Fetal growth restriction (FGR) leading to low birth weight (LBW) is a major cause of neonatal morbidity and mortality worldwide. Normal placental development involves a series of highly regulated processes involving a multitude of hormones, transcription factors, and cell lineages. Failure to achieve this leads to placental dysfunction and related placental diseases such as pre-clampsia and FGR. Early recognition of at-risk pregnancies is important because careful maternal and fetal surveillance can potentially prevent adverse maternal and perinatal outcomes by judicious pregnancy surveillance and careful timing of birth. Given the association between a variety of circulating maternal biomarkers, adverse pregnancy, and perinatal outcomes, screening tests based on these biomarkers, incorporating maternal characteristics, fetal biophysical or circulatory variables have been developed. However, their clinical utility has yet to be proven. Of the current biomarkers, placental growth factor and soluble fms-like tyrosine kinase 1 appear to have the most promise for placental dysfunction and predictive utility for FGR.

A small for gestational age (SGA) infant is variably defined as one with an estimated fetal weight (EFW) or birthweight (BW) less than the 10th centile for gestation [1–3]. Globally, almost 21 million infants are born SGA each year, the majority in low-income and middle-income countries [4]. These infants are at higher risk of morbidity and mortality particularly if they are born preterm [5] and are also more likely to develop chronic health complications through childhood and in adulthood [6].

Although SGA and fetal growth restriction (FGR) are often used interchangeably, FGR is defined as an infant that has not achieved its genetic growth potential [7]; however, as this is inherently unknown, it is impossible to determine if any infant has indeed achieved that potential prenatally. Importantly, not all infants with FGR will be SGA and not all SGA infants will have FGR. Regardless of this caveat, many SGA/FGR liveborn infants will have low birth weight (LBW) defined as a BW <2500 g irrespective of gestational age. Worldwide, LBW is an important public health indicator, especially in settings where accurate gestational age assessment is not possible and prenatal assessment of fetal size or growth is not available [5,8].

Normal placental development [9] involves a combination of highly regulated processes requiring a plethora of angiogenic growth factors, hormones, transcription factors, cytokines and cell adhesion molecules [10]. Failure to establish a high capacitance, low pressure maternal fetal vascular interface [9] leads to placental dysfunction and is causally related to several obstetric syndromes including pre-eclampsia and FGR [11]. Although there is considerable overlap between the pathogenesis of pre-eclampsia and FGR, the relationship between the extent of failure of spiral artery conversion, gestation at onset, type of disease, maternal and infant phenotype as well as clinical outcomes remains poorly understood [12–14].

The challenge obstetricians face is identifying the truly growth restricted fetus regardless of size, as these are the infants that are most at risk of adverse outcomes. Because placental dysfunction leading to inadequate nutrient and oxygen transfer [15] accounts for the majority of SGA/FGR infants [16,17], many investigators have focused attention on circulating biomarkers indicative of aberrant placental function [18–20]. As there is currently no treatment for placental dysfunction, early recognition of at-risk pregnancies is important because careful maternal and fetal surveillance can be instituted and adverse outcomes potentially prevented by judicious timing of birth [21–23]. The aim of this narrative review is to provide an overview of available evidence regarding circulating biomarkers associated with placental dysfunction and to discuss their clinical utility for the prediction of FGR. A comprehensive review of PubMed, Cochrane Library, and CINAHL was performed to identify appropriate publications between 1995 and October 2022 relevant to this review.

Circulating biomarkers are broadly classified into: (1) hormonal factors, polypeptides, and glycoproteins; (2) angiogenic factors; and (3) cell-free nucleic acids [12,24] (Figure 1). Some of these biomarkers are potentially expressed as a consequence of epigenetic changes during placental development [25–28].

Circulating maternal biomarkers derived from the placenta that are associated in placental dysfunction

Figure 1
Circulating maternal biomarkers derived from the placenta that are associated in placental dysfunction

A summary of various hormonal factors, polypeptides, glycoproteins, angiogenic factors, and nucleic acids, which are associated in placental dysfunction and pathophysiology of FGR.

Figure 1
Circulating maternal biomarkers derived from the placenta that are associated in placental dysfunction

A summary of various hormonal factors, polypeptides, glycoproteins, angiogenic factors, and nucleic acids, which are associated in placental dysfunction and pathophysiology of FGR.

Close modal

Table 1 lists various placental hormones, polypeptides, and glycoproteins associated with placental dysfunction and their potential roles for screening and diagnosis of FGR. These include beta-human chorionic gonadotrophin (β-hCG), pregnancy-associated plasma protein-A (PAPP-A), A Disintegrin and Metalloprotease 12 (ADAM12), placental protein 13 (PP13), alpha-fetoprotein (AFP), inhibin A, activin A, follistatin, placental growth hormone (PGH), neural cell adhesion molecule (N-CAM), fibroblast growth factor (FGF), Insulin-like growth factor-I (IGF-I), Insulin-like growth factor binding proteins-1, -3, -4 (IGFBP-1, IGFBP-3, and IGFBP-4), and serine protease inhibitor Kunitz type 1 (SPINT1).

Table 1
Circulating maternal biomarkers associated with FGR
BiomarkersFunctionsMaternal levels in FGR pregnanciesKey references
Hormonal factors, polypeptides, and glycoproteins 
Activin A Regulation of endometrial receptivity, implantation of embryo, and trophoblast development Unchanged [51
  Raised [50
ADAM12a Promotion of cell migration and trophoblast invasion Reduced [29,31,32,35,37
AFPb Function in human placenta is unclear Raised in first and second trimester [34,46,47
  Reduced in third trimester [48
β-HCGc Promotion of progesterone production by corpus luteal cells and maintenance of endometrial lining. Promotion of angiogenesis, immunosuppression, and growth of fetus organs Reduced in first trimester [30,32,37
  Unchanged in second trimester [34
Follistatin Inhibits the biological activity of Activin A. Inhibits follicular development in ovary by antagonizing follicle-stimulating hormone Reduced [50,51
Inhibin A Regulation of implantation and differentiation of developing embryo Unchanged [51–53
  Raised [50
IGF-Id Promotion of transplacental nutrient transfer to the fetus Reduced [58,61
IGFBP-1e Regulation of implantation and endometrial growth Reduced [58,59
IGFBP-3e Modulation of IGF-I effect in transplacental nutrient transfer Unchanged [58
IGFBP-4e Regulation of IGF bioavailability Raised [60
N-CAMf Cell signaling, adhesion, proliferation, and differentiation in fetal development. Maintenance of tissue integrity and regeneration of neural and non-neural tissues during early development of fetus Increased [61
PGHg Regulation of placental and fetal growth. Stimulation of IGF-I secretion Unchanged [57
PP13h Regulation of implantation and placental vascular development Unchanged [33,37,40–42,150
  Reduced [43
PAPP-Ai Interaction with IGF and regulation of trophoblast and fetal growth Reduced [19,29,30,32,34,37
SPINT1j Mediates secretion of trophoblast degradative enzymes that regulate invasion and remodeling of endometrial spiral arteries Reduced [68–70
Angiogenic factors 
PlGFk Angiogenic factor expressed in villous syncytiotrophoblast to promote development and maturation of placental vascular system Reduced [37,48,76,79,80,86,91,92,94–98,107,151–157
  Increased [158,159
  Unchanged [160,161
sFlt-1l Antiangiogenic protein that antagonizes the actions of vascular endothelial growth factor and placental growth factor Increased [48,80,86,91,92,94–98,152–154,156–158,162–166
  Reduced [151,166,159
  Unchanged [107,155,160,167
VEGF-Am Promotes placental vasculogenesis and angiogenesis throughout pregnancy by promoting formation of angioblasts and mesenchymal villi Increased [158
sEngn Inhibits transforming growth factor beta (TGF-β)-mediated cell signaling and endothelial function Increased [111,112,166,168
  Unchanged [113,158
FGFo Regulates placental growth, differentiation, and angiogenesis Increased [61
  Reduced [63
BiomarkersFunctionsMaternal levels in FGR pregnanciesKey references
Hormonal factors, polypeptides, and glycoproteins 
Activin A Regulation of endometrial receptivity, implantation of embryo, and trophoblast development Unchanged [51
  Raised [50
ADAM12a Promotion of cell migration and trophoblast invasion Reduced [29,31,32,35,37
AFPb Function in human placenta is unclear Raised in first and second trimester [34,46,47
  Reduced in third trimester [48
β-HCGc Promotion of progesterone production by corpus luteal cells and maintenance of endometrial lining. Promotion of angiogenesis, immunosuppression, and growth of fetus organs Reduced in first trimester [30,32,37
  Unchanged in second trimester [34
Follistatin Inhibits the biological activity of Activin A. Inhibits follicular development in ovary by antagonizing follicle-stimulating hormone Reduced [50,51
Inhibin A Regulation of implantation and differentiation of developing embryo Unchanged [51–53
  Raised [50
IGF-Id Promotion of transplacental nutrient transfer to the fetus Reduced [58,61
IGFBP-1e Regulation of implantation and endometrial growth Reduced [58,59
IGFBP-3e Modulation of IGF-I effect in transplacental nutrient transfer Unchanged [58
IGFBP-4e Regulation of IGF bioavailability Raised [60
N-CAMf Cell signaling, adhesion, proliferation, and differentiation in fetal development. Maintenance of tissue integrity and regeneration of neural and non-neural tissues during early development of fetus Increased [61
PGHg Regulation of placental and fetal growth. Stimulation of IGF-I secretion Unchanged [57
PP13h Regulation of implantation and placental vascular development Unchanged [33,37,40–42,150
  Reduced [43
PAPP-Ai Interaction with IGF and regulation of trophoblast and fetal growth Reduced [19,29,30,32,34,37
SPINT1j Mediates secretion of trophoblast degradative enzymes that regulate invasion and remodeling of endometrial spiral arteries Reduced [68–70
Angiogenic factors 
PlGFk Angiogenic factor expressed in villous syncytiotrophoblast to promote development and maturation of placental vascular system Reduced [37,48,76,79,80,86,91,92,94–98,107,151–157
  Increased [158,159
  Unchanged [160,161
sFlt-1l Antiangiogenic protein that antagonizes the actions of vascular endothelial growth factor and placental growth factor Increased [48,80,86,91,92,94–98,152–154,156–158,162–166
  Reduced [151,166,159
  Unchanged [107,155,160,167
VEGF-Am Promotes placental vasculogenesis and angiogenesis throughout pregnancy by promoting formation of angioblasts and mesenchymal villi Increased [158
sEngn Inhibits transforming growth factor beta (TGF-β)-mediated cell signaling and endothelial function Increased [111,112,166,168
  Unchanged [113,158
FGFo Regulates placental growth, differentiation, and angiogenesis Increased [61
  Reduced [63
a

A Disintegrin and Metalloprotease 12.

b

Alpha-fetoprotein.

c

Beta-human chorionic gonadotrophin.

d

Insulin-like growth factor-I.

e

Insulin-like growth factor binding proteins-1, -3, and -4.

f

Neural cell adhesion molecule.

g

Placental growth hormone.

h

Placental protein 13.

I

Pregnancy-associated plasma protein-A.

j

Serine protease inhibitor Kunitz type 1.

k

Placental growth factor.

l

Soluble fms-like tyrosine kinase 1.

m

Vascular endothelial growth factor-A.

n

Soluble endoglin.

o

Fibroblast growth factor.

βhCG, PAPP-A, and ADAM12

Lower concentrations of circulating maternal βhCG, PAPP-A, and ADAM12 measured at 11–14 weeks of gestation have been reported in women with SGA/FGR infants [29–33]. Pihl et al. observed that first trimester maternal serum concentrations of βhCG, PAPP-A, and ADAM12 in women with SGA infants (defined as BW <5th centile) were significantly lower compared with matched controls (βhCG: 0.74 vs. 1.04 multiples of median (MoM), PAPP-A: 0.64 vs. 1.02 MoM and ADAM12: 0.74 vs. 0.97 MoM). Combining βhCG and PAPP-A yielded a detection rate of 26% with a false-positive rate (FPR) of 5% for an SGA infant. However, the addition of ADAM12 only very modestly improved the detection rate by a further 2% [32]. In another study, Poon et al. found that first trimester βhCG and PAPP-A concentrations in combination with maternal characteristics and fetal nuchal translucency measurement predicted birth of an SGA infant [30]. Maternal βhCG and PAPP-A MoM were significantly lower in SGA pregnancies, and combining maternal factors, nuchal translucency thickness, PAPP-A, and free βhCG concentrations resulted in the highest area under receiver-operating curve (AUROC) of 0.747 (95% CI: 0.735–0.760) and a detection rate of 37% for a FPR of 10% [30]. In contrast, however, a screening test later in pregnancy using a similar combination of biomarkers, maternal factors, and fetal biometry at 19–24 weeks of gestation performed poorly for the prediction of an SGA infant [34].

