Hindawi

e Scientific World Journal

Volume 2019, Article ID 1519048, 8 pages
https://doi.org/10.1155/2019/1519048

Review Article
Fetal Growth Restriction Prediction: How to Move beyond

Debora F. B. Leite1,2,3 and Jose G. Cecatti 1

1
Department of Obstetrics and Gynecology, University of Campinas, School of Medical Sciences, Campinas, Sao Paulo, Brazil
2
Federal University of Pernambuco, Caruaru, Pernambuco, Brazil
3
Clinics Hospital of the Federal University of Pernambuco, Recife, Pernambuco, Brazil

Correspondence should be addressed to Jose G. Cecatti; [email protected]

Received 23 January 2019; Accepted 1 August 2019; Published 21 August 2019

Academic Editor: Hind A. Beydoun

Copyright © 2019 Debora F. B. Leite and Jose G. Cecatti. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
The actual burden and future burden of the small-for-gestational-age (SGA) babies turn their screening in pregnancy a question of
major concern for clinicians and policymakers. Half of stillbirths are due to growth restriction in utero, and possibly, a quarter of
livebirths of low- and middle-income countries are SGA. Growing body of evidence shows their higher risk of adverse outcomes at
any period of life, including increased rates of neurologic delay, noncommunicable chronic diseases (central obesity and metabolic
syndrome), and mortality. Although there is no consensus regarding its definition, birthweight centile threshold, or follow-up, we
believe birthweight <10th centile is the most suitable cutoff for clinical and epidemiological purposes. Maternal clinical factors
have modest predictive accuracy; being born SGA appears to be of transgenerational heredity. Addition of ultrasound parameters
improves prediction models, especially using estimated fetal weight and abdominal circumference in the 3rd trimester of
pregnancy. Placental growth factor levels are decreased in SGA pregnancies, and it is the most promising biomarker in dif-
ferentiating angiogenesis-related SGA from other causes. Unfortunately, however, only few societies recommend universal
screening. SGA evaluation is the first step of a multidimensional approach, which includes adequate management and long-term
follow-up of these newborns. Apart from only meliorating perinatal outcomes, we hypothesize SGA screening is a key for
socioeconomic progress.

1. Introduction In fact, human development goes far beyond genetic

inheritance. Lessons learned from pregnancies subjected to
The intrauterine environment influence on fetus develop- smoking [5, 6] or intermittent fasting [7], for instance, show
ment is a well-known determinant of individual’s long-term how intrauterine growth is adjustable. Posttranslational
health and quality of life. From the initial description of 23 changes in small-for-gestational-age (SGA) infants [8] re-
infants being born at term weighing less than 2000 g, inforce the thrifty phenotype hypothesis [9]. According to
Warkany et al. [1] introduced the idea of “intrauterine Hales and Barker, the nutritional deficiency, especially re-
growth retardation” (IUGR). Soon, they were followed by garding amino acids supply, would decrease the pancreatic
others [2–4]. They considered IUGR “all conditions leading beta-cells function and induce changes of the muscular,
to a marked reduction in size during intrauterine life” [1], hepatic, and adipose tissue systems functioning, for example
mainly represented by reduced birthweight. Although all of [9]. These newborns are at higher risk of neonatal morbidity
them have described pregnancies and infants with a wide and mortality [6, 10–18]; in adolescence and adulthood, they
variation of phenotype, with and without hypertensive present worse neurodevelopment [19, 20] and metabolic
syndromes or morphologic anomalies, for instance, the [21, 22] and cardiovascular [23] adverse outcomes. On the
turning points were to consider the environment in which contrary, the placenta—a shared organ by both the mother
the fetus was developing and the placenta role in this and the fetus—is responsible for adjusting maternal supply
process. to the fetus demands. Since it is difficult to realize which are
2 The Scientific World Journal

