Main findings
In this prospective longitudinal study, we have found that AGA fetuses who display low third trimester growth velocity exhibit antenatal, intrapartum and neonatal features suggestive of placental insufficiency. We report significant correlations between growth velocity and low CPR, reflective of fetal cerebral blood flow redistribution and increased placental resistance during pregnancy, development of acidosis under the hypoxic challenge of labour and reduced neonatal body fat stores. These clinical indicators of placental insufficiency are also associated with fetuses born SGA [
5,
8,
9,
25], who have three- to four-fold increased risk of stillbirth [
1,
3,
4]. Thus, the implications of our findings are that AGA fetuses that decline in growth trajectory may also be suffering from placental insufficiency, placing them at increased risk of stillbirth.
Interpretation of the findings and comparison with other studies
The only other study to examine fetal growth velocity exclusively among AGA fetuses was our previous pilot study [
22]. In 48 participants, our pilot study analysed the relationships between fetal growth velocity and both cerebral redistribution and operative delivery for suspected intrapartum compromise, but did not assess the associations with UA pH < 7.15 after labour, or neonatal BF% [
22]. Our pilot study led us to undertake this larger study, with expanded power and examination of more sophisticated measures of placental insufficiency.
Other studies have reported associations between reduced growth velocity and adverse perinatal outcome [
26‐
29], but have included SGA infants, who are known to have an increased risk of stillbirth. Notably, the Pregnancy Outcome Prediction (POP) study found low AC growth velocity to predict for adverse outcome in SGA fetuses, but not in the AGA [
26]. However, in contrast to our study, the POP study did not investigate for cerebral redistribution, did not assess neonatal body composition, and did not evaluate EFW growth velocity. Furthermore, the POP study did not examine AC growth velocity as a continuous variable, while we consistently found significantly increased odds of placental insufficiency indicators when AC, and EFW, growth velocities were analysed in this way. A recent, large retrospective study also investigated AC growth velocity and the CPR. In keeping with our results, a low CPR was significantly associated with a low AC growth velocity, birthweight centile and operative delivery for presumed fetal compromise, even when analysis was confined to AGA fetuses [
30].
That AGA fetuses with a declining growth trajectory may be at increased risk of stillbirth is supported by epidemiological data. The lowest rate of perinatal death occurs amongst those with birthweight between the 75th and 90th centiles [
31,
32], with perinatal mortality significantly increasing at every centile below the 50th. Compared to the 75th to 90th centile group, the adjusted odds for perinatal death are doubled for those with birthweight of 10th to 25th centile, and for those born between the 25th and 50th centiles the adjusted odds ratio is increased, at 1.58 [
31]. This stepwise increase in perinatal death with falling birthweight centile, even among the AGA, may in part be explained by placental insufficiency causing reduced growth velocity. That placental insufficiency plays a role is further supported by a progressive decrease in CPR seen with falling birthweight centile [
33], mirroring perinatal death rates [
6]. In the setting of poor placental function, fetal growth slows, but whether the final birthweight falls below the 10th centile depends upon the starting fetal weight centile, the severity of placental insufficiency and the duration of fetal exposure to placental insufficiency (determined by gestation at onset and birth).
It is not surprising that 81% (21/26) of the fetuses exhibiting low EFW third trimester growth velocity in this study had a customised birthweight between the 10th and 50th centiles – placing them within the range of significantly increased risk of perinatal death. However, 40% of all fetuses would be expected to be born with a birthweight within this range, so this categorisation would perform poorly as a predictive test of adverse outcome. In contrast, an EFW growth velocity of < –30 centiles over 8 weeks occurred in only 8.4% of AGA fetuses. Therefore, this may be a clinical tool with better predictive value in detecting the AGA fetus suffering placental insufficiency, at risk of stillbirth.
