third, we analyzed the relation between absolute values of CO and TPVR in pregnancies complicated by impaired fetal growth and gestational age of delivery. With increasing concurrent iatrogenic preterm delivery, CO was progressively lower and TPVR higher.
TABLE 2.
Difference in cardiac output and total peripheral vascular resistance in: (1) Impaired fetal growth based on weight (centile) or with additional criteria; (2) Impaired fetal growth with or without hypertensive disease in pregnancy; (3) Impaired fetal growth based on gestational age at delivery.
| First trimester | Second trimester | Third trimester | Non‐pregnant | |
|---|---|---|---|---|
| Cardiac output (L min−1) | ||||
| IFG based on weight (centile) (95% CI) | 5.82 (5.13–6.52) | 6.22 (5.31–7.12) | 5.98 (5.54–6.42) | 5.48 (5.27–5.69) |
| IFG with additional criteria (95% CI) | – | 5.03 (4.56–5.51) | 5.24 (4.86–5.61) | – |
| p‐value | NA | 0.068 | 0.022 | NA |
| IFG without HDP (95% CI) | 5.98 (4.65–7.32) | 5.94 (4.95–6.92) | 5.88 (5.44–6.32) | 5.55 (5.10–6.00) |
| IFG with HDP (95% CI) | 5.87 (3.91–7.83) | 5.29 (4.60–5.98) | 5.38 (4.89–5.87) | 5.40 (4.79–6.01) |
| p‐value | 0.922 | 0.474 | 0.175 | 0.702 |
| IFG with GA at delivery <32 wk (95% CI) | – | 5.03 (4.48–5.58) | – | – |
| IFG with GA at delivery 32‐37 wk (95% CI) | 5.39 (4.49–6.29) | 5.29 (4.77–5.82) | 5.27 (4.90–5.64) | 5.47 (5.22–5.72) |
| IFG with GA at delivery >37 wk (95% CI) | 5.97 (5.09–6.84) | 6.84 (6.07–7.61) | 6.10 (5.34–6.86) | 5.50 (5.14–5.86) |
| p‐value* | 0.675 | 0.002 | 0.006 | 0.788 |
| Total peripheral vascular resistance (dyne sec cm−5) | ||||
| IFG based on weight or centile (95% CI) | 1171 (1083–1260) | 1161 (994–1327) | 1266 (1192–1341) | 1092 (792–1392) |
| IFG with additional criteria (95% CI) | – | 1638 (1334–1943) | 1499 (1366–1633) | – |
| p‐value | NA | 0.001 | <0.001 | NA |
| IFG without HDP (95% CI) | 1089 (903–1275) | 1196 (1029–1362) | 1213 (1152–1274) | 1082 (565–1600) |
| IFG with HDP (95% CI) | 808 (663–953) | 1656 (1143–2169) | 1583 (1436–1731) | 845 (526–1164) |
| p‐value | 0.200 | 0.009 | <0.001 | 0.622 |
| IFG with GA at delivery <32 wk (95% CI) | – | 1746 (1475–2018) | – | – |
| IFG with GA at delivery 32–37 wk (95% CI) | 1294 (1074–1515) | 1382 (1213–1550) | 1564 (1421–1708) | – |
| IFG with GA at delivery >37 wk (95% CI) | 1133 (982–1285) | 927 (774–1080) | 1130 (1026–1235) | 1092 (792–1392) |
| p‐value* | 0.163 | <0.001 | <0.001 | 0.036 |
Note: Values are reported as absolute values with 95% confidence interval.
Abbreviations: CI, confidence interval; GA, gestational age; HDP, hypertensive disorders of pregnancy; IFG, impaired fetal growth; NA, not available/assessed; wk, week.
p for trend, GA not as categorical.
4. DISCUSSION
This study summarizes maternal central hemodynamic function preconception and over the course of pregnancy in women who ultimately gave birth to a growth‐restricted neonate, a potentially life‐threatening condition in offspring affecting long‐term health. Our meta‐analysis indicates that pregnancies complicated by impaired fetal growth relate to a lower absolute CO in the third trimester, and an increased absolute TPVR in the second and third trimester compared with pregnancies with appropriate fetal growth. Subgroup analyses demonstrate more pronounced hemodynamic parameter differences, predominantly vasoconstrictive, in more severe clinical phenotypes of impaired fetal growth, including impaired fetal growth accompanied by additional criteria, among abnormal Doppler flow measurements, concurrent HDP, and earlier (preterm) delivery.