the normal placental functioning patterns and the optimal syndromes” may share pathophysiological pathways [33],
fetal growth, it is reasonable to use the birthweight as a and it is possible that SGA may represent an underlying
measure of the intrauterine environment [24] and SGA condition for the other ones.
newborns as surrogates for fetal growth restriction (FGR) The “great obstetrical syndromes” are related to defective
[10–13]. deep placentation [33], and studies on placental biomarkers
Therefore, considering the long latency of some events, point in this direction [34, 35]. Not surprisingly, patho-
such as cognitive delays and cardiovascular diseases, SGA logical placental findings have been related to SGA preg-
has impacts of public health magnitude, especially in low- nancies, especially vascular malperfusions lesions,
and middle-income countries (LMICs) [13, 25]. In this infarction, and chronic villitis of unknown etiology [36–39].
review, we will discuss the importance of SGA screening in Vascular-mediated changes (e.g., decidual vasculopathy and
pregnancy and which are the best approaches and moments single or multiple infarctions) usually coexist with Doppler
to perform it. (uterine (UtA), umbilical (UA), or middle cerebral (MCA)
arteries) [37, 39] or biochemical abnormalities (such as low
2. Why We Should Screen for Fetal levels of placental growth factor (PlGF) [35] or alpha-
Growth Restriction? fetoprotein (AFP): pregnancy-associated plasma protein-A
(PAPP-A) ratio >10 [34]). These pathological and functional
The identification of FGR as a distinct pathophysiological observations are similar to those found in pregnancies af-
entity is merged with preterm birth history. In the first half fected by hypertensive disorders, preterm deliveries, and
of the 20th century, gestational age at birth and birthweight stillbirth [40–44], then possibly reflecting an elementary
concepts overlapped; the World Health Organization rec- chronic hypoxia mediating these outcomes.
ommended a birth weight of 2500 g or less to characterize Additionally, some clinical risk factors are similar be-
prematurity [26]. However, several authors and clinicians tween the “great obstetrical syndromes.” Multiple preg-
were intrigued by “pseudopremature” newborns, who would nancies and maternal chronic conditions, such as previous
be in chronic suffering due to placental insufficiency and hypertension, systemic lupus erythematosus, and diabetes
would benefit from earlier delivery [2–4]. Only in 1961, the mellitus, are all associated with them [45–47]. Nulliparity
terminology IUGR was first cited [1]. Apart from only [11, 14, 48], shorter height [11, 14, 48], lower pre-pregnancy
birthweight (<2000 g), Warkany et al. suggested that preterm weight [11, 14, 48] or body mass index [11, 14], previous
infants whose birthweight were 40% below the expected for a history of SGA [6, 11, 48], smoking [5, 6, 11, 32, 48], and
given gestational age should be considered IUGR. Two years being born SGA [49] are frequently related to SGA preg-
later, Battaglia and Lubchenco proposed to use the birth- nancies. Maternal age shows conflicting results, as well as
weight as a proxy for intrauterine development [27] and this ethnicity [11, 14], socioeconomic, and marital status [45],
is still a common practice in the 2000s [10–13], due to which may explain how maternal culture background and
difficulties in defining and measuring fetal growth [28–30]. environment influence SGA patterns in a given population.
Currently, the birthweight <10th centile, either by Regarding the outcomes of SGA newborns, extensive
population-based or customized charts, is the most accepted investigation has been performed on immediate
definition for SGA infants [28]. This mathematical threshold [10–14, 16, 18, 32, 50] and long-term endpoints
was initially chosen due to (i) the increased neonatal [19–23, 51, 52], demonstrating worse health performance at
mortality observed in this group when compared to those any period of life. Not surprisingly, the leading countries in
born between the 10th and the 90th centiles and (ii) the absolute numbers of fetal and neonatal deaths [53] are the
agreement on the 10th centile among studies up to the 1960s same as SGA [25]: India, Pakistan, and Nigeria. Indeed,
[27]. There are concerns that some of these infants are growth restriction can account for up to half of the fetal
“constitutionally small,” not at higher risk of (neonatal) deaths of unknown causes [54], being about 6-fold higher
adverse outcomes, and lower limits for SGA, such as ≤5th than the chance of stillbirth at term (relative risk, RR, 6.0;
[31], ≤3rd or even ≤2, and 3rd centile [32], are considered by 95% CI, 3.1–11.5) [11], or when the birthweight is <5th
some researchers. However, little is still known about the percentile (compared to the 10–90th centiles) [17]. Besides
long-term health endpoints of the “constitutionally small” perinatal death [6, 11, 12, 15–18, 55], preterm birth
newborns. Therefore, the 10th centile seems the most suitable [6, 11, 14], and other short-term adverse events are described
cutoff for epidemiological and clinical purposes, and it is the for SGA infants (Table 1); the adjusted odds ratio (aOR) for
adopted threshold in this review. composite neonatal morbidity can be as high as 3.22 (95%
The SGA prevalence varies according to the reference CI, 3.07–3.39) [12]. Interestingly, SGA suspicion in preg-
standards applied; it tends to be higher with customized nancy is associated with better neonatal outcomes [18, 57],
curves [11, 12, 14]. Using population-based charts, live births which turns SGA screening a cornerstone strategy for re-
between 19.3% [13] and 27% [25] in LMIC could have been ducing antepartum fetal loss [13, 58] and meliorating
classified as SGA in 2000s. A majority of them were term- neonatal morbidity ratios.
SGA (98% and 95.6%, respectively). This turns SGA the most Unfortunately, the higher risk of mortality goes beyond
important pregnancy-related syndrome since other patho- the neonatal period. Data from Sweden show a hazard ratio
logical conditions, such as pregnancy hypertension and (HR) of 1.37 (95% CI 1.28–1.47) of death up to 18 years old,
preterm birth, have markedly lower prevalence [11, 12, 14]. which increased to 2.61 (95% CI 2.19–3.10) for those neonates
It is interesting to note, however, that these “great obstetrical born <3rd centile [59]. Additionally, growth restriction is
The Scientific World Journal 3