The clinical significance of reduced fetal growth velocity has been addressed in a recently published expert consensus definition of FGR. The International Society for Ultrasound in Obstetrics and Gynaecology definition of FGR now includes “AC/EFW crossing centiles” (defined as > 2 quartiles or 50 centiles) as long as it occurs in a SGA fetus (<10th centile EFW or AC), and/or in conjunction with a low CPR or elevated UA PI [
34]. However, our findings support a more conservative threshold – of a fetus declining by an equivalent of > 30 EFW or AC centiles over 8 weeks – given the significant associations with robust measures of placental insufficiency we have demonstrated. A > 50 centile reduction occurred in only eight (2.6%) of our AGA study participants, and if the consensus definition’s SGA and/or abnormal Doppler criteria were also applied to our initial cohort, then only 1.4% (5/347) of fetuses would have been detected. This may mean that a number of AGA fetuses with placental insufficiency, who may be at risk of stillbirth, would be missed if a > 50 centiles threshold was utilised.
Strengths and limitations
A major strength of this study is the examination of multiple and diverse measures of placental insufficiency across the antenatal, intrapartum and neonatal periods. The antenatal feature of placental insufficiency used was the CPR at 36 weeks. The fetus adapts to hypoxia by preferentially perfusing the cerebral vasculature, which, together with what may be subtle increases in placental resistance, result in a low CPR. The CPR is the most sensitive ultrasound measure in late pregnancy [
5] and is associated with the development of fetal decompensation and acidosis in labour [
30,
35‐
39], neonatal unit admission [
36], and stillbirth [
40]. Umbilical artery pH is the most reliable and objective measure of intrapartum fetal compromise, and has the best correlation with key perinatal outcomes [
41], including neonatal mortality, hypoxic ischaemic encephalopathy and cerebral palsy [
19]. Finally, placental insufficiency results in reduced substrate supply and neonatal body fat among SGA infants [
9]. Ponderal index and skinfold thickness are widely used as anthropometric methods to diagnose impaired fetal growth, but ADP used to assess BF% is the gold standard for the assessment of newborn body composition [
21]. ADP is more accurate than dual-energy X-ray absorptiometry [
42,
43], and demonstrates better prediction of neonatal morbidity than birthweight centile [
24].
There were a number of other strengths to our study. This was a prospective study of large numbers; customisation of EFW and birthweight centiles was performed as customised centiles share a stronger association with adverse perinatal outcomes than population references [
44]; we interrogated fetal growth velocity using two approaches (EFW and AC); we obtained evidence to counter the possibility of selection or recruitment bias; and we demonstrated low inter- and intra-observer variation between ultrasound operators.
The main limitation of our study is that it was not powered to detect important but uncommon perinatal outcomes such as stillbirth or significant neonatal morbidity. In addition, the rate of low third trimester growth velocity (EFW velocity of < –30 centiles) was 7.6% among our entire cohort of AGA and SGA fetuses, which was lower than the 19% demonstrated in our pilot study [
22]. Further, we did not manage to collect an umbilical arterial cord gas from every study participant. Finally, the rate of neonatal acidosis was higher than anticipated (9% vs. 6%) among AGA infants who maintained their growth velocity [
8]. As such, we were underpowered to detect the 3.8-fold increased rate of neonatal acidosis among the low growth velocity cohort as originally intended. However, a trend towards this outcome was seen, and we were able to demonstrate a significant 3.5-fold increased neonatal acidosis risk among those with a EFW growth velocity of < –35 centiles. Overall, our cohort was small, and thus our results should be validated in a larger study.
Clinical and research implications
Our data raises the possibility that serial ultrasound growth assessments may have a role in the clinical management of pregnancy. However, there remains debate about universal ultrasound for all pregnant women at 28 and 36 weeks’ gestation given the significant cost implications and that we are yet to demonstrate improved clinical outcomes. However, for women already assessed by serial ultrasound due to risk factors, our data suggests that AGA fetuses who demonstrate a significant decline in growth trajectory may warrant increased surveillance and management, as might be instituted in cases of a SGA fetus with presumed placental insufficiency. Furthermore, our data may be used to inform the design of an appropriately powered interventional study to elucidate the value of enhanced fetal surveillance and timely birth for AGA fetuses with low third trimester growth velocity.