Major hemodynamic adjustments during pregnancy include a physiological reduction in TPVR, increased CO, and expanded plasma volume to meet the demands of advancing healthy pregnancy. 1 , 2 Early‐pregnancy reduction in TPVR is associated with increased arterial compliance, decreased vascular tone, decreased vascular responsiveness to vasoconstrictors, increased release and sensitivity to vasodilatory substances (including relaxin, nitric oxide, progesterone, and estrogen), and the opening of maternal protective regulatory microcirculatory and placental arterio‐venous shunts. 32 , 33 , 34 Following the activation of the renin‐angiotensin‐aldosterone system, plasma volume expands, leading to dilutional anemia and a reduction in blood viscosity, which may further decrease TPVR. 35 These adjustments might each be compromised during pregnancies ultimately complicated by impaired fetal growth.
Although differences in CO and TPVR might seem entirely pregnancy‐induced due to similar prepregnancy levels, there mostly is a prepregnancy circulatory predisposition to impaired cardiovascular adaptation to pregnancy. This predisposition strongly influences later impaired fetal growth, preterm delivery, and HDP. 36 Subnormal prepregnancy plasma volume predominantly affects the venous compartment, which is overlooked when focusing on arterial characteristics, including blood pressure, CO, and TPVR. Reduced venous dimensions lead to increased sympathetic tone to preserve venous return, which may restrict early‐pregnancy hemodynamic adjustments, affecting arterial tone, circulatory distribution, vascular shear, and endothelial function. 37 , 38 , 39 In addition to prepregnancy predisposition and attenuated plasma volume rise, especially in HDP, increased capillary leakage may further reduce cardiac preload abilities. Early maladjustments can increase TPVR with inadequate CO increase, while women who initially had normal values may develop endothelial leakage, leading to decreased CO, increased TPVR, and elevated sympathetic tone. 26
Inadequate maternal systemic hemodynamic adaptation may lead to impaired placentation and reduced production of angiogenic growth factors, followed by increased viscosity due to attenuated plasma volume expansion. 40 , 41 , 42 Inadequate uteroplacental circulation modifications can reduce utero‐placental‐fetal blood flow, commonly observed with fetal and maternal complications. The underlying pathophysiological mechanism is considered incomplete trophoblast invasion of the spiral arteries during the placentation process, preventing the transformation of placental‐bed arteries into low‐resistance vessels insensitive to adrenergic stimuli, which is believed to play a central role in the pathogenesis of early‐onset preeclampsia and FGR. 43 , 44
Two pathogenic phenomena have been hypothesized to contribute to FGR. Early‐onset FGR (<32 weeks of gestation) is associated with abnormal placentation, where defective extravillous trophoblast invasion leads to impaired uteroplacental perfusion, decreased CO, and increased TPVR. 45 In contrast, late‐onset FGR probably represents a more heterogeneous group that does not seem to be primarily determined by abnormal placentation in the first trimester. 46 Compared with early‐onset disease, these placentas show significantly less frequent histological abnormalities. 47 Functionally, first‐trimester uterine artery Doppler assessment as a proxy of placental reserve demonstrates a relation between the resistance index and the severity of growth restriction. 48 This clinical phenotype is thought to be accompanied by normal to increased CO and decreased TPVR. Maternal cardiovascular reserves might fail to meet the increased third trimester demands, leading to secondary placental dysfunction, altered maturation of the placental villous tree, and impaired fetal oxygenation and growth. 49 It is demonstrated that a de novo increase in uterine artery resistance in the late third trimester in women having previously exhibited normal indices has a higher risk of SGA delivery, suggesting maternal systemic and uterine vascular resistance changes occur independently of direct consequences of the degree of placental trophoblast invasion. 50 From a maternal perspective, both suggested different system‐biological mechanisms underlying early vs. late FGR, which our findings could support.
A clear distinction between SGA and FGR is clinically important but often difficult to establish. No single definition fully captures the complexity of FGR. Abnormal Doppler findings do not always indicate pathological FGR, while some constitutionally small infants may meet the SGA criteria without experiencing true growth restriction. On top of that, FGR distinction requires repeated and more extensive ultrasounds, including Doppler flow measurements of umbilical artery, middle cerebral artery, or the ratio of both, which we found largely to be unavailable in clinical research. In additions, a study by Perry et al. 51 demonstrated that, after correction for maternal stature and gestational age, CO did not differ in physiological SGA pregnancies but remained lower in “true” FGR (i.e., <3rd centile and/or abnormal Doppler flow profiles), underscoring the importance of maternal anthropometry as a cofounder. In this systematic review, anthropological correction was not feasible because individual patient‐level data were unavailable. We therefore sought to address potential differences in study outcomes between SGA and FGR by conducting subgroup analyses focused on more severe phenotypes of estimated growth restriction, namely SGA with abnormal Doppler flow, concurrent HDP, or preterm birth. Across all three definitions, the hemodynamic deviations were more pronounced compared with isolated SGA, with lower CO and higher TPVR being addressed. These findings suggest that maternal central hemodynamics differ particularly in cases of pathologically and/or more severe growth‐restricted rather than constitutionally small infants. As these subgroup analyses address interrelated clinical characteristics, the results should be interpreted as exploratory and descriptive rather than causal.