Other studies have shown that although there is good correlation between first trimester maternal serum ADAM12 concentrations with BW centile, it performs poorly as a standalone screening test [29]. A more recent study evaluated maternal plasma ADAM12 late in the third trimester (36 weeks) and despite finding significantly lower median concentrations in women with SGA infants compared with controls [14115 pg/ml (Interquartile range (IQR): 11510–16592 pg/ml) vs. 16582 pg/ml (IQR: 13658–20322 pg/ml)], it was not suitable as a screening test [35].

A systematic review and meta-analysis (32 studies; 175240 pregnancies) assessing the predictive utility of first trimester maternal serum PAPP-A concentrations for birth of an SGA infant, revealed poor predictive value with low positive (PLR) and negative (NLR) likelihood ratios for BW < 10th centile: PLR 1.96 (95% CI: 1.58–2.43), NLR 0.93 (95% CI: 0.89–0.98); BW < 5th centile: PLR 2.65 (95% CI: 2.35–2.99), NLR 0.85 (95% CI: 0.74–0.98) [36], suggesting that PAPP-A was not suitable as a standalone biomarker to predict SGA infants [19,36]. In another case–control study at 11–13 weeks of gestation, a combination of uterine artery pulsatility index (UtA-PI), maternal mean arterial pressure (MAP), and serum concentrations of PAPP-A, βhCG, PlGF, PP13, ADAM12 and fetal nuchal translucency thickness, yielded a detection rate of 73% and 46% for birth of a preterm and term SGA infant, respectively [37].

PP13 and AFP

PP13 is a glycan-binding protein mainly expressed in syncytiotrophoblast and secreted into the maternal circulation via exosomes or microvesicles [38]. Although an earlier observational study showed an association between low first trimester PP13 concentrations in maternal serum and FGR [39], subsequent studies [33,40] found limited predictive utility with no significant differences in median PP13 MoM levels in FGR-affected pregnancies even when combined with other first trimester screening markers such as PAPP-A [33] and ADAM12 [40]. Another study also showed that median PP13 concentrations in the first trimester of women with SGA infants (BW < 3rd, < 5th, and < 10th centiles) were not significantly lower than the control arms (0.978, 1.058, 1.051, and 1.083 MoM (controls) for each BW centiles, respectively) [41]. These findings were further corroborated in another study [42], which also failed to demonstrate the utility of PP13 for prediction of FGR [41]. In another study, median first trimester PP13 concentrations were significantly lower in FGR pregnancies compared with controls (86.6 vs. 132.5 pg/ml) but the overall sensitivity for the prediction of FGR was low at 33% at a specificity rate of 90% [43]. Two systematic reviews of first trimester serum PP13 in combination with maternal characteristics for the prediction of SGA infants reported low sensitivity of 32% (95% CI: 18–48%) [44] and 36% (95% CI: 33–41%) [45], respectively. The overall evidence thus far suggests that PP13 has limited clinical utility for predicting FGR.

In a study of 9715 singleton pregnancies (including 481 SGA infants with BW < 5th percentile), higher mean log10 MoM value of maternal serum AFP at 19–24 weeks of gestation was seen in the SGA cohort. When AFP levels were combined with maternal factors, fetal biometry, and maternal PlGF concentrations, detection rates of 100%, 76%, and 38% were achieved for SGA infants delivered at <32, 32–36, and ≥37 weeks gestation, respectively [34]. The addition of UtA-PI measurement further improved detection rates of SGA infants to 78% at 32–36 weeks and 42% at >37 weeks, respectively [46]. Another retrospective study [47] showed that while elevated serum AFP concentrations (≥2.5 MoM) in the first trimester was associated with birth of an SGA infant, its predictive utility for SGA and FGR was low with an AUROC of <0.6 [47]. Similarly, other studies have also demonstrated that although third trimester AFP concentrations are significantly lower in women with SGA infants, the overall detection rate using this biomarker is low at 26%, and even when it is combined with maternal PlGF concentrations detection rates only modestly increase to 32% [48]. A recent meta-analysis (39 cohort studies; 93968 women) reported that the relative risk (RR) for birth of an SGA infant in women with elevated AFP concentrations was increased (RR: 2.02, 95% CI: 1.75–2.33) and this risk was higher when ultrasound evidence of SGA was present (RR: 5.28, 95% CI: 3.46–8.06) [49].

Inhibin A, activin A, and follistatin

Maternal serum concentrations of activin A, inhibin A, and the activin:follistatin ratio in the third trimester have been reported to be significantly increased in FGR pregnancies compared with controls [50]. However, in another study, there was no difference in activin A or inhibin A concentrations in normotensive women with SGA infants compared with controls [51]. A study by Miranda et al. [52] showed that although mean inhibin A concentrations were significantly higher in women with SGA infants, a multivariable integrative model of maternal characteristics, fetoplacental ultrasound, and maternal biochemical markers only modestly improved the detection of SGA/FGR cases at 32–36 weeks’ gestation when compared with screening based on EFW centiles alone. Other studies [53] have also shown that the clinical utility of activin A, inhibin A, and follistatin as predictors for SGA/FGR is poor.

PGH, IGF-I, IGFBP, N-CAM, and FGF

PGH is mainly expressed by syncytiotrophoblast and stimulates gluconeogenesis and anabolic pathways to support the growing fetoplacental unit [54]. Earlier observational studies reported an association between low maternal serum PGH concentrations in the second and third trimesters and birth of an SGA infant [55,56]. However, in a later study [57], first trimester median maternal serum PGH concentrations in SGA pregnancies were not different to controls (0.95 MoM, 95% CI: 0.60–1.30 vs. 1.00 MoM, 95% CI: 0.70–1.30) and there was no association with BW centile.

Another study reported that although median maternal serum concentrations of IGF-I (61.8 ng/ml, IQR: 43.4–93.4 vs. 94.9 ng/ml, IQR: 56.7–131.2), IGFBP-1 (58.2 ng/ml, IQR: 39.8–84.9 vs. 81.4 ng/ml, IQR: 57.3–105.5), and IGFBP-3 (54.5 ng/ml, IQR: 45.6–61.5 vs. 55.4 ng/ml, IQR: 47.4–64.9) were significantly lower in women with SGA infants compared with controls [58], after multiple regression analyses and adjustment for maternal characteristics, these biomarkers were ultimately not useful for the prediction of SGA. Similarly, in another study, although a significant negative correlation between log IGFBP-1 and BW standard deviation score was noted, after adjusting for maternal body mass index, the relationship became nonsignificant [59]. IGFBP-4 is highly expressed by extravillous trophoblasts at the maternal–fetal interface [60] and circulating maternal IGFBP-4 concentrations in early pregnancy have been reported to be significantly higher in women with FGR infants (defined as BW < 5th centile) compared with controls [Odds ratio (OR) 22.3, (95% CI: 2.7–181.5)] with 93% positive predictive value (PPV) [60]. Current evidence, however, does not support the use of PGH, IGF-I, or IGFBP as reliable markers for the prenatal prediction of FGR [57–60].

A small observational study [61] reported an association between increased placental expression of N-CAM and FGF in cytotrophoblasts of pregnancies complicated by SGA (N-CAM immunoreactive cells median [range]: 26.0 [8–110] vs. 15.0 [8–29] (control group) and FGF: 45.0 [18–36] vs. 14.5 [5–26]). Another study showed that FGF-21 concentrations were significantly increased in amniotic fluid of SGA/FGR fetuses [62]. However, Hill et al. found that although maternal serum immunoreactive FGF-2 concentrations were lower in SGA pregnancies as compared with controls, the differences were not statistically significant [63]. The available evidence so far for the use of N-CAM and FGF for prediction of SGA/FGR is limited, and thus they should not be used in clinical practice until more data are available.

A systematic review and meta-analysis (103 studies; 432621 women) evaluating first trimester biomarkers (PAPP-A, βhCG, PlGF, and PP13) for the prediction of SGA reported low overall predictive accuracy [45]. Another review of AFP, βhCG, unconjugated estriol, PAPP-A, and inhibin A measured before 25 weeks gestation also reported poor predictive utility for SGA for all analytes [64]. However, high AFP and βhCG concentrations (>2 or >2.5 MoM) combined, appears to have better predictive utility for SGA infants (PLR: 6.18; 95% CI: 1.84–20.85) compared with unconjugated estriol, PAPP-A, and inhibin A [64,65]. Overall, however, the predictive value of AFP, βhCG, unconjugated estriol, PAPP-A, and inhibin A as biomarkers for SGA/FGR is low, either separately or in combination or incorporating maternal characteristics or ultrasound fetal biophysical variables [36,44,45,64–66].

SPINT1

SPINT1 is a circulating protein highly expressed by villous cytotrophoblasts. It is involved in the conversion of maternal spiral arteries into low pressure, high capacitance vessels by modulating trophoblast secretion of proteolytic enzymes (serine proteinases, metalloproteinases, and collagenases) that regulate transformation of spiral arteries in normal placentation [67]. In vitro and animal studies suggest that SPINT1 is modulated by hypoxia and decreased in FGR placentae. In a study of 2003 women [68] at 36 weeks’ gestation, a strong association between low plasma SPINT1 concentrations and SGA (defined as <10th centile) was seen. Using a SPINT1 cutoff threshold of <0.63 MoM, the risk of delivering an SGA infant with BW <3rd, <5th, and <10th centile was 14.1%, 19.7%, and 28.2%, respectively [68]. A recent cohort study [69] found maternal plasma SPINT1 concentrations were significantly lower at 20 weeks gestation in women who subsequently delivered an SGA infant; however, the AUROC was modest at 0.62 for BW <3rd centile and 0.56 for BW <19th centile, respectively. Murphy et al. [70] reported reduced plasma SPINT1 concentration in women with pre-eclampsia who subsequently delivered an SGA infant (median [IQR]: 18857 pg/ml [10782–29890] in SGA vs. 40168 pg/ml [22172342–75] in controls). Another study by Murphy et al. [67] found an association between elevated plasma serine protease inhibitor Kunitz type 2 (SPINT2), which is functionally related to SPINT1 in pregnancies complicated by pre-eclampsia and/or SGA. However, the evidence for SPINT1 as a suitable biomarker to predict SGA/FGR is limited, and more evidence is required to validate its clinical utility.

Table 1 presents angiogenic biomarkers associated with SGA or FGR. Both vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) play an important role in facilitating angiogenesis in placenta and transforming spiral arteries into low resistance capacitance vessels [71–73]. Failure of remodeling of spiral arteries by extravillous trophoblast is seen in placentae from pregnancies complicated by pre-eclampsia or FGR and when there is an imbalance of proangiogenic (PlGF) and antiangiogenic factors [soluble fms-like tyrosine kinase 1 (sFlt-1)] [72]. Indeed the 2021 International Society for the Study of Hypertension in Pregnancy (ISSHP) [74] now includes angiogenic factors as a criterion to define uteroplacental dysfunction (placental abruption, PlGF <5th centile for gestational age or sFlt-1/PlGF ratio >38, FGR, abnormal umbilical artery Doppler waveform analysis or intrauterine fetal death).

PlGF, sFlt-1, and sFlt-1/PlGF ratio

In a recent publication, Gaccioli et al. [75] showed that although the sFlt-1/PlGF ratio was increased in both pre-eclampsia and FGR in both placenta and maternal serum, in pre-eclampsia the sFlt-1/PlGF ratio was strongly associated with placental sFlt-1 concentrations (r=0.45; P<0.0001) but not placental PlGF concentrations (r=−0.17; P=0.16). In FGR pregnancies, however, the sFlt-1/PlGF ratio was strongly associated with placental PlGF concentrations (r=−0.35; P=0.02) but not placental sFlt-1 concentrations (r=0.04; P=0.81) suggesting that in pre-eclampsia the elevated sFlt-1/PlGF ratio is primarily driven by increased placental sFlt-1, whereas in FGR, it is mainly due to decreased placental PlGF.

In a prospective cohort study [76], low plasma PlGF (<5th percentile for gestational age) identified FGR infants and significant placental dysfunction on histopathological examination with sensitivity of 98.2% (95% CI: 90.5–99.9) and PPV of 58.5% (95% CI: 47.9–68.6), respectively. Low maternal PlGF outperformed gestational age, fetal abdominal circumference, and umbilical artery Doppler resistance indices in predicting FGR secondary to placental dysfunction. In another study, high sFlt-1 expression was present in 28% of placental tissue from pregnancies complicated by SGA/FGR without pre-eclampsia and in this group, 90% had abnormal umbilical Doppler and lower mean BW [77].

