Population description
Following exclusions, we considered 67,968 deliveries for the analysis.
Table S1 summarizes each country’s contribution to the overall
population. The median maternal age was 26 (IQR: 22 – 31) years, with
differences across countries. There were also differences in nulliparity
rate, ethnicity, and educational level. The median gestational age at
delivery in the study population was 39.5 (IQR: 38.5 – 39.5) weeks. The
rate of preterm delivery was 7.9% (5359/67,968). The proportion of
neonates classified as SGA was significantly different between the two
standards. The WHO growth standard classified the neonates as follows:
at or above the 10th percentile: 58,542 (86.1%) and
SGA: 9426 (13.9%), while for IG-21st, 63,244 (93%)
neonates were at or above the 10th percentile, and
4724 (7%) neonates were identified as SGA. Thus, the rate of neonates
classified as SGA by the IG-21st was almost two times
lower than that classified by the WHO (7 vs. 13.9%, p<0.001).
Similarly, the proportion of neonates classified as FGR was
significantly different between the two standards. The WHO growth
standard classified the neonates as follows: at or above the
3rd percentile: 63,730 (93.8%) and FGR: 4238 (6.2%),
while for IG-21st, 66,517 (97.9%) neonates were at or
above the 3rd percentile, and 1451 (2.1%) neonates
were classified as FGR. Thus, the rate of neonates classified as FGR by
the IG-21st was almost three times fewer than that
classified by the WHO (2.1% vs. 6.2%, p<0.001).
Figures 1A and 1B are Venn diagrams describing the classification of
newborns according to the percentiles of each standard (at or above the
10th percentile vs. SGA and FGR) using both standards
simultaneously. Specifically, 86.1% (58,523/67,968) were considered at
or above the 10th percentile by both standards, 6.95%
(4721/67,968) of neonates were classified as SGA only by the WHO
standard (SGA-WHO only), 0.03% (19/67,968) of neonates were classified
as SGA only by the IG-21 standard (IG-21st- only), and
6.92% (4705/67,968) were classified as SGA by both standards (Figure
1A). All neonates identified as SGA by IG-21st alone
were preterm births. With respect to FGR, 93.7% (63,718/67,968) were
considered above the 3rd percentile by both standards,
4.1% (2799/67,968) of neonates were classified as FGR only by the WHO
standard (FGR-WHO only), 0.02% (12/67,968) of neonates were classified
as FGR only by the IG-21 standard (IG-21 only), and 2.1% (1439/67,968)
were classified as SGA by both standards (Figure 1B).
Table 1 describes clinical characteristics and perinatal outcomes for
pregnancies assigned as SGA and FGR by WHO standard alone, by both
standards, and those classified as at or above the
10th percentile for both curves. The rate of preterm
delivery was higher in the newborns classified as FGR by WHO alone and
by both standards than in those classified as above the
10th percentile by the two standards (all p values
<0.001). However, the rate of preterm delivery was
significantly higher in those classified as SGA by the two curves than
in those classified as AGA (16.3% vs. 7.32%, p<0.05). In
addition, there were significant differences in the cesarean section
rate among the groups, being significantly higher in neonates classified
as SGA and FGR by both standards compared to those classified as above
the 10th percentile by the two standards (59.4% vs.
46.2%, p<0.001) (Table 1).
The rate of a low APGAR score was significantly higher for neonates
classified as SGA and FGR by both standards (1.51% and 2.64%,
respectively), followed by neonates classified as FGR only by the WHO
(0.82%), being significantly lower in neonates classified as at or
above the 10th percentile by both curves (0.46%).
Notably, there were no significant differences in the rate of low APGAR
scores between those neonates classified as SGA only by WHO and neonates
classified as at or above the 10th percentile by both
curves (0.40% vs. 0.46%, p=0.64, Table 1). Figures 2A and 2B show the
RRs for a low APGAR score or ponderal index, respectively, in neonates
identified as SGA and FGR. Neonates classified as SGA and FGR by both
standards exhibited the most significant RR for an APGAR score below
seven at five minutes (RR: 3.27; [95% CI: 2.52 – 4.24], and 5.57
[3.99 – 7.78], respectively). Importantly, neonates classified as
SGA only by WHO alone did not have a significantly higher risk of a low
APGAR score (RR: 0.87; 95% CI: 0.55 – 1.39) (Figure 2A).
The median ponderal index was significantly lower in the group of
neonates classified as SGA and FGR by both standards than in those
classified as above the 10th percentile by both
standards (FGR by both standards: 22.5 [IQR: 20.6 – 24.7] & SGA by
both standards: 23.5 [IQR: 21.7 – 25.4] vs. 26.7 [24.9 –
28.6]; all p values <0.001). Similarly, the rate of a
ponderal index below the 5th percentile was
significantly higher in these groups. Neonates classified as SGA and FGR
by both standards exhibited the most significant RR for a low ponderal
index (RR: 11.95; [95% CI: 10.7 – 13.4], and 14.9 [13.2 –
16.8], respectively) (Figure 2). Furthermore, neonates classified as
SGA only by WHO alone also had a significantly higher risk of a low
ponderal index (RR: 4.75; 95% CI: 4.1 – 5.53) (Figure 2B). Finally,
the cephalization index was significantly higher in neonates classified
as SGA by WHO alone and in those classified as SGA and FGR by both
standards, displaying, in addition, a trend toward worst values in the
latter groups (Table 2). Table S2 shows the odds ratios of SGA by each
standard for neonatal outcomes under a hierarchical logistic regression
model. In brief, we found that SGA babies only by WHO had an OR of 0.98
(95% CI: 0.61 – 1.57) for a low APGAR score at five minutes and 4.14
(95% CI: 3.52 – 4.86) and a ponderal index below the
5th percentile, respectively.
Table 2 displays the diagnostic performance of the WHO and
IG-21st for identifying an APGAR score below seven at
5 minutes and a ponderal index below the 5thpercentile. Both charts exhibited low sensitivities for low Apgar scores
(below 30%) and high specificity. We next assessed the diagnostic
effectiveness of both fetal growth charts for specific obstetric
outcomes, demonstrating that the IG-21st had the
highest diagnostic odds ratios (DORs) (Table 2). As an overall measure
of diagnostic performance for a low Apgar score, the diagnostic odds
ratio was higher when SGA (3.70 vs. 2.02, mean difference: 0.61, 95%
CI: (0.45 – 76.6), p <0.001) and FGR (6.22 vs. 3.01, mean
difference 0.72, 95% CI: (0.48 – 0.96), p <0.001) were
defined by IG-21st than by WHO charts. Similarly, the
diagnostic odds ratio for a low ponderal index was also higher when SGA
(10.4 vs. 9.01, mean difference 0.14, 95% CI: (0.06 – 0.23) p-value =
0.001) and FGR (14.6 vs. 10.6, mean difference 0.32, 95% CI: (0.2 –
0.42) p<0.001) were defined by IG-21st than
by WHO charts. When we applied both fetal growth charts for the
identification of a low APGAR score and ponderal index, the
IG-21st fetal growth charts marginally improved the
prediction of a low APGAR score based on the area under the receiver
operating characteristic (ROC) curve (AUC), estimated using 2,000-fold
bootstrapping to account for overfitting (Table S3). Specifically, for
low APGAR scores, the AUC of the identification of SGA neonates for WHO
fetal growth charts were 55.3 (95% CI: 53.1 – 57.5) vs. 57.3 (55.2 –
59.4) for IG-21st, p =0.005 (two-sided) (Table
S3).