Table 1: Neonatal adverse events associated with being born SGA. booking can identify several risk factors and guide refer-
Perinatal asphyxia encing to tertiary care facilities.
5th-minute Apgar score <7 [10, 11, 14] Single maternal clinical factors demonstrate poor
5th-minute Apgar score <5 [10, 12, 16, 18] prediction accuracy (Table 2), and, as a result, are generally
Admission to neonatal intensive care unit [6, 10, 11, 55] considered in a multidimensional model. Smoking, al-
Hypoglycemia requiring treatment [38, 50] though less prevalent in the early years of the 21st century,
Phototherapy [50] still demonstrates effects on fetal growth [5, 6, 48] and is the
Respiratory distress syndrome [12, 14, 16, 50]
most common maternal variable to compose a prediction
Ventilatory support [11, 12, 16, 56]
Necrotizing enterocolitis [12, 56] model. Lower maternal stature and weight appear associ-
Neonatal sepsis [12, 16, 50] ated with SGA in some studies [11, 14, 48] but showed only
Seizures [12, 16, 18] 43% and 73% of sensitivity, respectively [64]. Body mass
Intraventricular hemorrhage [12, 16, 18] index (BMI) and maternal weight gain throughout preg-
Neonatal death [11, 12, 15, 16] nancy demonstrate an area under the (AUC) receiver
operating characteristic (ROC) curve of 0.56 and 0.60,
respectively [64]. The performance of symphysial-fundal
associated with a lower Bailey score, especially in com- height (SFH) measurement in predicting SGA newborns
munication skills domain [19], sleep disorders [52], and increases with gestational age [68], but it is not different to
hyperactivity [56]. If SGA fetuses experience any degree of Leopold’s maneuvers (RR1. 32, 95% CI 0.92–1.90) [69].
brain-sparing effect, the delayed motor skills and cognitive However, since it is inexpensive and already part of the
development are even more pronounced [19, 51]. Re- routine obstetrical examination, Cochrane reviewers advise
garding metabolic repercussions, insulin and insulin re- its use and health professionals should associate it with
sistance index (HOMA IR) are higher in SGA children at some other technique or evaluation of fetal growth.
6–8 years old and those born <3rd centile also have higher Other maternal factors have been combined differently,
levels of leptin [22]. evidencing how SGA syndrome can be heterogeneous in
Evidence from adults exposed to famine in utero shows distinct settings. In a multicenter international nulliparous
increased odds for metabolic syndrome [21] and obesity [60] cohort, a family history of coronary heart disease, maternal
in SGA newborns, perhaps in a sex-specific manner, birthweight <3000 g, infertility, college student, smoking at
depending on childhood nutritional parameters (especially the 2nd trimester, proteinuria, daily vigorous exercise, and
weight gain velocity). Proportionate biometric measure- diastolic blood pressure ≥80 mmHg, combined with the
ments at birth were the initial observations of Barker et al.
protective factors rising random glucose, recreational
who related the ponderal index, head circumference, and
walking (≥4x/week), and Rhesus negative blood group,
birthweight <2495 g to cardiovascular mortality [23]. Al-
provided an AUC of 0.63 [6]. This same AUC (0.66, 95% CI
though maternal undernourishment is not synonymous of
0.61–0.70) was achieved by combining maternal age and
SGA infant and considering that the birthweight approach
height, smoking, previous SGA infant, and chronic hyper-
has changed over time, these findings mean that adequate
tension in Spain [70]. In the United Kingdom, a logistic
fetal development is the standpoint for long-term health.
regression model included maternal height, weight, parity,
There is greater visceral fat thickness (in women) [61], higher
ethnic background, smoking, and previous history of pre-
fat-free soft tissue mass [62], and increased trunk and ab- eclampsia or SGA [71]. In this model, maternal factors
dominal fat mass proportion (of both sexes) [63] in adults evaluation between 35 and 37 w have had similar AUC for
born SGA. These epidemiological data ground current delivery within two weeks (0.744; 95% CI 0.731–0.756) and
theories of epigenetic modifications in SGA infants, leading
term delivery (0.712; 95% CI 0.700–0.725) for SGA without
to enriched (i.e., with increased DNA methylation) pathways
preeclampsia.
involved with fat, sugar, and protein metabolism [8].
Therefore, timely recognition of SGA—still in preg-
nancy—is a real concern for obstetricians, perinatologists, 3.2. Ultrasound Scans. Adding ultrasound scan (US) pa-
health workers, and policymakers. Unfortunately, only a rameters to maternal clinical factors improves the perfor-
small proportion of SGA babies are suspected before birth mance of prediction models, although not consistently
[18, 57], leading to a lack of appropriate short- and long- [6, 71]. Crown-rump length (CRL) [43]; nuchal translucency
term follow-up of these newborns. SGA suspicion will (NT) [43]; head circumference (HC) [6]; abdominal cir-
provide adequate management of the mother and fetus/ cumference (AC) [6, 72]; AC growth velocity (ACGV)
newborn, including referencing to a specialized facility for [72, 73]; femur length (FL) [74]; estimated fetal weight
antenatal care and delivery and individualized follow-up in (EFW) [32, 44, 71, 73, 75, 76]; uterine arteries pulsatility
childhood, adolescence, and adulthood. index (UtA-PI) or resistance (UtA-RI) index, or notches
[6, 32, 71, 76]; umbilical artery PI (UA-PI); middle cerebral
3. When and How We Should Screen for Fetal artery PI (MCA-PI); cerebral-placental ratio (CPR: MCA-
Growth Restriction? PI/UA-PI) [32, 66, 76]; and umbilical vein blood flow
(UVBF) [32] were studied for SGA prediction. Except for
3.1. Clinical Factors. Clinical risk assessment is the first NT, the lower the fetal biometry, the higher the odds for
approach to antenatal care. A detailed maternal history at SGA; in general, there is a trend towards better US predictive
4 The Scientific World Journal