The sFlt-1/PlGF ratio is inversely correlated with BW [78,79] and a high ratio is present in pregnancies complicated by FGR [80]. Furthermore, although the sFlt-1/PlGF ratio is elevated regardless of the gestation at which FGR is diagnosed, early-onset FGR is associated with higher ratios compared with late-onset FGR, suggesting a possible lesser degree of placental dysfunction in the latter group [78,81]. A high sFlt-1/PlGF ratio also predicts a shorter time to delivery interval, which in turn is even more strongly correlated with the magnitude of daily increase of the ratio [82]. A recent study by Mitlid-Mork et al. [83] showed that compared with controls, women with pregnancies complicated by placental syndromes (pre-eclampsia and/or FGR) median maternal concentrations of PlGF (104 vs. 165 pg/ml) were significantly lower while sFlt-1 (6927 vs. 4371 pg/ml) and the sFlt-1/PlGF ratio (73.1 vs. 28.4) were significantly higher. In another study that evaluated 120 cases of early-onset FGR, 75% had an sFlt-1/PlGF ratio ≥85 with an associated probability of delivery within 1 week of diagnosis of 36%. In contrast, a ratio of <85 was associated with a >70% probability of prolongation of pregnancy for >4 weeks [84]. A more recent study of early-onset FGR demonstrated a negative predictive value (NPV) (using an sFlt-1/PlGF cutoff threshold of 38) of 100% (95% CI: 0.92–1.00) for delivery within 2 weeks of diagnosis and a NPV of 50% for delivery within 1 week if the ratio was >85 [85]. Gaccioli et al. [86] reported that using an EFW of <10th centile for gestation and sFlt-1/PlGF ratio of >5.78 at 28 weeks resulted in a PLR of 41.1 (95% CI: 23.0–73.6) and PPV of 21.3% (95% CI: 11.6–35.8) for preterm birth of an SGA infant. Using a higher threshold sFlt-1/PlGF ratio of >38 at 36 weeks resulted in a PLR of 17.5 (95% CI: 11.8–25.9) for subsequent birth of an SGA infant associated with either maternal pre-eclampsia or perinatal morbidity or mortality [86]. Other observational studies have also reported similar associations between a high sFlt-1/PlGF ratio with SGA/FGR and a shorter duration to delivery interval [87,88]. A recent systematic review and meta-analysis (33 studies; 9426 women) showed that while PlGF, sFlt-1, and the sFlt-1/PlGF ratio showed promise for the prediction of adverse maternal and perinatal outcomes including SGA/FGR and time to delivery, PlGF was equivalent to the sFlt-1/PlGF ratio for predictive utility [89].

In a prospective study of 3953 singleton pregnancies at 35–37 weeks of gestation, Valino et al. showed that prediction of SGA (detection rate: 62.8%) was best achieved by maternal serum PlGF, ultrasound EFW, and UtA-PI [90]. However, compared with maternal serum PlGF, sFlt-1 does not provide significant independent prediction of SGA [90,91]. Another study by Valino et al. that screened 8268 singleton pregnancies at an earlier gestation of 30–34 weeks demonstrated that prediction of SGA using EFW, PlGF, sFlt-1, UtA-PI, umbilical artery pulsatility index, and middle cerebral artery pulsatility index resulted in a detection rates of 88% and 51% for birth of a preterm and term SGA infant, respectively [92].

A recent systematic review and meta-analysis (eight studies; 5450 women) [93] evaluating the diagnostic capacity of the sFlt-1/PlGF ratio for FGR showed that a ratio of >33 was predictive for FGR, [Sensitivity 63% (95% CI: 54–71), specificity 84%, (95% CI: 83–85)] but had a low PLR of 3.55 (95% CI: 1.98–6.34). A higher ratio of ≥85 resulted in higher sensitivity 79% (95% CI: 66–89) but with similarly low PLR of 3.23 (95% CI: 0.94–11.11). Given the clear correlation of elevated sFlt-1 and sFlt-1/PlGF ratio with placental dysfunction and SGA/FGR infants both in early [94–96] and late gestation [86,97,98], there is increasing evidence supporting their use together with maternal characteristics and fetal biophysical ultrasound parameters in screening tests for SGA/FGR [22,24,99,100]. A high sFlt-1/PlGF ratio also appears to be predictive of adverse neonatal outcomes (admission to neonatal intensive care unit, severe respiratory disorders, and necrotizing enterocolitis) in SGA neonates [101,102]. There is some evidence however that fetal sex may also influence the sFlt-1/PlGF ratio. In a recent study, normotensive women with male fetuses had significantly higher sFlt-1 concentrations and sFlt-1/PlGF ratio compared with normotensive women with a female fetus. However, this difference was not observed in pregnant women with hypertensive disorders [103]. In another study, the sFlt-1/SPINT1 ratio was significantly raised in pregnancies with pre-eclampsia and/or SGA with median ratios (IQR) of 1.4 [0.44–2.54] and 0.82 [0.28–1.39] for BW <3rd and 3rd–10th centiles, respectively [70].

Another retrospective cohort study [104] reported that a low sFlt-1/PlGF ratio of <23 ruled out early-onset pre-eclampsia between 24- and 33+6-weeks’ gestation (NPV of 100%), while a ratio of >45 in combination with N-terminal-pro b-type natriuretic peptide (NT-proBNP) concentrations of >174 pg/ml increased the PPV from 49.5% to 86% (95% CI: 79.2–92.6). The median concentrations of NT-proBNP were significantly higher in women with pre-eclampsia (156.5 pg/ml, IQR: [78–343]) compared with those with isolated FGR (48 pg/ml, IQR: [24–59]) and normal pregnancy (47.5 pg/ml, IQR: [25–89]) [105].

In twin pregnancies, the sFlt-1/PlGF ratio measured in the second trimester is associated with increased odds for FGR (OR: 39.6, 95% CI: 6.31–248.17) [106]. However, as a standalone marker, PlGF does not appear to be sufficiently robust (sensitivity 27%) for the prediction of FGR for women with multiple pregnancy [107].

Soluble endoglin

Another placenta-derived antiangiogenic factor associated with placental dysfunction is soluble endoglin (sEng). sEng is a soluble transforming growth factor-β (TGF-β) coreceptor, which has been shown to be elevated in sera of women with pre-eclampsia and FGR [108–110]. An early small observational study (44 women) reported positive correlation between sEng and sFlt-1 concentrations (Pearson 0.653; P<0.05) with significantly higher sEng concentrations in FGR pregnancies compared with controls. However, concentrations of sEng were lower in FGR compared with pre-eclampsia pregnancies [111]. More recent study showed that sEng is strongly correlated with sFlt-1/PlGF ratio with higher concentrations observed in FGR (OR: 2.28, 95% Cl: 1.55–3.4 and 2.38, 95% CI: 1.64–3.44 for sEng and sFlt-1/PlGF, respectively) [112]. Another study, however, did not find any significant association between maternal concentrations of sEng and time of delivery in pregnancies complicated by FGR [113]. The current evidence for the utility of sEng for the prediction of SGA/FGR is limited.

Circulating cell-free fetal DNA (cffDNA) is used for aneuploidy screening, determination of fetal red cell antigen status, fetal sex, and screening for single-gene disorders [114–116]. cffDNA concentrations increase with gestational age and significantly higher levels are seen pregnancies complicated by placental dysfunction [117,121]. The data however from pregnancies complicated by FGR are conflicting, with some studies suggesting an increase [117–119] in cffDNA concentrations while others showing a decrease [120–122] compared with controls.

Lower median cffDNA fractions were observed only in women with early but not late FGR [121,122], suggesting that the lower fetal fraction could be the consequence of a smaller placental mass. However, other studies report that cffDNA concentrations are increased in pregnancies complicated by FGR with abnormal umbilical artery Doppler velocimetry raising the possibility that fetal DNA release is associated more with chronic fetal hypoxia than with fetal size [123]. Caramelli et al. [118] reported a more than twofold increase in cffDNA concentration in pregnancies complicated by FGR and abnormal uterine artery Doppler waveforms when compared with controls [117]. In another analysis, Smid et al. [119] showed that maternal plasma fetal DNA concentration in pregnancies complicated by FGR, median cffDNA concentrations were higher compared with controls (308.1 vs. 74.8 g.e./ml).

Poon et al. [124] measured plasma cffDNA from 1949 singleton pregnancies at 11–13 weeks of gestation and found that although concentrations were inversely related to maternal weight and UtA-PI, compared with controls, there was no difference with pregnancies complicated by SGA/FGR [124]. Other observational studies have also reported the lack of difference between cffDNA concentrations in FGR and control cohorts [125].

In a retrospective cohort study of 4317 singleton pregnancies [120], the fetal fraction was inversely correlated with MAP, UtA-PI, and positively associated with maternal PAPP-A and PlGF concentrations. A lower fetal fraction was associated with a higher risk of preterm FGR. Given the limited and inconsistent data regarding the relationship between maternal cffDNA concentrations and SGA/FGR, its utility as a reliable predictive marker remains unclear and further research is required [126–128].

MicroRNAs (miRNAs) are small nonprotein-coding, single-stranded RNA molecules of up to 19–25 nucleotides. They influence post-transcriptional gene expression and help regulate cell development, differentiation, proliferation, and apoptosis [129,130]. Because they are relatively stable and resistant to degradation by temperature and pH changes circulating miRNAs have potential as biomarkers for the prediction of adverse placenta-related outcomes [131].

The placenta expresses many generic as well as placenta-specific miRNAs, which influence angiogenesis as well as trophoblast differentiation, proliferation, invasion, and migration [132]. Placentally derived miRNAs are exported from syncytiotrophoblast cells into the maternal circulation via exosomes [133]. Table 2 [134–140] details currently known circulating miRNAs associated with FGR.

Table 2
Circulating miRNAs in FGR
miRNA typeExpression in FGR/SGAReferences
miR-210 Increased [140
miR-21 Increased [140
miR-424 Increased [140
miR-199a Increased [140
miR-20b Decreased [137
miR-942-5p Decreased [137
miR-324-3p Decreased [137
miR-127-3p Decreased [137
miR-223-5p Decreased [137
miR-17-5p Decreased [134
miR-146a-5p Decreased [134
miR-574-3p Decreased [134
miR-221-3p Decreased [134
miR-374a-5p Increased [136
Let-7d-5p Increased [136
miR-191-5p Increased [136
miR-107 Decreased [136
miR-30e-5p Decreased [136
miR-4454+7975 Decreased [136
miR-27b-3p Increased [138
miR-16-5p Increased [138
miR-103-3p Increased before 32 weeks of gestation
Decreased between 32 and 37 weeks of gestation 
[138
miR-107-3p Increased before 32 weeks of gestation
Decreased between 32 and 37 weeks of gestation 
[138
miR-346 Increased [139
miR-582-3p Increased [139
miR-16-5p Increased [135
miR-20a-5p Increased [135
miR-146a-5p Increased [135
miR-155-5p Increased [135
miR-181a-5p Increased [135
miR-195-5p Increased [135
miR-145-5p Increased [135
miR-342-3p Increased [135
miR-574-3p Increased [135
miR-1-3p Increased [135
miR-20b-5p Increased [135
miR-126-3p Increased [135
miR-130b-3p Increased [135
miR-499a-5p Increased [135
miRNA typeExpression in FGR/SGAReferences
miR-210 Increased [140
miR-21 Increased [140
miR-424 Increased [140
miR-199a Increased [140
miR-20b Decreased [137
miR-942-5p Decreased [137
miR-324-3p Decreased [137
miR-127-3p Decreased [137
miR-223-5p Decreased [137
miR-17-5p Decreased [134
miR-146a-5p Decreased [134
miR-574-3p Decreased [134
miR-221-3p Decreased [134
miR-374a-5p Increased [136
Let-7d-5p Increased [136
miR-191-5p Increased [136
miR-107 Decreased [136
miR-30e-5p Decreased [136
miR-4454+7975 Decreased [136
miR-27b-3p Increased [138
miR-16-5p Increased [138
miR-103-3p Increased before 32 weeks of gestation
Decreased between 32 and 37 weeks of gestation 
[138
miR-107-3p Increased before 32 weeks of gestation
Decreased between 32 and 37 weeks of gestation 
[138
miR-346 Increased [139
miR-582-3p Increased [139
miR-16-5p Increased [135
miR-20a-5p Increased [135
miR-146a-5p Increased [135
miR-155-5p Increased [135
miR-181a-5p Increased [135
miR-195-5p Increased [135
miR-145-5p Increased [135
miR-342-3p Increased [135
miR-574-3p Increased [135
miR-1-3p Increased [135
miR-20b-5p Increased [135
miR-126-3p Increased [135
miR-130b-3p Increased [135
miR-499a-5p Increased [135
Table 3
Essential miRNAs in pre-eclampsia with or without FGR
Pre-eclampsia with FGRPre-eclampsia without FGR
miR-210 miR-144 
miR-17 miR-152 
miR-16 miR-182 
miR-21 miR-29a 
miR-103 miR-29b 
miR-181a miR-24 
miR-130b-3p miR-26a 
miR-155 miR-299 
miR-181a miR-342-3p 
miR-20a miR-215 
miR-20b miR-650 
miR-126 miR-423-5p 
miR-519a miR-629-5p 
miR-141 miR-18a 
miR-194 miR-195 
miR-520a-5p miR-376c 
miR-525  
miR-146a-5p  
miR-221-3p  
miR-574-3p  
miR-346  
miR-582-3p  
miR-126  
Pre-eclampsia with FGRPre-eclampsia without FGR
miR-210 miR-144 
miR-17 miR-152 
miR-16 miR-182 
miR-21 miR-29a 
miR-103 miR-29b 
miR-181a miR-24 
miR-130b-3p miR-26a 
miR-155 miR-299 
miR-181a miR-342-3p 
miR-20a miR-215 
miR-20b miR-650 
miR-126 miR-423-5p 
miR-519a miR-629-5p 
miR-141 miR-18a 
miR-194 miR-195 
miR-520a-5p miR-376c 
miR-525  
miR-146a-5p  
miR-221-3p  
miR-574-3p  
miR-346  
miR-582-3p  
miR-126  

miR-210, a hypoxia-induced miRNA is expressed in different subtypes of placental trophoblasts and its deficiency is causally related to pre-eclampsia and placental adaptation to maternal hypoxia [141–143]. In pregnancies complicated by FGR, decreased expression of some placenta-specific miRNAs (miR-21, miR-16, miR-516b, miR-518b, miR-520h, miR-526b, miR-515-5p, miR-519d, and miR-1323) [144,145] have been reported. Table 3 lists the essential miRNAs in pre-eclampsia with or without FGR. miR-16 (OR: 4.13, 95% CI: 1.42–12.05) and miR-21 (OR: 2.43, 95% CI: 0.93–6.37), in particular, are strongly associated with birth of an SGA infant [144]. However, in another study, although four specific miRNAs (has – miR-518b, has – miR-1323, has – miR-520h, and has – miR-519d) were confirmed as FGR-associated, placenta-specific miRNAs, there was no difference in maternal plasma concentrations between FGR and uncomplicated pregnancies [145].