Across the included studies, various methods were used to assess maternal hemodynamics, including echocardiography, USCOM, and NICOM. Although absolute values differ between these techniques, the direction and magnitude of findings were consistent. In modality‐specific subgroup analyses, CO was lower and TPVR higher in pregnancies with impaired fetal growth across all major modalities. These results suggest that methodological heterogeneity, while inherent to hemodynamic research, did not affect the overall conclusions and instead supports the robustness and reproducibility of the observed patterns.
To the best of our knowledge, this is the first systematic review and meta‐analysis on this topic. The study's strengths include the large number of included studies, the use of trimester‐specific analyses, and the exploration of multiple clinically relevant subgroups. Demonstrating that subnormal maternal TPVR and CO precede impaired fetal growth from the second trimester onwards. Moreover, we empirically confirmed the hypothesis that “true” FGR concurs with more vasoconstriction maternal circulation than SGA pregnancies in general. The clinical severity, reflected by maternal hypertensive involvement or earlier (preterm) birth, also concurs with a more vasoconstrictive hemodynamic profile. However, several limitations should be acknowledged. First, definitions of impaired fetal growth were not uniform in the included studies, and many studies only reported SGA. Not all SGA neonates are pathologically growth‐restricted, and including these neonates might have influenced the overall findings However, both SGA and “true” FGR predispose to increased morbidity and mortality risks compared with pregnancies with appropriate fetal growth. Therefore, we combined all used definitions in one complicated group for our primary analysis; subgroup analysis revealed a more pronounced difference in hemodynamic function between SGA and FGR. Second, not all studies reported medication use at the time of measurements, which may have affected our findings, especially with antihypertensive drugs altering cardiac and vascular function. Third, the central hemodynamic functions of women with coexistent hypertensive disorders might have been affected using antihypertensive drugs. Given the pharmacologically divergent effects of various antihypertensive medications used during pregnancy on central hemodynamic parameters, it is not possible to interpret these effects. Fourth, methodological heterogeneity across studies, including differences in measurement modality, timing of assessment, and study design, may have introduced variability. However, the consistency of results across modalities suggests that this limitation did not substantially affect the direction of the findings. Finally, pregnancy outcomes, including the proportion of women with coexistent HDP and gestational age at delivery, were reported in aggregate per study, possibly mitigating the found associations; an individual patient data meta‐analysis could address this limitation.
Monitoring maternal hemodynamics offers a novel, non‐invasive approach to identifying women at increased risk of impaired fetal growth, enabling timely interventions and vigilant antenatal follow‐up. 52 , 53 As central hemodynamic alterations emerge from the second trimester, CO and TPVR may be less effective for guiding the institution of generic strategies among daily low‐dose aspirin, starting before the end of the first trimester. However, they may be helpful in hemodynamic modulatory drugs, that is, antihypertensives. 54 When FGR is detected, maternal hemodynamic assessment, alongside Doppler velocity measurements, may help differentiate between pathological and non‐pathological impaired fetal growth, allowing more accurate selection and clinical control of patients at risk for an adverse pregnancy outcome. Moreover, detecting hemodynamic differences raises the possibility of interventions to optimize maternal cardiovascular function and potentially prevent related complications, such as HDP. Future treatment strategies could focus on improving maternal hemodynamic function in a timely manner to improve fetal growth and prevent FGR. One study demonstrated that administering vasodilators and plasma volume expanders in women with FGR and preeclampsia improved maternal hemodynamics, prolonged pregnancy, and increased BW, though treatment was initiated post‐diagnosis. 55 A current multicenter trial is investigating the vasodilating effect of organic nitrates on fetal growth in women with impaired mid‐gestation uterine artery Doppler. 56 The potential beneficial effect of an intervention with early hemodynamic modification, when the placenta is still developing, on fetal growth needs to be evaluated in future trials.
5. CONCLUSION
From the second trimester onwards, women who give birth to growth‐restricted neonates exhibit subnormal CO and TVPR, being significantly different from women with appropriately grown neonates. More pronounced hemodynamic deviations are observed in more severe clinical phenotypes of impaired fetal growth. Monitoring maternal hemodynamic changes during pregnancy may help to identify women at risk for a pathological growth‐restricted neonate, with the potential to improve growth by general preventive measures and future treatment opportunities by improving maternal cardiac and vascular function during pregnancy.