Table 2: Accuracy for clinical factors, ultrasound parameters, and placental biomarkers for SGA prediction (birthweight <10th centile).
Predictive factors AUC S (95% CI) Sp (95% CI) When
Maternal height [64] 0.59 0.43 (0.27–0.60) 0.70 (0.53–0.83) At booking
Maternal weight [64] 0.57 0.73 (0.60–0.83) 0.35 (0.23–0.51) At booking
Maternal weight gain [64] 0.60 0.50 (0.42–0.59) 0.66 (0.57–0.73) At booking
PAPP-A [43] 0.16 (0.14–0.19) 0.90 (0.89–0.90) 1st trimester
PlGF [65] 0.49 (0.44–0.53) 0.64 (0.63–0.66) 2nd trimester
Cerebroplacental ratioa [66] 0.43 (0.39–0.47) 0.94 (0.84–0.98) 3rd trimester
Estimated fetal weightb [67] 0.79 0.38 (0.31–0.46) 0.95 (0.93–0.97) >32 w
Abdominal circumference [67] 0.92 0.35 (0.20–0.52) 0.97 (0.95–0.98) >32 w
a
MCA-PI/UA-PI <10th centile or ≤1.08; bestimated fetal weight <10th centile for gestational age. AUC: area under the receiver operator characteristic curve; S:
sensitivity; Sp: specificity; PAPP-A: pregnancy-associated plasma protein-A; PlGF: placental growth factor.