Whitehead et al. [140] found three- to sixfold increased concentrations of miR-210, miR-424, miR-21, miR-199a, and miR-20b in women with severe preterm FGR, which correlated with ultrasound Doppler velocimetry. On the other hand, higher circulating maternal serum concentrations of miR-20b-5p, miR-324-3p, miR-223-5p, and miR-127-3p in the second trimester were associated with lower odds of having an SGA infant [137]. Hromadnikova et al. [146] showed that in pregnancies complicated by FGR, significantly decreased concentrations of seven miRNAs were seen: miR-100-5p, miR-125b-5p, miR-199a-5p, miR-17-5p, miR-146a-5p, miR-221-3p, and miR-574-3p. Kim et al. [136] identified two unique miRNAs (hsa-miR374a-5p and hsa-let-7d-5p) that were expressed in significantly higher concentrations in plasma of women with SGA infants, indicating their potential for early prediction of SGA/FGR. Another recent study by Hromadnikova et al. [135] assessed the association of 29 cardiovascular disease-associated miRNAs in first trimester maternal blood samples and found that concentrations of six miRNAs were significantly increased in SGA/FGR pregnancies: miR-16-5p, miR-20a-5p, miR-146a-5p, miR-155-5p, miR-181a-5p, and miR-195-5p. A combination of four miRNAs (miR-1-3p, miR-20a-5p, miR-146a-5p, and miR-181a-5p) detected almost 76% of SGA infants, while a combination of seven miRNAs (miR-16-5p, miR-20a-5p, miR-145-5p, miR-146a-5p, miR-181a-5p, miR-342-3p, and miR-574-3p) detected approximately 43% of FGR infants [135].

Tagliaferri et al. [138] evaluated a group of hypoxia-regulated miRNAs and found elevated circulating concentrations of miR-16-5p, miR-103-3p, miR-107-3p, and miR-27b-3p in early FGR (<32 weeks of gestation), while reduced concentrations of miR-103-3p and miR-107-3p were noted in late FGR (measured between 32 and 37 weeks of gestation). Kim et al. [136] assessed 50 miRNAs profiles across gestation in SGA (defined as BW < 5th percentile) pregnancies and found significantly increased maternal plasma concentrations of miR-374a-5p, let-7d-5p, and miR-191-5p and decreased concentrations of miR-107, miR-30e-5p and miR-4454+7975. Of these miRNAs, miR-374a-5p and let-7d-5p showed reasonable predictive value for SGA when evaluated individually (AUROC: 0.71, 95% CI: 0.56–0.86 and 0.74, 95% CI: 0.55–0.93), respectively, with improvement when both were combined (AUROC 0.772, 95% CI: 0.601–0.943) [136]. Although there are some specific miRNAs that are associated with placental dysfunction, which may have a role to play for either the prediction or diagnosis of FGR, their utility thus far, as reliable clinical biomarkers is uncertain.

Early prenatal identification of infants at high risk of SGA/FGR or adverse perinatal outcomes such as stillbirth, neonatal morbidity, and mortality is important because it potentially allows decisions regarding intensity of antenatal surveillance, timing of birth, model of maternity care, parental counselling, and co-ordination of neonatal resources to be made. Thus, the attraction of a simple and acceptable screening test early in pregnancy is obvious. However, there are several circulating biomarkers that are clearly associated with adverse outcomes, none have yet, either alone or in combination, been shown to be sufficiently reliable to be used in clinical practice [147]. Some, such as PlGF [148] and sFlt-1 [149] show the most promise but require further validation to determine their screening performance. More importantly, however, it is important to determine if a policy of screening for disorders related to placental dysfunction results in improvements in clinical outcomes.

All data are included within the main article.

The authors declare that there are no competing interests associated with the manuscript.

Open access for the present article was enabled by the participation of University of Queensland in an all-inclusive Read & Publish agreement with Portland Press and the Biochemical Society under a transformative agreement with CAUL.

Jesrine Hong: Conceptualization, Data curation, Writing—original draft, Writing—review & editing. Sailesh Kumar: Conceptualization, Resources, Supervision, Writing—review & editing.