AUTHOR CONTRIBUTIONS
LJ and EM performed the literature search, study selection, and analyzed the data. LJ wrote the initial draft of the article, revised the paper, and finalized the manuscript together with BK. LJ, EM, and MS conceptualized the manuscript. CGD, JvD, RS, CL, SdH, EJ, and MS critically reviewed the manuscript.
CONFLICTS OF INTEREST
There are no conflicts of interest.
Supporting information
Table S1. Search strings to enroll articles.
Table S2. Study and population characteristics of included studies.
Table S3. Quality assessment of included studies based on QUIPS criteria.
Table S4. Absolute values of hemodynamic parameters during pregnancies with impaired fetal growth compared with pregnancies with normal growth.
Figure S1. Forest plot of absolute cardiac output values with 95% confidence interval during pregnancy and non‐pregnant in women whose pregnancy is complicated by impaired fetal growth.
Figure S2. Forest plot of absolute total peripheral vascular resistance values with 95% confidence interval during pregnancy and non‐pregnant in women whose pregnancy is complicated by impaired fetal growth.
Figure S3. Forest plot of echocardiography‐derived absolute cardiac output values with 95% confidence interval during pregnancy and non‐pregnant in women whose pregnancy is complicated by impaired fetal growth.
Figure S4. Forest plot of USCOM‐derived absolute cardiac output values with 95% confidence interval during pregnancy and non‐pregnant in women whose pregnancy is complicated by impaired fetal growth.
Figure S5. Forest plot of NICOM‐derived absolute cardiac output values with 95% confidence interval during pregnancy and non‐pregnant in women whose pregnancy is complicated by impaired fetal growth.
Figure S6. Forest plot of echocardiography‐derived absolute total peripheral vascular resistance values with 95% confidence interval during pregnancy and non‐pregnant in women whose pregnancy is complicated by impaired fetal growth.
Figure S7. Forest plot of USCOM‐derived absolute total peripheral vascular resistance values with 95% confidence interval during pregnancy and non‐pregnant in women whose pregnancy is complicated by impaired fetal growth.
Figure S8. Forest plot of NICOM‐derived absolute total peripheral vascular resistance values with 95% confidence interval during pregnancy and non‐pregnant in women whose pregnancy is complicated by impaired fetal growth.
Kempener BMJG, Jorissen LM, Mulder EG, et al. Hemodynamic changes in pregnancies with impaired fetal growth: A systematic review and meta‐analysis. Acta Obstet Gynecol Scand. 2026;105:215‐224. doi: 10.1111/aogs.70102
Britt Kempener and Laura Jorissen share first authorship.
DATA AVAILABILITY STATEMENT
The data that supports the findings of this study are available in the Supporting Information of this article.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1. Search strings to enroll articles.
Table S2. Study and population characteristics of included studies.
Table S3. Quality assessment of included studies based on QUIPS criteria.
Table S4. Absolute values of hemodynamic parameters during pregnancies with impaired fetal growth compared with pregnancies with normal growth.
Figure S1. Forest plot of absolute cardiac output values with 95% confidence interval during pregnancy and non‐pregnant in women whose pregnancy is complicated by impaired fetal growth.
Figure S2. Forest plot of absolute total peripheral vascular resistance values with 95% confidence interval during pregnancy and non‐pregnant in women whose pregnancy is complicated by impaired fetal growth.
Figure S3. Forest plot of echocardiography‐derived absolute cardiac output values with 95% confidence interval during pregnancy and non‐pregnant in women whose pregnancy is complicated by impaired fetal growth.
Figure S4. Forest plot of USCOM‐derived absolute cardiac output values with 95% confidence interval during pregnancy and non‐pregnant in women whose pregnancy is complicated by impaired fetal growth.
Figure S5. Forest plot of NICOM‐derived absolute cardiac output values with 95% confidence interval during pregnancy and non‐pregnant in women whose pregnancy is complicated by impaired fetal growth.
Figure S6. Forest plot of echocardiography‐derived absolute total peripheral vascular resistance values with 95% confidence interval during pregnancy and non‐pregnant in women whose pregnancy is complicated by impaired fetal growth.
Figure S7. Forest plot of USCOM‐derived absolute total peripheral vascular resistance values with 95% confidence interval during pregnancy and non‐pregnant in women whose pregnancy is complicated by impaired fetal growth.
Figure S8. Forest plot of NICOM‐derived absolute total peripheral vascular resistance values with 95% confidence interval during pregnancy and non‐pregnant in women whose pregnancy is complicated by impaired fetal growth.
Data Availability Statement
The data that supports the findings of this study are available in the Supporting Information of this article.