accuracy for lower birthweight centiles (especially <3rd) an SGA infant when both EFW and ACGV (between 28 and
[67, 76]. Unfortunately, participants’ selection criteria, study 36 w) were <10th centile [73]. In this study, the sensitivity of
protocol of follow-up, and outcome measures differ between EFW <10th centile was higher with universal screening for
studies, precluding interpretation and evaluation of US in SGA <10th (57%) or <3rd centile (77%) than with clinically
clinical practice [67]. In Table 2, predictive accuracy mea- oriented US evaluation (20% and 32%, respectively) [73].
sures of EFW and AC are shown. More recently, magnetic resonance imaging (MRI) has
In the 1st trimester, decreased values of NT were asso- been explored in maternal-fetal surveillance. Carlin et al.
ciated to lesser odds for SGA (OR 0.79; 95% CI 0.70–0.89), but [78] have demonstrated no difference in EFW ≤3rd or ≤5th
the CRL has shown no relationship (OR 0.99, 95% CI centile by US or MRI before delivery (48 h). However, DR of
0.99–1.00) [43]. In the 2nd trimester, McCowan et al. [6] SGA ≤10th centile was superior with MRI (100.0; 95% CI
demonstrated that only a limited increase in AUC (from 0.66 81.5–100.0, FPR of 10%) than the US (77.8; 95% CI 52.4–
to 0.73) was observed with the addition of 20 w US data to 93.6, FPR 10%).
maternal data: HC z-score <10th centile, AC z-score <10th
centile, and UtA-RI ≥ 0.05. The higher the UtA-RI, the higher
the OR for SGA, reaching 4.56 (95% CI 2.45 to 8.48) when 3.3. Biomarkers. Biomarker measurements of placental
0.8–1.0. At 35–37 w, Fadigas et al. [71] have combined ma- functioning-related substances have had significant devel-
ternal variables with EFW z-score, which improved AUC opment in the last three decades. Many of these compounds
from 0.81 (95% CI 0.802–0.824) to 0.98 (95% CI 0.98–0.98) are also involved with antenatal detection of chromosomal
for delivering an SGA infant <3rd centile in less than two anomalies, or preeclampsia, such as PAPP-A, AFP, PlGF, or
weeks. In this cohort, adding mean arterial pressure and UtA- sFLt-1 [41] (Table 2). Studies from the mid 1980s have
PI has not improved the prediction performance (AUC 0.98; evaluated the human placental lactogen (hPL), when it
95% CI 0.98–0.99). demonstrated a diagnostic odds ratio (DOR) of 4.78 (95% CI
Interestingly, a single measurement is better than lon- 3.21–7.13), whereas more recent data focus on angiogenic
gitudinal follow-up [32, 67, 72, 73, 75]. In the 2nd trimester, biomarkers [44].
the femur length <5th centile is associated with increased The AFP: PAPP-A ratio >10 at 12 w of pregnancy
odds for IUGR or SGA (3.24, 95% CI 2.34–4.48) [74]. The provided a risk ratio of 3.74 (95% CI 2.3–6.09) for SGA <3rd
performance of EFW <10th centile at 35–37 w in predicting centile [34]. In early 2nd trimester (15 w), serum levels of
delivery within two weeks is better for SGA <3rd (83%; 95% PAPP-A, PlGF, and insulin are significantly lower in SGA
CI 80–86) than for SGA <10th (69%; 95% CI 67–71) [76]. pregnancies [79], while increased plasma levels of vascular
Although EFW <10th centile is related to a higher risk of any growth factor (VEGF) between 34 and 37 weeks were related
adverse perinatal outcomes [77], it demonstrates poor to a lower chance of restricted fetuses (OR 0, 8; 95% CI 0,
prediction performance (26%; 95% CI 28–30; for SGA <3rd 71–0, 92) [80]. Conversely, a model built by EFW, UtA-PI,
delivering in 2 w) [76]. In another example, Triunfo et al. and PlGF at 35–37w has provided an AUC 0.883 (95% CI
have demonstrated better prediction performance of EFW at 0.867–0.899) [81].
37 w for SGA <3rd (0.85; 95% CI 0.82–0.89), when compared PlGF has consistently lower levels in SGA pregnancies,
to the 4–10th centiles (0.93; 95% CI 0.89–0.97) but reached a in 2nd and 3rd trimesters [82–84], especially for BW < 5th or
disappointing AUC of 0.54 (95% CI 0.48–0.61) for pre- <10th centiles. For higher sFlt-1/PlGF ratios, there is better
dicting adverse perinatal outcomes [32]. This is also true for AUC for preeclampsia-associated SGA [40, 41]. These
AC cross-sectional evaluation at 32 w seemed compared to findings point in the direction of angiogenesis-mediated
ACGV (difference from 32 w results and 2nd trimester) [72]. pathophysiology of SGA, especially when there are Doppler
The detection rate (DR) of SGA <10th centile was 49.1 (95% abnormal parameters [37]. Unfortunately, PlGF shows poor
CI 44.2–52.8; false positive rate, FPR, 10%) and 81.2 (95% CI accuracy to be implemented in clinical practice: the com-
75.3–88.1) for SGA <3rd centile or suspected before birth by bined AUC was 0, 66 (95% IC 0, 44–0, 87) for FGR pre-
abnormal Doppler results. This finding partially contradicts diction [65]. Perhaps, this finding is due to the diverse PlGF
the Pregnancy Outcome Prediction (POP) Study, which measurements and FGR definitions used by the studies
found a relative risk of 17.6 (95% CI 9.2–34.0) for delivering included in the systematic review, which considered either
The Scientific World Journal 5