β-hCG

beta-human chorionic gonadotrophin

ADAM12

a disintegrin and metalloprotease 12

AFP

alpha-fetoprotein

AUROC

area under receiver-operating curve

BW

birthweight

cffDNA

cell-free fetal DNA

EFW

estimated fetal weight

FGF

fibroblast growth factor

FGR

fetal growth restriction

FPR

false-positive rate

IGF-I

insulin-like growth factor-I

IGFBP-1, -3, -4

IGF-binding protein-1, -3, -4

IQR

Interquartile range

LBW

low birth weight

MAP

maternal mean arterial pressure

MoM

multiples of median

N-CAM

neural cell adhesion molecule

NLR

negative likelihood ratio

NPV

negative predictive value

NT-proBNP

N-terminal-pro b-type natriuretic peptide

OR

odds ratio

PAPP-A

pregnancy-associated plasma protein-A

PGH

placental growth hormone

PIGF

placental growth factor

PLR

positive likelihood ratio

PP13

placental protein 13

PPV

positive predictive value

RR

relative risk

sEng

soluble endoglin

sFlt-1

soluble fms-like tyrosine kinase 1

SGA

small for gestational age

SPINT1

serine protease inhibitor Kunitz type 1

TGF-β

transforming growth factor-beta

UtA-PI

uterine artery pulsatility index

VEGF

vascular endothelial growth factor

1.
World Health Organization
(
1995
)
WHO Expert Committee on Physical Status: the Use and Interpretation of Anthropometry (1993: Geneva, Switzerland) & World Health Organization. Report
,
WHO
,
https://apps.who.int/iris/handle/10665/37003
2.
Group WHOMGRS
(
2006
)
WHO Child Growth Standards based on length/height, weight and age
.
Acta Paediatr. Suppl.
450
,
76
85
[PubMed]
3.
de Onis
M.
,
Onyango
A.
,
Borghi
E.
,
Siyam
A.
,
Blössner
M.
and
Lutter
C.
et al.
(
2012
)
Worldwide implementation of the WHO Child Growth Standards
.
Public Health Nutr.
15
,
1603
1610
[PubMed]
4.
UNICEF
(
2019
)
UNICEF-WHO low birthweight estimates: levels and trends 2000-2015
.
5.
Katz
J.
,
Lee
A.C.
,
Kozuki
N.
,
Lawn
J.E.
,
Cousens
S.
and
Blencowe
H.
et al.
(
2013
)
Mortality risk in preterm and small-for-gestational-age infants in low-income and middle-income countries: a pooled country analysis
.
Lancet
382
,
417
425
[PubMed]
6.
de Mendonca
E.
,
de Lima Macena
M.
,
Bueno
N.B.
,
de Oliveira
A.C.M.
and
Mello
C.S.
(
2020
)
Premature birth, low birth weight, small for gestational age and chronic non-communicable diseases in adult life: a systematic review with meta-analysis
.
Early Hum. Dev.
149
,
105154
[PubMed]
7.
Hocquette
A.
,
Durox
M.
,
Wood
R.
,
Klungsøyr
K.
,
Szamotulska
K.
and
Berrut
S.
(
2021
)
International versus national growth charts for identifying small and large-for-gestational age newborns: a population-based study in 15 European countries
.
Lancet Reg. Health Eur.
8
,
100167
[PubMed]
8.
Hughes
M.M.
,
Black
R.E.
and
Katz
J.
(
2017
)
2500-g low birth weight cutoff: history and implications for future research and policy
.
Matern. Child Health J.
21
,
283
289
[PubMed]
9.
Ventolini
G.
and
Neiger
R.
(
2006
)
Placental dysfunction: pathophysiology and clinical considerations
.
J. Obstet. Gynaecol.
26
,
728
730
[PubMed]
10.
Regnault
T.R.
,
Galan
H.L.
,
Parker
T.A.
and
Anthony
R.V.
(
2002
)
Placental development in normal and compromised pregnancies– a review
.
Placenta
23
,
S119
S129
[PubMed]
11.
Brosens
I.
,
Pijnenborg
R.
,
Vercruysse
L.
and
Romero
R.
(
2011
)
The “Great Obstetrical Syndromes” are associated with disorders of deep placentation
.
Am. J. Obstet. Gynecol.
204
,
193
201
[PubMed]
12.
Aplin
J.D.
,
Myers
J.E.
,
Timms
K.
and
Westwood
M.
(
2020
)
Tracking placental development in health and disease
.
Nat. Rev. Endocrinol.
16
,
479
494
[PubMed]
13.
Gibbs
I.
,
Leavey
K.
,
Benton
S.J.
,
Grynspan
D.
,
Bainbridge
S.A.
and
Cox
B.J.
(
2019
)
Placental transcriptional and histologic subtypes of normotensive fetal growth restriction are comparable to preeclampsia
.
Am. J. Obstet. Gynecol.
220
,
110e111
110e121
14.
Kingdom
J.C.
and
Kaufmann
P.
(
1997
)
Oxygen and placental villous development: origins of fetal hypoxia
.
Placenta
18
,
613
621
,
discussion 623-616
[PubMed]
15.
Gude
N.M.
,
Roberts
C.T.
,
Kalionis
B.
and
King
R.G.
(
2004
)
Growth and function of the normal human placenta
.
Thromb. Res.
114
,
397
407
[PubMed]
16.
Burton
G.J.
and
Jauniaux
E.
(
2018
)
Pathophysiology of placental-derived fetal growth restriction
.
Am. J. Obstet. Gynecol.
218
,
S745
S761
[PubMed]
17.
Bendix
I.
,
Miller
S.L.
and
Winterhager
E.
(
2020
)
Editorial: Causes and consequences of intrauterine growth restriction
.
Front. Endocrinol. (Lausanne)
11
,
205
[PubMed]
18.
Maynard
S.E.
,
Min
J.Y.
,
Merchan
J.
,
Lim
K.
,
J.
Li
and
Mondal
S.
et al.
(
2003
)
Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia
.
J. Clin. Invest.
111
,
649
658
[PubMed]
19.
Dugoff
L.
,
Hobbins
J.C.
,
Malone
F.D.
,
Porter
T.F.
,
Luthy
D.
and
Comstock
C.H.
et al.
(
2004
)
First-trimester maternal serum PAPP-A and free-beta subunit human chorionic gonadotropin concentrations and nuchal translucency are associated with obstetric complications: a population-based screening study (the FASTER Trial)
.
Am. J. Obstet. Gynecol.
191
,
1446
1451
[PubMed]
20.
Gaccioli
F.
,
Aye
I.
,
Sovio
U.
,
Charnock-Jones
D.S.
and
Smith
G.C.S.
(
2018
)
Screening for fetal growth restriction using fetal biometry combined with maternal biomarkers
.
Am. J. Obstet. Gynecol.
218
,
S725
S737
[PubMed]
21.
Sibley
C.P.
(
2017
)
Treating the dysfunctional placenta
.
J. Endocrinol.
234
,
R81
R97
[PubMed]
22.
Heazell
A.E.
,
Hayes
D.J.
,
Whitworth
M.
,
Takwoingi
Y.
,
Bayliss
S.E.
and
Davenport
C.
(
2019
)
Biochemical tests of placental function versus ultrasound assessment of fetal size for stillbirth and small-for-gestational-age infants
.
Cochrane Database Syst. Rev.
5
,
CD012245
[PubMed]
23.
de Bernis
L.
,
Kinney
M.V.
,
Stones
W.
,
Hoope-Bender
P.T.
,
Vivio
D.
and
Leisher
S.H.
et al.
(
2016
)
Stillbirths: ending preventable deaths by 2030
.
Lancet North Am. Ed.
387
,
703
716
24.
Ruchob
R.
,
Rutherford
J.N.
and
Bell
A.F.
(
2018
)
A systematic review of placental biomarkers predicting small-for-gestational-age neonates
.
Biol. Res. Nurs.
20
,
272
283
[PubMed]
25.
Weinhold
B.
(
2006
)
Epigenetics: the science of change
.
Environ. Health Perspect.
114
,
A160
A167
[PubMed]
26.
Henikoff
S.
and
Greally
J.M.
(
2016
)
Epigenetics, cellular memory and gene regulation
.
Curr. Biol.
26
,
R644
R648
[PubMed]
27.
Apicella
C.
,
Ruano
C.S.M.
,
Mehats
C.
,
Miralles
F.
and
Vaiman
D.
(
2019
)
The role of epigenetics in placental development and the etiology of preeclampsia
.
Int. J. Mol. Sci.
20
,
2837
28.
Nelissen
E.C.
,
van Montfoort
A.P.
,
Dumoulin
J.C.
and
Evers
J.L.
(
2011
)
Epigenetics and the placenta
.
Hum. Reprod. Update
17
,
397
417
[PubMed]
29.
Poon
L.C.
,
Chelemen
T.
,
Granvillano
O.
,
Pandeva
I.
and
Nicolaides
K.H.
(
2008
)
First-trimester maternal serum a disintegrin and metalloprotease 12 (ADAM12) and adverse pregnancy outcome
.
Obstet. Gynecol.
112
,
1082
1090
[PubMed]
30.
Poon
L.C.
,
Karagiannis
G.
,
Staboulidou
I.
,
Shafiei
A.
and
Nicolaides
K.H.
(
2011
)
Reference range of birth weight with gestation and first-trimester prediction of small-for-gestation neonates
.
Prenat. Diagn.
31
,
58
65
[PubMed]
31.
Cowans
N.J.
and
Spencer
K.
(
2007
)
First-trimester ADAM12 and PAPP-A as markers for intrauterine fetal growth restriction through their roles in the insulin-like growth factor system
.
Prenat. Diagn.
27
,
264
271
[PubMed]
32.
Pihl
K.
,
Larsen
T.
,
Krebs
L.
and
Christiansen
M.
(
2008
)
First trimester maternal serum PAPP-A, beta-hCG and ADAM12 in prediction of small-for-gestational-age fetuses
.
Prenat. Diagn.
28
,
1131
1135
[PubMed]
33.
Stamatopoulou
A.
,
Cowans
N.J.
,
Matwejew
E.
,
von Kaisenberg
C.
and
Spencer
K.
(
2011
)
Placental protein-13 and pregnancy-associated plasma protein-A as first trimester screening markers for hypertensive disorders and small for gestational age outcomes
.
Hypertens. Pregnancy
30
,
384
395
[PubMed]
34.
Lesmes
C.
,
Gallo
D.M.
,
Gonzalez
R.
,
Poon
L.C.
and
Nicolaides
K.H.
(
2015
)
Prediction of small-for-gestational-age neonates: screening by maternal serum biochemical markers at 19-24 weeks
.
Ultrasound Obstet. Gynecol.
46
,
341
349
[PubMed]
35.
Andres
F.
,
Wong
G.P.
,
Walker
S.P.
,
MacDonald
T.M.
,
Keenan
E.
and
Cannon
P.
et al.
(
2022
)
A disintegrin and metalloproteinase 12 (ADAM12) is reduced at 36 weeks' gestation in pregnancies destined to deliver small for gestational age infants
.
Placenta
117
,
1
4
[PubMed]
36.
Morris
R.K.
,
Bilagi
A.
,
Devani
P.
and
Kilby
M.D.
(
2017
)
Association of serum PAPP-A levels in first trimester with small for gestational age and adverse pregnancy outcomes: systematic review and meta-analysis
.
Prenat. Diagn.
37
,
253
265
[PubMed]
37.
Karagiannis
G.
,
Akolekar
R.
,
Sarquis
R.
,
Wright
D.
and
Nicolaides
K.H.
(
2011
)
Prediction of small-for-gestation neonates from biophysical and biochemical markers at 11-13 weeks
.
Fetal Diagn. Ther.
29
,
148
154
[PubMed]
38.
Gadde
R.
,
Cd
D.
and
Sheela
S.R.
(
2018
)
Placental protein 13: an important biological protein in preeclampsia
.
J Circ Biomark
7
,
1849454418786159
[PubMed]
39.
Burger
O.
,
Pick
E.
,
Zwickel
J.
,
Klayman
M.
,
Meiri
H.
and
Slotky
R.
et al.
(
2004
)
Placental protein 13 (PP-13): effects on cultured trophoblasts, and its detection in human body fluids in normal and pathological pregnancies
.
Placenta
25
,
608
622
[PubMed]
40.
Deurloo
K.L.
,
Linskens
I.H.
,
Heymans
M.W.
,
Heijboer
A.C.
,
Blankenstein
M.A.
and
van Vugt
J.M.
(
2013
)
ADAM12s and PP13 as first trimester screening markers for adverse pregnancy outcome
.
Clin. Chem. Lab. Med.
51
,
1279
1284
[PubMed]
41.
Cowans
N.J.
,
Spencer
K.
and
Meiri
H.
(
2008
)
First-trimester maternal placental protein 13 levels in pregnancies resulting in adverse outcomes
.
Prenat. Diagn.
28
,
121
125
[PubMed]
42.
Seravalli
V.
,
Grimpel
Y.I.
,
Meiri
H.
,
Blitzer
M.
and
Baschat
A.A.
(
2016
)
Relationship between first-trimester serum placental protein-13 and maternal characteristics, placental Doppler studies and pregnancy outcome
.
J. Perinat. Med.
44
,
543
549
[PubMed]
43.
Chafetz
I.
,
Kuhnreich
I.
,
Sammar
M.
,
Tal
Y.
,
Gibor
Y.
and
Meiri
H.
et al.
(
2007
)
First-trimester placental protein 13 screening for preeclampsia and intrauterine growth restriction
.
Am. J. Obstet. Gynecol.
197
,
35e31
35e37
44.
Schneuer
F.J.
,
Nassar
N.
,
Khambalia
A.Z.
,
Tasevski
V.
,
Guilbert
C.
and
Ashton
A.W.
et al.
(
2012
)
First trimester screening of maternal placental protein 13 for predicting preeclampsia and small for gestational age: in-house study and systematic review
.
Placenta
33
,
735
740
[PubMed]
45.
Zhong
Y.
,
Zhu
F.
and
Ding
Y.
(
2015
)
Serum screening in first trimester to predict pre-eclampsia, small for gestational age and preterm delivery: systematic review and meta-analysis
.
BMC Pregnancy Childbirth
15
,
191
[PubMed]
46.
Poon
L.C.
,
Lesmes
C.
,
Gallo
D.M.
,
Akolekar
R.
and
Nicolaides
K.H.
(
2015
)
Prediction of small-for-gestational-age neonates: screening by biophysical and biochemical markers at 19-24 weeks
