Introduction

To understand any discussion, it is of paramount importance to be consistent in defining the discussed subject. This is a particular problem when dealing with impaired fetal growth. Even though the measurement of fetal size has significant challenges of its own, comparing this measurement to previously observed variation in a population provides a comparison to a reference standard that is measurable and agreed upon. However, “smallness” or being small for gestational age (SGA) in itself is not the item of interest, but rather “pathological smallness of uteroplacental origin” – otherwise termed fetal growth restriction (FGR). FGR is a functional problem of unmet fetal need, and the definition should include descriptions of pathological functional processes.

FGR is a descriptive term for a pathological process and not easily defined. FGR can be described as the process where a fetus that has a certain growth potential based on genetic criteria is limited in its growth because of a pathological environmental influence. It is distinct from the term small for gestational age (SGA). SGA is much easier to define because it is a statistical deviation from a population reference standard.

As such, many studies erroneously assume that SGA is synonymous with FGR. Because overlap between the two subgroups is significant, this is a tempting strategy that does still come up with results. However, this assumption may attenuate or even obscure important associations or identify spurious associations that may be misleading. In this chapter, the pathophysiology of FGR is shortly discussed and FGR is defined by functional parameters and compared to definitions of SGA.

Pathophysiology of Uteroplacental Insufficiency

The classical pathophysiological concept of FGR is that of poor placentation. In early pregnancy, the uterine spiral arteries are invaded by the developing endovascular trophoblast, resulting in uteroplacental blood circulation. In adequate placentation, the uterine spiral arteries are remodeled into dilated inelastic tubes without maternal vasomotor control. This is a process that probably occurs between 8–18 weeks of pregnancy [1]. The physiological consequence of vascular remodeling is that a low-resistance unit is accomplished that allows liberal blood flow. If this process is imperfect, the disturbed remodeling will not change the high-resistance unit adequately, leading to the maintenance of high uteroplacental vascular resistance. This can be measured in early pregnancy, by Doppler measurements of the upstream uterine artery. High pulsatility indices already in the first trimester reflect an increased risk for clinical disorders related to poor placentation: fetal growth restriction and preeclampsia [2,3].

The pathophysiological pathways for this defective placentation process are plentiful and none is completely explanatory in itself. Immunological factors, endogenous vascular factors, and thrombogenic factors have been shown to have consistent relationships with the process and the clinical phenotype [1]. Most of these theories were derived from work restricted to cases of preeclampsia. Since most of the pathophysiology on the placental level is shared between hypertensive disorders of pregnancy and FGR, some of this knowledge can be extended into the field of FGR.

Poor placentation is particularly associated with early-onset phenotype of both preeclampsia and FGR. Before 34 weeks’ gestation, most women presenting with maternal hypertensive disorders will also have FGR – and both conditions share comparable placental pathology [4]. At later gestations, this association becomes less obvious – at or near term, neonates from mothers with preeclampsia are usually not growth-restricted [5]. Thus, both late FGR and late preeclampsia require another explanation. For this, some hypothesize a secondary placental cause based on the evidence that slowing of placental growth in term pregnancy is more prominent in the largest placentas [1]. This finding suggests that placental growth has a physical limit, depending on size and not gestational age. At term, the placenta apparently becomes more “crowded,” compromising intervillous perfusion and predisposing to dysfunction – leading to a similar process as in early-onset FGR and preeclampsia. For the maternal phenotype, the most likely etiology is maternal constitutional susceptibility, among which are (cardio)vascular dysfunction [6,7] and an excessive immunological response [8]. These findings, negating early placentation disorders as an explanation for late FGR and late preeclampsia, are consistent with the finding that the placental pathology in term FGR and preeclampsia is not very discriminative between cases and normal controls [9]. Since term fetuses have less placental reserve capacity, the interval between onset of the disease and subsequent adverse outcome is shorter. Both hypotheses explain why late-onset FGR is less easy to predict and harder to distinguish from pregnancies with normal growth.