the estimated fetal weight, birth weight, or the presence of hPL: Human placental lactogen
additional findings of severity (e.g., oligohydramnios). HR: Hazard ratio
After all, better accuracy was achieved by combining IUGR: Intrauterine growth restriction
multiple maternal, ultrasonographic, and biochemical clinical LMIC: Low- and middle-income countries
factors. In an international cohort of nulliparous women [79], MCA: Middle cerebral artery
PlGF has had an AUC of 0.84 (95% CI 0.78–0.89) for hy- MRI: Magnetic resonance imaging
pertensive-SGA when combined with smoking, proteinuria, NT: Nuchal translucency
uterine artery Doppler, PAPP-A, and triglycerides. In the 2nd PAPP-A: Placental protein-A
trimester (19–24 w), PlGF and AFP, combined with maternal PlGF: Placental growth factor
factors and fetal biometry, made up an AUC of 0.96 for birth POP: Pregnancy outcome prediction
below 32 weeks in SGA newborns [31]. RI: Resistance index
ROC: Receiver operator characteristic
4. Conclusions SFH: Symphysial fundal height
SGA: Small for gestational age
Fetal growth restriction is related to adverse outcomes in the UA: Umbilical artery
perinatal period, childhood, and adulthood; the estimated US: Ultrasound
actual burden of SGA [13, 25] might be even higher in the UtA-PI: Uterine artery pulsatility index
next few years. Starting antenatal care at early pregnancy UVBF: Umbilical vein blood flow
leads to adequate risk management and additional evalua- VEGF: Vascular growth factor.
tion assessment, with US or biomarkers. The “inverted
pyramid” of prenatal care claims attention to the early
pregnancy risk evaluation [85], and we strongly believe Disclosure
screening is the first step towards a better disease diagnosis This manuscript is part of the PhD thesis of Debora F Leite
and management. Screening for FGR is a major cornerstone under the tutorial of Jose G. Cecatti, presented to the
for coordinating care from pregnancy to the postpartum Postgraduate Program of Obstetrics and Gynecology from
period, which affects both maternal and fetal/neonatal the University of Campinas, Brazil. The content is solely the
outcomes [86]. The low velocity in which stillbirth and responsibility of the authors and does not necessarily rep-
neonatal death rates have decreased in the past 30 years is an resent the official views of CAPES. It did not influence the
“unfinished agenda” [86]. content of the manuscript. CAPES had no role in the au-
Although the cost-effectiveness of short-term preg- thors’ decision of drafting or submitting this manuscript.
nancy-related adverse outcomes is still a matter of debate
[87], little is known about the future consequences of a
health policy devoted to primary prevention of pregnancy- Conflicts of Interest
associated illness in a long-term [49, 59, 88]. On the con-
trary, the lack of definition of a high-risk group of women The authors declare that there are no conflicts of interest at
that could benefit from a more directed approach delays all.
scientific and clinical evaluation of SGA. As maternal factors
have a different magnitude between settings and placental Authors’ Contributions
biomarkers are not a reality in most LMIC countries, cur-
rently, the 3rd trimester US seems the best approach for SGA DFBL has proposed the review and drafted the first man-
prediction [44]. In near future, we envision an integrated uscript. JGC has supervised and checked the drafting. Both
approach of pregnant women at booking [85], aiming a authors have read and agreed with this submission.
transgenerational [49] effect of long-term health, both at
individual and populational levels. Acknowledgments
Abbreviations The authors kindly thank Prof. Renato Passini Júnior and
Prof. Maria Laura Costa for their pertinent suggestions to
AC: Abdominal circumference this manuscript. DFBL was supported by the Brazilian
AFP: Alpha-fetoprotein Federal Agency for Support and Evaluation of Graduate
AUC: Area under the curve Education (CAPES; process number 88881.134512/2016-01)
BW: Birth weight while visiting the University College Cork (Cork, Ireland).
CPR: Cerebral-placental ratio
DOR: Diagnostic odds ratio
DR: Detection rate References
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