.
Ultrasound Obstet. Gynecol.
46
,
437
445
[PubMed]
47.
Hu
J.
,
Zhang
J.
,
He
G.
,
Zhu
S.
,
Tang
X.
and
Su
J.
et al.
(
2020
)
First-trimester maternal serum alpha-fetoprotein is not a good predictor for adverse pregnancy outcomes: a retrospective study of 3325 cases
.
BMC Pregnancy Childbirth
20
,
104
[PubMed]
48.
Bakalis
S.
,
Peeva
G.
,
Gonzalez
R.
,
Poon
L.C.
and
Nicolaides
K.H.
(
2015
)
Prediction of small-for-gestational-age neonates: screening by biophysical and biochemical markers at 30-34 weeks
.
Ultrasound Obstet. Gynecol.
46
,
446
451
[PubMed]
49.
Goto
E.
(
2021
)
Association of high maternal blood alpha-fetoprotein level with risk of delivering small for gestational age: a meta-analysis
.
Pediatr. Res.
89
,
1742
1750
[PubMed]
50.
Bobrow
C.S.
,
Holmes
R.P.
,
Muttukrishna
S.
,
Mohan
A.
,
Groome
N.
and
Murphy
D.J.
et al.
(
2002
)
Maternal serum activin A, inhibin A, and follistatin in pregnancies with appropriately grown and small-for-gestational-age fetuses classified by umbilical artery Doppler ultrasound
.
Am. J. Obstet. Gynecol.
186
,
283
287
[PubMed]
51.
Keelan
J.A.
,
Taylor
R.
,
Schellenberg
J.C.
,
Groome
N.P.
,
Mitchell
M.D.
and
North
R.A.
(
2002
)
Serum activin A, inhibin A, and follistatin concentrations in preeclampsia or small for gestational age pregnancies
.
Obstet. Gynecol.
99
,
267
274
[PubMed]
52.
Miranda
J.
,
Rodriguez-Lopez
M.
,
Triunfo
S.
,
Sairanen
M.
,
Kouru
H.
and
Parra-Saavedra
M.
et al.
(
2017
)
Prediction of fetal growth restriction using estimated fetal weight vs a combined screening model in the third trimester
.
Ultrasound Obstet. Gynecol.
50
,
603
611
[PubMed]
53.
Kim
S.M.
,
Yun
H.G.
,
Kim
R.Y.
,
Chung
Y.H.
,
Cheon
J.Y.
and
Wie
J.H.
et al.
(
2017
)
Maternal serum placental growth factor combined with second trimester aneuploidy screening to predict small-for-gestation neonates without preeclampsia
.
Taiwan J. Obstet. Gynecol.
56
,
801
805
[PubMed]
54.
Fuglsang
J.
and
Ovesen
P.
(
2006
)
Aspects of placental growth hormone physiology
.
Growth Horm. IGF Res.
16
,
67
85
[PubMed]
55.
Mirlesse
V.
,
Frankenne
F.
,
Alsat
E.
,
Poncelet
M.
,
Hennen
G.
and
Evain-Brion
D.
(
1993
)
Placental growth hormone levels in normal pregnancy and in pregnancies with intrauterine growth retardation
.
Pediatr. Res.
34
,
439
442
[PubMed]
56.
McIntyre
H.D.
,
Serek
R.
,
Crane
D.I.
,
Veveris-Lowe
T.
,
Parry
A.
and
Johnson
S.
et al.
(
2000
)
Placental growth hormone (GH), GH-binding protein, and insulin-like growth factor axis in normal, growth-retarded, and diabetic pregnancies: correlations with fetal growth
.
J. Clin. Endocrinol. Metab.
85
,
1143
1150
[PubMed]
57.
Sifakis
S.
,
Akolekar
R.
,
Kappou
D.
,
Mantas
N.
and
Nicolaides
K.H.
(
2012
)
Maternal serum placental growth hormone at 11-13 weeks' gestation in pregnancies delivering small for gestational age neonates
.
J. Matern. Fetal Neonatal Med.
25
,
1796
1799
[PubMed]
58.
Sifakis
S.
,
Akolekar
R.
,
Kappou
D.
,
Mantas
N.
and
Nicolaides
K.H.
(
2012
)
Maternal serum insulin-like growth factor (IGF-I) and binding proteins IGFBP-1 and IGFBP-3 at 11-13 weeks' gestation in pregnancies delivering small for gestational age neonates
.
Eur. J. Obstet. Gynecol. Reprod. Biol.
161
,
30
33
[PubMed]
59.
Holmes
R.P.
,
Holly
J.M.
and
Soothill
P.W.
(
2000
)
Maternal insulin-like growth factor binding protein-1, body mass index, and fetal growth
.
Arch. Dis. Child. Fetal Neonatal Ed.
82
,
F113
F117
[PubMed]
60.
Qiu
Q.
,
Bell
M.
,
Lu
X.
,
Yan
X.
,
Rodger
M.
and
Walker
M.
et al.
(
2012
)
Significance of IGFBP-4 in the development of fetal growth restriction
.
J. Clin. Endocrinol. Metab.
97
,
E1429
E1439
[PubMed]
61.
Ozkan
S.
,
Vural
B.
,
Dalcik
C.
,
Tas
A.
and
Dalcik
H.
(
2008
)
Placental expression of insulin-like growth factor-I, fibroblast growth factor-basic and neural cell adhesion molecule in pregnancies with small for gestational age fetuses
.
J. Perinatol.
28
,
468
474
[PubMed]
62.
Vrachnis
N.
,
Argyridis
S.
,
Vrachnis
D.
,
Antonakopoulos
N.
,
Valsamakis
G.
and
Iavazzo
C.
et al.
(
2021
)
Increased fibroblast growth factor 21 (FGF21) concentration in early second trimester amniotic fluid and its association with fetal growth
.
Metabolites
11
,
581
[PubMed]
63.
Hill
D.J.
,
Tevaarwerk
G.J.
,
Arany
E.
,
Kilkenny
D.
,
Gregory
M.
and
Langford
K.S.
et al.
(
1995
)
Fibroblast growth factor-2 (FGF-2) is present in maternal and cord serum, and in the mother is associated with a binding protein immunologically related to the FGF receptor-1
.
J. Clin. Endocrinol. Metab.
80
,
1822
1831
[PubMed]
64.
Morris
R.K.
,
Cnossen
J.S.
,
Langejans
M.
,
Robson
S.C.
,
Kleijnen
J.
and
Riet
G.T.
et al.
(
2008
)
Serum screening with Down's syndrome markers to predict pre-eclampsia and small for gestational age: systematic review and meta-analysis
.
BMC Pregnancy Childbirth
8
,
33
[PubMed]
65.
Hui
D.
,
Okun
N.
,
Murphy
K.
,
Kingdom
J.
,
Uleryk
E.
and
Shah
P.S.
(
2012
)
Combinations of maternal serum markers to predict preeclampsia, small for gestational age, and stillbirth: a systematic review
.
J. Obstet. Gynaecol. Can.
34
,
142
153
[PubMed]
66.
Goto
E.
(
2017
)
Maternal blood biomarkers of placentation to predict low-birth-weight newborns: a meta-analysis
.
J. Obstet. Gynaecol. Can.
39
,
635
644
[PubMed]
67.
Murphy
C.N.
,
Walker
S.P.
,
MacDonald
T.M.
,
Keenan
E.
,
Hannan
N.J.
and
Wlodek
M.E.
et al.
(
2021
)
Elevated circulating and placental SPINT2 is associated with placental dysfunction
.
Int. J. Mol. Sci.
22
,
7467
68.
Kaitu'u-Lino
T.J.
,
MacDonald
T.M.
,
Cannon
P.
,
Nguyen
T.V.
,
Hiscock
R.J.
and
Haan
N.
et al.
(
2020
)
Circulating SPINT1 is a biomarker of pregnancies with poor placental function and fetal growth restriction
.
Nat. Commun.
11
,
2411
[PubMed]
69.
Tong
S.
,
Walker
S.P.
,
Keenan
E.
,
MacDonald
T.M.
,
Taylor
R.
and
McCowan
L.M.E.
et al.
(
2022
)
Circulating serine peptidase inhibitor Kunitz type 1 (SPINT1) in the second trimester is reduced among pregnancies that end in low birthweight neonates: cohort study of 2006 pregnancies
.
Am. J. Obstet. Gynecol. MFM
4
,
100618
[PubMed]
70.
Murphy
C.N.
,
Cluver
C.A.
,
Walker
S.P., Keenan, E., Hastie, R., MacDonald, T.M.
et al.
(
2022
)
Circulating SPINT1 is reduced in a preeclamptic cohort with co-existing fetal growth restriction
.
J. Clin. Med.
11
,
901
71.
Pereira
R.D.
,
De Long
N.E.
,
Wang
R.C.
,
Yazdi
F.T.
,
Holloway
A.C.
and
Raha
S.
(
2015
)
Angiogenesis in the placenta: the role of reactive oxygen species signaling
.
Biomed. Res. Int.
2015
,
814543
[PubMed]
72.
Rana
S.
,
Burke
S.D.
and
Karumanchi
S.A.
(
2022
)
Imbalances in circulating angiogenic factors in the pathophysiology of preeclampsia and related disorders
.
Am. J. Obstet. Gynecol.
226
,
S1019
S1034
[PubMed]
73.
Bushway
M.E.
,
Gerber
S.A.
,
Fenton
B.M.
,
Miller
R.K.
,
Lord
E.M.
and
Murphy
S.P.
(
2014
)
Morphological and phenotypic analyses of the human placenta using whole mount immunofluorescence
.
Biol. Reprod.
90
,
110
[PubMed]
74.
Magee
L.A.
,
Brown
M.A.
,
Hall
D.R.
,
Gupte
S.
,
Hennessy
A.
and
Karumanchi
S.A.
et al.
(
2022
)
The 2021 International Society for the study of hypertension in pregnancy classification, diagnosis & management recommendations for international practice
.
Pregnancy Hypertens.
27
,
148
169
[PubMed]
75.
Gaccioli
F.
,
Sovio
U.
,
Gong
S.
,
Cook
E.
,
Charnock-Jones
D.S.
and
Smith
G.C.S.
(
2022
)
Increased placental sFLT1 (soluble fms-like tyrosine kinase receptor-1) drives the antiangiogenic profile of maternal serum preceding preeclampsia but not fetal growth restriction
.
Hypertension
,
80
,
325
334
[PubMed]
76.
Benton
S.J.
,
McCowan
L.M.
,
Heazell
A.E.
,
Grynspan
D.
,
Hutcheon
J.A.
and
Senger
C.
et al.
(
2016
)
Placental growth factor as a marker of fetal growth restriction caused by placental dysfunction
.
Placenta
42
,
1
8
[PubMed]
77.
Spiel
M.
,
Salahuddin
S.
,
Pernicone
E.
,
Zsengeller
Z.
,
Wang
A.
and
Modest
A.M.
et al.
(
2017
)
Placental soluble fms-like tyrosine kinase expression in small for gestational age infants and risk for adverse outcomes
.
Placenta
52
,
10
16
[PubMed]
78.
Kwiatkowski
S.
,
Bednarek-Jedrzejek
M.
,
Ksel
J.,
Tousty
P.
,
Kwiatkowska
E.
and
Cymbaluk
A.
et al.
(
2018
)
sFlt-1/PlGF and Doppler ultrasound parameters in SGA pregnancies with confirmed neonatal birth weight below 10th percentile
.
Pregnancy Hypertens
14
,
79
85
[PubMed]
79.
Baekgaard Thorsen
L.H.
,
Bjorkholt Andersen
L.
,
Birukov
A.
,
Lykkedegn
S.
,
Dechend
R.
,
Stener Jørgensen
J.
et al.
(
2020
)
Prediction of birth weight small for gestational age with and without preeclampsia by angiogenic markers: an Odense Child Cohort study
.
J. Matern. Fetal Neonatal Med.
33
,
1377
1384
[PubMed]
80.
Garcia-Manau
P.
,
Mendoza
M.
,
Bonacina
E.
,
Garrido-Gimenez
C.
,
Fernandez-Oliva
A.
and
Zanini
J.
et al.
(
2021
)
Soluble fms-like tyrosine kinase to placental growth factor ratio in different stages of early-onset fetal growth restriction and small for gestational age
.
Acta Obstet. Gynecol. Scand.
100
,
119
128
[PubMed]
81.
Kwiatkowski
S.
,
Bednarek-Jedrzejek
M.
,
Kwiatkowska
E.
,
Cymbaluk-Ploska
A.
and
Torbe
A.
(
2021
)
Diagnosis of placental insufficiency independently of clinical presentations using sFlt-1/PLGF ratio, including SGA patients
.
Pregnancy Hypertens
25
,
244
248
[PubMed]
82.
Andrikos
A.
,
Andrikos
D.
,
Schmidt
B.
,
Birdir
C.
,
Kimmig
R.
and
Gellhaus
A.
et al.
(
2022
)
Course of the sFlt-1/PlGF ratio in fetal growth restriction and correlation with biometric measurements, feto-maternal Doppler parameters and time to delivery
.
Arch. Gynecol. Obstet.
305
,
597
605
[PubMed]
83.
Mitlid-Mork
B.
,
Bowe
S.
,
Staff
A.C.
and
Sugulle
M.
(
2022
)
Alterations in maternal sFlt-1 and PlGF: Time to labor onset in term-/late-term pregnancies with and without placental dysfunction
.
Pregnancy Hypertens
30
,
148
153
[PubMed]
84.
Quezada
M.S.
,
Rodriguez-Calvo
J.
,
Villalain
C.
,
Gomez-Arriaga
P.I.
,
Galindo
A.
and
Herraiz
I.
(
2020
)
sFlt-1/PlGF ratio and timing of delivery in early-onset fetal growth restriction with antegrade umbilical artery flow
.
Ultrasound Obstet. Gynecol.
56
,
549
556
[PubMed]
85.
Bonacina
E.
,
Mendoza
M.
,
Farras
A.
,
Garcia-Manau
P.
,
Serrano
B.
and
Hurtado
I.
et al.
(
2022
)
Angiogenic factors for planning fetal surveillance in fetal growth restriction and small-for-gestational-age fetuses: a prospective observational study
.
BJOG
129
,
1870
1877
[PubMed]
86.
Gaccioli
F.
,
Sovio
U.
,
Cook
E.
,
Hund
M.
,
Charnock-Jones
D.S.
and
Smith
G.C.S.
(
2018
)
Screening for fetal growth restriction using ultrasound and the sFLT1/PlGF ratio in nulliparous women: a prospective cohort study
.
Lancet Child Adolesc. Health
2
,
569
581
[PubMed]
87.
Shinohara
S.
,
Uchida
Y.
,
Kasai
M.
and
Sunami
R.
(
2017
)
Association between the high soluble fms-like tyrosine kinase-1 to placental growth factor ratio and adverse outcomes in asymptomatic women with early-onset fetal growth restriction
.
Hypertens. Pregnancy