In conclusion, it is likely that there are two main routes to FGR based on placental dysfunction or insufficiency. The first is the classic concept of defective placentation leading to early-onset overt FGR, which is easily diagnosed because of abnormal fetal size and related biophysical/biochemical parameters. The second concept is that of a maturational process leading to placental hypoperfusion and late-onset FGR that is difficult to diagnose because size and accompanying parameters may not be severely abnormal. Combinations of the two can also occur, explaining intermediate phenotypes.

Definition of SGA

SGA is a defined statistical deviation from the population standard. Antenatal measurement variation for fetal, maternal, or observer reasons does introduce some uncertainty, but the comparison with a reference standard is a rather uniform practice. Reference ranges (as opposed to standards) are population curves constructed from observed fetal dimensions on ultrasound and birth weights. These ranges are usually normally distributed, because the majority of cases do not have pathological growth. However some skewing may occur, particularly at lower gestational ages and at the lower margin of the curve, where pathological growth is more common. When the charts are constructed prospectively using strict criteria to define an “optimal” population, then “optimal” reference standards are created, such as in the recent Intergrowth-project [10].

In obstetric populations, centiles usually describe the position of a fetus/newborn within the curve. Within a perfectly normally distributed population, this has large commonalities with the more statistically correct standard deviation scores (SD or z-scores) where the position is expressed as the number of standard deviations the fetus/newborn is from the mean. An alternative option, less statistically correct but with some clinical and statistical advantages, is the weight ratio – the ratio between the observed weight and the median weight for the gestational age (multiples of the median or MoMs).

Defining SGA is a dichotomization within the chosen curve. In most studies, the 10th and 90th centiles are chosen as the cut-off, defining those below the 10th centile as SGA. Other commonly used cut-offs are the 5th centile or the 2.3rd centile. With lowering of the chosen cut-off, the concentration of pathology within the defined group increases. However, because there are no thresholds to distinguish normal growth from pathological growth, no specific cut-off will define a totally abnormal or normal population correctly [11].

Definition of FGR

The definition of FGR is more difficult because the gold standard is not defined. Thus, all attempts focus on defining the process where a fetus with a certain genetic growth potential is limited in its growth because of a pathological environmental influence. This pathological influence is frequently termed uteroplacental insufficiency to express that the limitation is located in the transfer of nutrients and waste substances across the placenta. Thus, it is abnormal placental function that needs to be defined accurately in FGR. There are several candidates of measurable parameters to signal impaired placental function and abnormal fetal growth. These parameters have different statistical time relationships with the occurrence of fetal distress (Figure 2.1) [12].

Figure 2.1 Trends over time of variables in relation to time before delivery and reference ranges (±2 SD) for Group 1 (fetuses delivered before or at 32 weeks of gestation). ___, umbilical artery; ___, ductus venosus; ___, aorta; ___, inferior vena cava; ___, short-term variation; ___, middle cerebral artery; ___, amniotic fluid index.

Source: Reproduce Figure 3 with permission from Hecher et al. [12].

Figure 2.2 PIGF concentrations in the circulation of women with placental IUGR/FGR fetuses, constitutionally small fetuses, and normal pregnancies at the time of sampling. Constitutionally small fetuses (red triangles) and normal pregnancy controls (black squares) had increased PIGF levels compared with placental IUGR/FGR cases (blue triangles). The gray dashed black line represent the fifth percentile PIGF concentration cutoff according to the product insert. The y-axis is log transformed. Two blue triangles overlap at 33+2 weeks’ gestation because of the sampling of these women occurring at the same gestational age.IUGR, intrauterine growth restriction; PIGF, placental growth factor.

Figure reproduced with permission from Benton et al. [23].

Figure 2.3 Fitted 3rd, 50th, and 97th smoothed centile curves of fetal measurements.

Fitted 3rd (bottom dashes line), 50th (middle dashed line), and 97th (top dashed line) smoothed centile curves for fetal abdominal circumference measured by ultrasound according to gestational age. Open red circles show empirical values for each week of gestation and open grey show actual observations.

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