Results
Overall, 8,339 pregnancies were eligible for analysis (Figure 1). The
most common reasons for exclusion were delivery beyond 41 weeks (n=897)
and loss to follow-up at delivery (n=353). An additional 1,059
participants were excluded from derivation of the fetal growth equation
for complications known to be associated with abnormal growth.
Therefore, 7,280 participants were included in a lower-risk nested
cohort for the primary analysis to derive a sex-specific fetal growth
standard, with 80% of people contributing 3 measurements, 19%
contributing 2 measurements, and 1% contributing one measurement. The
distribution of weight assessments across gestation is illustrated in
Figure 2a. Because study ultrasounds were occasionally performed later
than planned, EFW measurements extended to 34 weeks, with nearly all
being completed before 32 weeks (Fig 2a). Characteristics of the study
population are described in Table 1.
First, a longitudinal equation of fetal growth was generated without
accounting for fetal sex. When we derived a separate equation for each
sex, both had similar parameter estimates (Supplemental Table S1). We
then estimated a single equation with fetal sex included as a three-way
interaction term. The interaction was not significant, (p=0.48), and was
removed. In an equation with two-way interactions parameterized with
sex, neither the quadratic term for gestational age and sex nor the main
effect for gestational age and sex were significant (p=0.48 and 0.69,
respectively), so both were removed. When sex was accounted for using a
sex-specific intercept, it was statistically significant
(p<0.001). From this point forward in the analysis, we used
the following sex-specific equation: LN(expected weight) = 0.6325 +
0.03324[if male] + 0.3305*GA -0.00359*GA^2. The sex-neutral and
nuMoM2b sex-specific curves are plotted in Figure 2b with the
accompanying formulas in Figure 2c. Across all gestational ages, the
standard deviation of fetal weights was ±11.38% of the expected weight,
such that the formula for fetal weight z score could be expressed asz = (weight – expected weight) / (expected weight*0.1138). The
aforementioned iterations of the final fetal growth equation are
available in the appendix (Table S2).
When we applied the sex-neutral and sex-specific standards to the
cohort, we found that the sex-neutral standard labeled significantly
more female newborns as SGA than male (21% vs 13%, p<0.001),
whereas the sex-specific standard did not (9% vs 10%, p=0.23). The
sex-neutral standard labeled significantly more male newborns as LGA
than female (5% vs 3%, p<0.001), while the sex-specific
standard did not (13% vs 13%, p=0.58). Rates of SGA by the
sex-specific standard were the same as when using a national
sex-specific birth weight standard while rates of LGA were higher
(Supplemental Figure S2).
For our secondary objective to assess intervention measures and
outcomes, we included the whole eligible cohort (N=8,339) in order to
better represent an unselected population (Figure 1). The distribution
of weights across gestation in this full unselected cohort are
illustrated in supplemental Figure S1. Of the 1,498 newborns classified
as SGA by the sex-neutral standard, 591 (39.5%, 95% CI 37.0 – 42.0%)
were reclassified as AGA by the sex-specific standard. Conversely, of
the 5,753 considered AGA by the sex-neutral standard, only 5 (0.09%,
95% CI 0.03-0.2%) were reclassified as SGA by the sex-specific
standard.
When analyzed by sex, female newborns reclassified from SGA to AGA by
the sex-specific standard had lower rates of the composite perinatal
morbidity and similar rates of cesarean delivery for “non-reassuring
fetal status” as the group considered AGA by both standards, despite
being more likely to receive a prenatal diagnosis of FGR, to be admitted
for labor and delivery for FGR, and to be delivered for FGR
(p<0.001 for all 3 comparisons, Table 2a). Male newborns
reclassified from SGA to AGA by the sex-specific standard had comparable
rates of the composite perinatal morbidity to the group considered AGA
by both standards. However, they were more likely to be diagnosed with
FGR before birth, to be admitted to labor and delivery for FGR, to be
delivered for FGR than male newborns considered AGA by both standards,
and to undergo cesarean for “non-reassuring fetal status”
(p<0.05 for all four comparisons). Neither female nor male
fetuses who were reclassified from SGA to AGA by the sex-specific
standard experienced higher rates of scheduled delivery before 39 weeks
compared to those considered AGA by both standards (Table 2a). Due to
the small number reclassified from AGA to SGA by the sex-specific
standard (n=5, all male), we did not perform a pairwise comparison of
this group against the group that were AGA by both standards. However,
it is noteworthy that all 5 newborns reclassified as SGA by the
sex-specific standard that would be considered AGA by the sex-neutral
standard experienced the composite morbidity outcome (Appendix, Table
S3). Comparisons across all possible growth classifications are
available in the Appendix (Tables S3, S4).
We also assessed outcomes according to LGA classification by sex-neutral
and sex-specific standards using the whole eligible cohort (N=8,339). Of
the 6,485 newborns classified as AGA by the sex-neutral standard, 737
(11.4%, 95% CI 10.6 – 12.2%) were reclassified as LGA by the
sex-specific standard. Conversely, of the 351 considered LGA by the
sex-neutral standard, none were reclassified as AGA by the sex-specific
standard.
Both male and female newborns reclassified from AGA to LGA by the
sex-specific standard had comparable rates of perinatal morbidity to the
group considered AGA by both standards. However, their births were more
likely to be complicated by cesarean delivery for arrest of descent,
cesarean delivery for arrest of dilation, and shoulder dystocia. Female
newborns reclassified as LGA also had a higher rate of brachial plexus
injury, whereas male newborns did not (Table 2b).