36
,
269
275
[PubMed]
88.
Bonacina
E.
,
Armengol-Alsina
M.
,
Hurtado
I.
,
Garcia-Manau
P.
,
Ferrer-Oliveras
R.
and
Monreal
S.
et al.
(
2022
)
sFlt-1 to PlGF ratio cut-offs to predict adverse pregnancy outcomes in early-onset FGR and SGA: a prospective observational study
.
J. Obstet. Gynaecol.
,
42
,
2840
2845
89.
Lim
S.
,
Li
W.
,
Kemper
J.
,
Nguyen
A.
,
Mol
B.W.
and
Reddy
M.
(
2021
)
Biomarkers and the prediction of adverse outcomes in preeclampsia: a systematic review and meta-analysis
.
Obstet. Gynecol.
137
,
72
81
[PubMed]
90.
Valino
N.
,
Giunta
G.
,
Gallo
D.M.
,
Akolekar
R.
and
Nicolaides
K.H.
(
2016
)
Biophysical and biochemical markers at 35-37 weeks' gestation in the prediction of adverse perinatal outcome
.
Ultrasound Obstet. Gynecol.
47
,
203
209
[PubMed]
91.
Fadigas
C.
,
Peeva
G.
,
Mendez
O.
,
Poon
L.C.
and
Nicolaides
K.H.
(
2015
)
Prediction of small-for-gestational-age neonates: screening by placental growth factor and soluble fms-like tyrosine kinase-1 at 35-37 weeks
.
Ultrasound Obstet. Gynecol.
46
,
191
197
[PubMed]
92.
Valino
N.
,
Giunta
G.
,
Gallo
D.M.
,
Akolekar
R.
and
Nicolaides
K.H.
(
2016
)
Biophysical and biochemical markers at 30-34 weeks' gestation in the prediction of adverse perinatal outcome
.
Ultrasound Obstet. Gynecol.
47
,
194
202
[PubMed]
93.
Chen
W.
,
Wei
Q.
,
Liang
Q.
,
Song
S.
and
Li
J.
(
2022
)
Diagnostic capacity of sFlt-1/PlGF ratio in fetal growth restriction: a systematic review and meta-analysis
.
Placenta
127
,
37
42
[PubMed]
94.
Birdir
C.
,
Fryze
J.
,
Frolich
S.
,
Schmidt
M.
,
Köninger
A.
and
Kimmig
R.
et al.
(
2017
)
Impact of maternal serum levels of Visfatin, AFP, PAPP-A, sFlt-1 and PlGF at 11-13 weeks gestation on small for gestational age births
.
J. Matern. Fetal Neonatal Med.
30
,
629
634
[PubMed]
95.
Triunfo
S.
,
Crovetto
F.
,
Rodriguez-Sureda
V.
,
Scazzocchio
E.
,
Crispi
F.
and
Dominguez
C.
et al.
(
2017
)
Changes in uterine artery Doppler velocimetry and circulating angiogenic factors in the first half of pregnancies delivering a small-for-gestational-age neonate
.
Ultrasound Obstet. Gynecol.
49
,
357
363
[PubMed]
96.
Crovetto
F.
,
Triunfo
S.
,
Crispi
F.
,
Rodriguez-Sureda
V.
,
Dominguez
C.
and
Figueras
F.
et al.
(
2017
)
Differential performance of first-trimester screening in predicting small-for-gestational-age neonate or fetal growth restriction
.
Ultrasound Obstet. Gynecol.
49
,
349
356
[PubMed]
97.
Birdir
C.
,
Droste
L.
,
Fox
L.
,
Frank
M.
,
Fryze
J.
and
Enekwe
A.
et al.
(
2018
)
Predictive value of sFlt-1, PlGF, sFlt-1/PlGF ratio and PAPP-A for late-onset preeclampsia and IUGR between 32 and 37weeks of pregnancy
.
Pregnancy Hypertens
12
,
124
128
[PubMed]
98.
Herraiz
I.
,
Droge
L.A.
,
Gomez-Montes
E.
,
Henrich
W.
,
Galindo
A.
and
Verlohren
S.
(
2014
)
Characterization of the soluble fms-like tyrosine kinase-1 to placental growth factor ratio in pregnancies complicated by fetal growth restriction
.
Obstet. Gynecol.
124
,
265
273
[PubMed]
99.
Conde-Agudelo
A.
,
Papageorghiou
A.T.
,
Kennedy
S.H.
and
Villar
J.
(
2013
)
Novel biomarkers for predicting intrauterine growth restriction: a systematic review and meta-analysis
.
BJOG
120
,
681
694
[PubMed]
100.
Sherrell
H.
,
Dunn
L.
,
Clifton
V.
and
Kumar
S.
(
2018
)
Systematic review of maternal Placental Growth Factor levels in late pregnancy as a predictor of adverse intrapartum and perinatal outcomes
.
Eur. J. Obstet. Gynecol. Reprod. Biol.
225
,
26
34
[PubMed]
101.
Witwicki
J.
,
Chaberek
K.
,
Szymecka-Samaha
N.
,
Krysiak
A.
,
Pietruski
P.
and
Kosinska-Kaczynska
K.
(
2021
)
sFlt-1/PlGF ratio in prediction of short-term neonatal outcome of small for gestational age neonates
.
Children (Basel)
8
,
718
[PubMed]
102.
Shim
S.H.
,
Jeon
H.J.
,
Ryu
H.J.
,
Kim
S.H.
,
Min
S.G.
and
Kang
M.K.
et al.
(
2021
)
Prenatal serum sFlt-1/PlGF ratio predicts the adverse neonatal outcomes among small-for-gestational-age fetuses in normotensive pregnant women: A prospective cohort study
.
Medicine (Baltimore).
100
,
e24681
[PubMed]
103.
Arenas
G.A.
,
Docheva
N.
,
Lopes Perdigao
J.
,
Mueller
A.
,
Dada
T.
and
Rana
S.
(
2022
)
Association of fetal sex with angiogenic factors in normotensive and hypertensive pregnancy states
.
Pregnancy Hypertens
29
,
108
115
[PubMed]
104.
Lafuente-Ganuza
P.
,
Lequerica-Fernandez
P.
,
Carretero
F.
,
Escudero
A.I.
,
Martinez-Morillo
E.
and
Sabria
E.
et al.
(
2020
)
A more accurate prediction to rule in and rule out pre-eclampsia using the sFlt-1/PlGF ratio and NT-proBNP as biomarkers
.
Clin. Chem. Lab. Med.
58
,
399
407
[PubMed]
105.
Sabria
E.
,
Lequerica-Fernandez
P.
,
Lafuente-Ganuza
P.
,
Eguia-Ángeles
E.
,
Escudero
A.I.
and
Martínez-Morillo
E.
et al.
(
2018
)
Addition of N-terminal pro-B natriuretic peptide to soluble fms-like tyrosine kinase-1/placental growth factor ratio > 38 improves prediction of pre-eclampsia requiring delivery within 1 week: a longitudinal cohort study
.
Ultrasound Obstet. Gynecol.
51
,
758
767
[PubMed]
106.
Martinez-Varea
A.
,
Martinez-Saez
C.
,
Domenech
J.
,
Desco-Blay
J.
,
Monfort-Pitarch
S.
and
Hueso
M.
et al.
(
2022
)
sFlt-1/PlGF ratio at 24 weeks gestation in twin pregnancies as a predictor of preeclampsia or fetal growth restriction
.
Fetal Diagn. Ther.
49
,
206
214
[PubMed]
107.
Boucoiran
I.
,
Thissier-Levy
S.
,
Wu
Y.
,
Wei
S.Q.
,
Luo
Z.C.
and
Delvin
E.
et al.
(
2013
)
Risks for preeclampsia and small for gestational age: predictive values of placental growth factor, soluble fms-like tyrosine kinase-1, and inhibin A in singleton and multiple-gestation pregnancies
.
Am. J. Perinatol.
30
,
607
612
[PubMed]
108.
Levine
R.J.
,
Lam
C.
,
Qian
C.
,
Yu
K.F.
,
Maynard
S.E.
and
Sachs
B.P.
et al.
(
2006
)
Soluble endoglin and other circulating antiangiogenic factors in preeclampsia
.
N. Engl. J. Med.
355
,
992
1005
[PubMed]
109.
Venkatesha
S.
,
Toporsian
M.
,
Lam
C.
,
Hanai
J.
,
Mammoto
T.
and
Kim
Y.M.
et al.
(
2006
)
Soluble endoglin contributes to the pathogenesis of preeclampsia
.
Nat. Med.
12
,
642
649
[PubMed]
110.
Margioula-Siarkou
G.
,
Margioula-Siarkou
C.
,
Petousis
S.
,
Margaritis
K.
,
Vavoulidis
E.
and
Gullo
G.
et al.
(
2022
)
The role of endoglin and its soluble form in pathogenesis of preeclampsia
.
Mol. Cell. Biochem.
477
,
479
491
[PubMed]
111.
Stepan
H.
,
Kramer
T.
and
Faber
R.
(
2007
)
Maternal plasma concentrations of soluble endoglin in pregnancies with intrauterine growth restriction
.
J. Clin. Endocrinol. Metab.
92
,
2831
2834
[PubMed]
112.
Iannaccone
A.
,
Reisch
B.
,
Mavarani
L.
,
Darkwah Oppong
M.
,
Kimmig
R.
and
Mach
P.
et al.
(
2022
)
Soluble endoglin versus sFlt-1/PlGF ratio: detection of preeclampsia, HELLP syndrome, and FGR in a high-risk cohort
.
Hypertens. Pregnancy
,
41
, 159
172
[PubMed]
113.
Erol Deniz
M.
,
Deniz
A.
,
Mendilcioglu
I.
,
Sanhal
C.Y.
,
Ozdem
S.
and
Kucukcetin
I.O.
et al.
(
2021
)
Serial measurement of soluble endoglin for risk assessment at the diagnosis of fetal growth restriction
.
Int. J. Clin. Pract.
75
,
e14840
[PubMed]
114.
Rafi
I.
and
Chitty
L.
(
2009
)
Cell-free fetal DNA and non-invasive prenatal diagnosis
.
Br. J. Gen. Pract.
59
,
e146
e148
[PubMed]
115.
van der Schoot
C.E.
,
Hahn
S.
and
Chitty
L.S.
(
2008
)
Non-invasive prenatal diagnosis and determination of fetal Rh status
.
Semin. Fetal Neonatal Med.
13
,
63
68
[PubMed]
116.
Norton
M.E.
,
Jacobsson
B.
,
Swamy
G.K.,
Laurent
L.C.
,
Ranzini
A.C.
and
Brar
H.
et al.
(
2015
)
Cell-free DNA analysis for noninvasive examination of trisomy
.
N. Engl. J. Med.
372
,
1589
1597
[PubMed]
117.
Alberry
M.S.
,
Maddocks
D.G.
,
Hadi
M.A.,
Metawi
H.
,
Hunt
L.P.
and
Abdel-Fattah
S.A.
et al.
(
2009
)
Quantification of cell free fetal DNA in maternal plasma in normal pregnancies and in pregnancies with placental dysfunction
.
Am. J. Obstet. Gynecol.
200
,
98e91
98e96
118.
Caramelli
E.
,
Rizzo
N.
,
Concu
M.
,
Simonazzi
G.
,
Carinci
P.
and
Bondavalli
C.
et al.
(
2003
)
Cell-free fetal DNA concentration in plasma of patients with abnormal uterine artery Doppler waveform and intrauterine growth restriction–a pilot study
.
Prenat. Diagn.
23
,
367
371
[PubMed]
119.
Smid
M.
,
Vassallo
A.
,
Lagona
F.
,
Valsecchi
L.
,
Maniscalco
L.
and
Danti
L.
et al.
(
2001
)
Quantitative analysis of fetal DNA in maternal plasma in pathological conditions associated with placental abnormalities
.
Ann. N. Y. Acad. Sci.
945
,
132
137
[PubMed]
120.
Rolnik
D.L.
,
da Silva Costa
F.
,
Lee
T.J.
,
Schmid
M.
and
McLennan
A.C.
(
2018
)
Association between fetal fraction on cell-free DNA testing and first-trimester markers for pre-eclampsia
.
Ultrasound Obstet. Gynecol.
52
,
722
727
[PubMed]
121.
Morano
D.
,
Rossi
S.
,
Lapucci
C.
,
Pittalis
M.C.
and
Farina
A.
(
2018
)
Cell-free DNA (cfDNA) fetal fraction in early- and late-onset fetal growth restriction
.
Mol. Diagn. Ther.
22
,
613
619
[PubMed]
122.
Adiyaman
D.
,
Konuralp Atakul
B.
,
Kuyucu
M.,
Toklu
G.
,
Golbasi
H.
and
Koc
A.
et al.
(
2020
)
Can fetal fractions in the cell-free DNA test predict the onset of fetal growth restriction?
J. Perinat. Med.
,
48
,
395
401
123.
Smid
M.
,
Galbiati
S.
,
Lojacono
A.,
Valsecchi
L.
,
Platto
C.
and
Cavoretto
P.
et al.
(
2006
)
Correlation of fetal DNA levels in maternal plasma with Doppler status in pathological pregnancies
.
Prenat. Diagn.
26
,
785
790
[PubMed]
124.
Poon
L.C.
,
Musci
T.
,
Song
K.
,
Syngelaki
A.
and
Nicolaides
K.H.
(
2013
)
Maternal plasma cell-free fetal and maternal DNA at 11-13 weeks' gestation: relation to fetal and maternal characteristics and pregnancy outcomes
.
Fetal Diagn. Ther.
33
,
215
223
[PubMed]
125.
Sekizawa
A.
,
Jimbo
M.
,
Saito
H.
,
Iwasaki
M.
,
Matsuoka
R.
and
Okai
T.
et al.
(
2003
)
Cell-free fetal DNA in the plasma of pregnant women with severe fetal growth restriction
.
Am. J. Obstet. Gynecol.
188
,
480
484
[PubMed]
126.
Carbone
I.F.
,
Conforti
A.
,
Picarelli
S.
,
Morano
D.
,
Alviggi
C.
and
Farina
A.
(
2020
)
Circulating nucleic acids in maternal plasma and serum in pregnancy complications: are they really useful in clinical practice? A systematic review
Mol. Diagn. Ther.
24
,
409
431
[PubMed]
127.
Sifakis
S.
,
Koukou
Z.
and
Spandidos
D.A.
(
2015
)
Cell-free fetal DNA and pregnancy-related complications (review)
.
Mol. Med. Rep.
11
,
2367
2372
[PubMed]
128.
Scheffer
P.G.
,
Wirjosoekarto
S.A.M.
,
Becking
E.C.
,
Weiss
M.M.
,
Bax
C.J.
and
Oepkes
D.
et al.
(
2021
)
Association between low fetal fraction in cell-free DNA testing and adverse pregnancy outcome: a systematic review
.
Prenat. Diagn.
41
,
1287
1295
[PubMed]
129.
Lagos-Quintana
M.
,
Rauhut
R.
,
Lendeckel
W.
and
Tuschl
T.
(
2001
)
Identification of novel genes coding for small expressed RNAs
.
Science
294
,
853
858
[PubMed]
130.
Chim
S.S.
,
Shing
T.K.
,
Hung
E.C.
,
Leung
T.Y.
,
Lau
T.K.
and
Chiu
R.W.
et al.
(
2008
)
Detection and characterization of placental microRNAs in maternal plasma
.
Clin. Chem.
54
,
482
490
[PubMed]
131.
Arroyo
J.D.
,
Chevillet
J.R.
,
Kroh
E.M.,
Ruf
I.K.
,
Pritchard
C.C.
and
Gibson
D.F.
et al.
(
2011
)
Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma
.
Proc. Natl. Acad. Sci. U.S.A.
108
,
5003
5008
[PubMed]
132.
Fu
G.
,
Brkic
J.
,
Hayder
H.
and
Peng
C.
(
2013
)
MicroRNAs in human placental development and pregnancy complications
.
Int. J. Mol. Sci.
14
,
5519
5544
[PubMed]
133.
Luo
S.S.
,
Ishibashi
O.
,
Ishikawa
G.
,
Ishikawa
T.
,
Katayama
A.
and
Mishima
T.
et al.
(
2009
)
Human villous trophoblasts express and secrete placenta-specific microRNAs into maternal circulation via exosomes
.
Biol. Reprod.
81
,
717
729
[PubMed]
134.
Hromadnikova
I.
,
Kotlabova
K.
,
Hympanova
L.
and
Krofta
L.
(
2015
)
Cardiovascular and cerebrovascular disease associated microRNAs are dysregulated in placental tissues affected with gestational hypertension, preeclampsia and intrauterine growth restriction
.
PloS ONE
10
,
e0138383
[PubMed]
135.
Hromadnikova
I.
,
Kotlabova
K.
and
Krofta
L.
(
2022
)
First-trimester screening for fetal growth restriction and small-for-gestational-age pregnancies without preeclampsia using cardiovascular disease-associated microRNA biomarkers
.
Biomedicines
10
,
718
136.
Kim
S.H.
,
MacIntyre
D.A.
,
Binkhamis
R.
,
Cook
J.
,
Sykes
L.
and
Bennett
P.R.
et al.
(
2020
)
Maternal plasma miRNAs as potential biomarkers for detecting risk of small-for-gestational-age births
.
EBioMedicine
62
,
103145
[PubMed]
137.
Rodosthenous
R.S.
,
Burris
H.H.
,
Sanders
A.P.
,
Just
A.C.
,
Dereix
A.E.
and
Svensson
K.
et al.
(
2017
)
Second trimester extracellular microRNAs in maternal blood and fetal growth: an exploratory study
.
Epigenetics
12
,
804
810
[PubMed]
138.
Tagliaferri
S.
,
Cepparulo
P.
,
Vinciguerra
A.
,
Campanile
M.
,
Esposito
G.
and
Maruotti
G.M.
et al.
(
2021
)
miR-16-5p, miR-103-3p, and miR-27b-3p as early peripheral biomarkers of fetal growth restriction
.
Front. Pediatr.
9
,
611112
[PubMed]
139.
Tsai
P.Y.
,
Li
S.H.
,
Chen
W.N.
,
Tsai
H.L.
and
Su
M.T.
(
2017
)
Differential miR-346 and miR-582-3p expression in association with selected maternal and fetal complications
.
Int. J. Mol. Sci.
18
,
1570
140.
Whitehead
C.L.
,
Teh
W.T.
,
Walker
S.P.
,
Leung
C.
,
Larmour
L.
and
Tong
S.
(
2013
)
Circulating microRNAs in maternal blood as potential biomarkers for fetal hypoxia in-utero
.
PloS ONE
8
,
e78487
[PubMed]
141.
Anton
L.
,
Olarerin-George
A.O.
,
Schwartz
N.
,
Srinivas
S.
,
Bastek
J.
and
Hogenesch
J.B.
et al.
(
2013
)
miR-210 inhibits trophoblast invasion and is a serum biomarker for preeclampsia
.
Am. J. Pathol.
183
,
1437
1445
[PubMed]
142.
Luo
R.
,
Wang
Y.
,
Xu
P.
,
Cao
G.
,
Zhao
Y.
and
Shao
X.
et al.
(
2016
)
Hypoxia-inducible miR-210 contributes to preeclampsia via targeting thrombospondin type I domain containing 7A
.
Sci. Rep.
6
,
19588
[PubMed]
143.
Bian
X.
,
Liu
J.
,
Yang
Q.
,
Liu
Y.
,
Jia
W.
and
Zhang
X.
et al.
(
2021
)
MicroRNA-210 regulates placental adaptation to maternal hypoxic stress during pregnancydagger
.
Biol. Reprod.
104
,
418
429
[PubMed]
144.
Maccani
M.A.
,
Padbury
J.F.
and
Marsit
C.J.
(
2011
)
miR-16 and miR-21 expression in the placenta is associated with fetal growth
.
PloS ONE
6
,
e21210
[PubMed]
145.
Higashijima
A.
,
Miura
K.
,
Mishima
H.
,
Kinoshita
A.
,
Jo
O.
and
Abe
S.
et al.
(
2013
)
Characterization of placenta-specific microRNAs in fetal growth restriction pregnancy
.
Prenat. Diagn.
33
,
214
222
[PubMed]
146.
Hromadnikova
I.
,
Kotlabova
K.
,
Hympanova
L.
and
Krofta
L.
(
2016
)
Gestational hypertension, preeclampsia and intrauterine growth restriction induce dysregulation of cardiovascular and cerebrovascular disease associated microRNAs in maternal whole peripheral blood
.
Thromb. Res.
137
,
126
140
[PubMed]
147.
Parry
S.
,
Carper
B.A.
,
Grobman
W.A.,
Wapner
R.J.
,
Chung
J.H.
and
Haas
D.M.
et al.
(
2022
)
Placental protein levels in maternal serum are associated with adverse pregnancy outcomes in nulliparous patients
.
Am. J. Obstet. Gynecol.
227
,
497e491e413
497e497e413
148.
Stepan
H.
,
Galindo
A.
,
Hund
M.
,
Schlembach
D.
,
Sillman
J.
and
Surbek
D.
et al.
(
2022
)
Clinical utility of sFlt-1 and PlGF in screening, prediction, diagnosis and monitoring of pre-eclampsia and fetal growth restriction
.
Ultrasound Obstet. Gynecol.
,
61
,
168
180
149.
Zeisler
H.
,
Llurba
E.
,
Chantraine
F.
,
Vatish
M.
,
Staff
A.C.
and
Sennström
M.
et al.
(
2016
)
Predictive Value of the sFlt-1:PlGF ratio in women with suspected preeclampsia
.
N. Engl. J. Med.
374
,
13
22
[PubMed]
150.
Yu
N.
,
Cui
H.
,
Chen
X.
and
Chang
Y.
(
2017
)
First trimester maternal serum analytes and second trimester uterine artery Doppler in the prediction of preeclampsia and fetal growth restriction
.
Taiwan J. Obstet. Gynecol.
56
,
358
361
[PubMed]
151.
Fruscalzo
A.
,
Frommer
J.
,
Londero
A.P.
,
Henze
A.
,
Schweigert
F.J.
and
Nofer
J.R.
et al.
(
2017
)
First trimester TTR-RBP4-ROH complex and angiogenic factors in the prediction of small for gestational age infant's outcome
.
Arch. Gynecol. Obstet.
295
,
1157
1165
[PubMed]
152.
Hendrix
M.L.E.
,
Bons
J.A.P.
,
Snellings
R.R.G.
,
Bekers
O.
,
van Kuijk
S.M.J.
and
Spaanderman
M.E.A.
et al.
(
2019
)
Can fetal growth velocity and first trimester maternal biomarkers improve the prediction of small-for-gestational age and adverse neonatal outcome?
Fetal Diagn. Ther.
46
,
274
284
[PubMed]
153.
Furuta
I.
,
Umazume
T.
,
Kojima
T.
,
Chiba
K.
,
Nakagawa
K.
and
Hosokawa
A.
et al.
(
2017
)
Serum placental growth factor and soluble fms-like tyrosine kinase 1 at mid-gestation in healthy women: association with small-for-gestational-age neonates
.
J. Obstet. Gynaecol. Res.
43
,
1152
1158
[PubMed]
154.
Ciobanou
A.
,
Jabak
S.
,
De Castro
H.
,
Frei
L.
,
Akolekar
R.
and
Nicolaides
K.H.
(
2019
)
Biomarkers of impaired placentation at 35-37 weeks' gestation in the prediction of adverse perinatal outcome
.
Ultrasound Obstet. Gynecol.
54
,
79
86
[PubMed]
155.
Shibata
E.
,
Rajakumar
A.
,
Powers
R.W.
,
Larkin
R.W.
,
Gilmour
C.
and
Bodnar
L.M.
et al.
(
2005
)
Soluble fms-like tyrosine kinase 1 is increased in preeclampsia but not in normotensive pregnancies with small-for-gestational-age neonates: relationship to circulating placental growth factor
.
J. Clin. Endocrinol. Metab.
90
,
4895
4903
[PubMed]
156.
Wallner
W.
,
Sengenberger
R.
,
Strick
R.
,
Strissel
P.L.
,
Meurer
B.
and
Beckmann
M.W.
et al.
(
2007
)
Angiogenic growth factors in maternal and fetal serum in pregnancies complicated by intrauterine growth restriction
.
Clin. Sci. (Lond.)
112
,
51
57
[PubMed]
157.
MacDonald
T.M.
,
Tran
C.
,
Kaitu'u-Lino
T.J.
,
Brennecke
S.P.
,
Hiscock
R.J.
and
Hui
L.
et al.
(
2018
)
Assessing the sensitivity of placental growth factor and soluble fms-like tyrosine kinase 1 at 36 weeks' gestation to predict small-for-gestational-age infants or late-onset preeclampsia: a prospective nested case-control study
.
BMC Pregnancy Childbirth
18
,
354
[PubMed]
158.
Darling
A.M.
,
McDonald
C.R.
,
Conroy
A.L.,
Hayford
K.T.
,
Liles
W.C.
and
Wang
M.
et al.
(
2014
)
Angiogenic and inflammatory biomarkers in midpregnancy and small-for-gestational-age outcomes in Tanzania
.
Am. J. Obstet. Gynecol.
211
,
509e501
509e508
159.
Triunfo
S.
,
Parra-Saavedra
M.
,
Rodriguez-Sureda
V.
,
Crovetto
F.
,
Dominguez
C.
and
Gratacós
E.
et al.
(
2016
)
Angiogenic factors and doppler evaluation in normally growing fetuses at routine third-trimester scan: prediction of subsequent low birth weight
.
Fetal Diagn. Ther.
40
,
13
20
[PubMed]
160.
Thadhani
R.
,
Mutter
W.P.
,
Wolf
M.
,
Levine
R.J.
,
Taylor
R.N.
and
Sukhatme
V.P.
et al.
(
2004
)
First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia
.
J. Clin. Endocrinol. Metab.
89
,
770
775
[PubMed]
161.
Rizos
D.
,
Eleftheriades
M.
,
Karampas
G.
,
Rizou
M.
,
Haliassos
A.
and
Hassiakos
D.
et al.
(
2013
)
Placental growth factor and soluble fms-like tyrosine kinase-1 are useful markers for the prediction of preeclampsia but not for small for gestational age neonates: a longitudinal study
.
Eur. J. Obstet. Gynecol. Reprod. Biol.
171
,
225
230
[PubMed]
162.
Borras
D.
,
Perales-Puchalt
A.
,
Ruiz Sacedon
N.
and
Perales
A.
(
2014
)
Angiogenic growth factors in maternal and fetal serum in pregnancies complicated with intrauterine growth restriction
.
J. Obstet. Gynaecol.
34
,
218
220
[PubMed]
163.
Savvidou
M.D.
,
Yu
C.K.
,
Harland
L.C.
,
Hingorani
A.D.
and
Nicolaides
K.H.
(
2006
)
Maternal serum concentration of soluble fms-like tyrosine kinase 1 and vascular endothelial growth factor in women with abnormal uterine artery Doppler and in those with fetal growth restriction
.
Am. J. Obstet. Gynecol.
195
,
1668
1673
[PubMed]
164.
Chaiworapongsa
T.
,
Espinoza
J.
,
Gotsch
F.,
Kim
Y.M.
,
Kim
G.J.
and
Goncalves
L.F.
et al.
(
2008
)
The maternal plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated in SGA and the magnitude of the increase relates to Doppler abnormalities in the maternal and fetal circulation
.
J. Matern. Fetal Neonatal Med.
21
,
25
40
[PubMed]
165.
Boutsikou
T.
,
Malamitsi-Puchner
A.
,
Economou
E.
,
Boutsikou
M.
,
Puchner
K.P.
and
Hassiakos
D.
(
2006
)
Soluble vascular endothelial growth factor receptor-1 in intrauterine growth restricted fetuses and neonates
.
Early Hum. Dev.
82
,
235
239
[PubMed]
166.
Asvold
B.O.
,
Vatten
L.J.
,
Romundstad
P.R.
,
Jenum
P.A.
,
Karumanchi
S.A.
and
Eskild
A.
(
2011
)
Angiogenic factors in maternal circulation and the risk of severe fetal growth restriction
.
Am. J. Epidemiol.
173
,
630
639
[PubMed]
167.
Wathen
K.A.
,
Tuutti
E.
,
Stenman
U.H.
,
Alfthan
H.
,
Halmesmäki
E.
and
Finne
P.
et al.
(
2006
)
Maternal serum-soluble vascular endothelial growth factor receptor-1 in early pregnancy ending in preeclampsia or intrauterine growth retardation
.
J. Clin. Endocrinol. Metab.
91
,
180
184
[PubMed]
168.
Nanjo
S.
,
Minami
S.
,
Mizoguchi
M.,
Yamamoto
M.
,
Yahata
T.
and
Toujima
S.
et al.
(
2017
)
Levels of serum-circulating angiogenic factors within 1 week prior to delivery are closely related to conditions of pregnant women with pre-eclampsia, gestational hypertension, and/or fetal growth restriction
.
J. Obstet. Gynaecol. Res.
43
,
1805
1814
[PubMed]
169.
Kochhar
P.
,
Vukku
M.
,
Rajashekhar
R.
and
Mukhopadhyay
A.
(
2022
)
microRNA signatures associated with fetal growth restriction: a systematic review
.
Eur. J. Clin. Nutr.
76
,
1088
1102
[PubMed]
170.
Ashraf
U.M.
,
Hall
D.L.
,
Rawls
A.Z.
and
Alexander
B.T.
(
2021
)
Epigenetic processes during preeclampsia and effects on fetal development and chronic health
.
Clin. Sci. (Lond.)
135
,
2307
2327
[PubMed]
171.
Hornakova
A.
,
Kolkova
Z.
,
Holubekova
V.
,
Loderer
D.
,
Lasabova
Z.
and
Biringer
K.
et al.
(
2020
)
Diagnostic potential of microRNAs as biomarkers in the detection of preeclampsia
.
Genet Test Mol. Biomarkers
24
,
321
327
[PubMed]
172.
Sheikh
A.M.
,
Small
H.Y.
,
Currie
G.
and
Delles
C.
(
2016
)
Systematic review of micro-RNA expression in pre-eclampsia identifies a number of common pathways associated with the disease
.
PloS ONE
11
,
e0160808
[PubMed]
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