Methods
We conducted a secondary analysis of the prospective observational
Nulliparous Pregnancy Outcomes Study: monitoring mothers-to-be
(nuMoM2b), which has been described in detail
elsewhere.16 Briefly, 10,038 pregnant participants
were recruited from 8 U.S. clinical centers between 2010 and 2013.
Recruitment was of singleton pregnancies with a 1sttrimester ultrasound and no prior deliveries beyond 20 weeks’ gestation.
Study visits occurred at 6 0/7 – 13 6/7 weeks (visit 1), 16 0/7 – 21
6/7 weeks (visit 2), and at 22 0/7 – 29 6/7 weeks (visit 3) and
included collection of clinical parameters, ultrasound, and detailed
questionnaires. Outcomes were ascertained by medical record abstraction
after birth. Ultrasounds generating EFWs using biparietal diameter, head
circumference, abdominal circumference, and femur length took place at
visits 2 and 3. EFW was calculated using the 4 fetal biometric
parameters.17 The nuMoM2b study was approved by
ethical review committees at participating institutions and was
registered at clinicaltrials.gov (NCT01322529).
Our analysis included nuMoM2b participants who delivered at or beyond 24
weeks’ gestation with available delivery information. We excluded
participants who underwent pregnancy termination, had missing key
information, newborns not assigned a sex at birth, born after 41 weeks
when birth weight percentile could not be calculated, or with
implausible fetal weight measurements. From these, we selected a nested
cohort of lower-risk participants to carry out our primary objective to
derive a prescriptive, sex-specific fetal growth standard. For this
nested cohort, we excluded those with pregnancies affected by several
complications known to be associated with poor fetal growth, including
preterm birth, preexisting hypertension, pre-gestational diabetes,
suspected chromosomal or fetal anomalies, or stillbirth. To carry out
our secondary objective to assess the sex-specific standard, we used the
full cohort, including participants initially excluded for risk factors
for abnormal growth so as to approximate an unselected population that
would be more generalizable to clinical practice. Therefore, the
analysis to address our second objective was carried out using the full
eligible cohort and only excluded those missing key variables or whose
pregnancies ended prior to 24 weeks.
Our primary endpoint was birth weight percentile. SGA was defined as
birth weight <10th percentile, LGA was
defined as birth weight >90th percentile,
and appropriate for gestational age (AGA) was defined as birth weight
10th-90th percentile. Because the
primary endpoints utilize birth weight, all weights
<10th percentile are referred to as “SGA”
in this analysis and “FGR” is only used when referring to nuMoM2b
variables reflecting a prenatal diagnosis.
The Hadlock formula was used as the referent sex-neutral standard to
calculate weight-for-age percentiles, which were applied to both EFWs
and birth weights in order to maintain continuity between weights
measured before and after delivery. Hereafter, the Hadlock standard is
referred to as the “sex-neutral” standard. Birth weight percentiles
were also assigned using the Olsen standard, a national sex-specific
birth weight reference.8
To complete our primary objective, we used the lower-risk nested cohort
to derive a prescriptive sex-specific fetal growth standard. To do this,
we regressed EFWs and birth weights on fetal sex and weeks’ gestation
using a longitudinal mixed-effects regression model to estimate an
equation representing fetal growth. Two equation parameterization
approaches were assessed; first, using fetal sex as an interaction term
to determine whether a separate equation was needed for each sex;
second, using sex as an intercept only, which uses the same equation for
both sexes but from different starting points. Our equation was modeled
after the Hadlock approach because of its simplicity and ease of
clinical use. The Hadlock method calculates a z score for the difference
between the observed and expected weight and transforms the z-score into
a percentile.11 The standard deviation for estimated
fetal weight was calculated from an approach mirroring that from the
original Hadlock publication. For each week of gestation, the residual
standard deviation as a percent of the predicted weight was calculated.
The average of percent residual standard deviation across weeks is
reported as the standard deviation of fetal weights. Once the
sex-specific, longitudinal equation was finalized, percentiles were
calculated for birth weights using the new sex-specific standard, the
sex-neutral standard, and the Olsen birth weight standard, comparing the
proportion of SGA and LGA newborns by fetal sex using each. Rather than
assume that male and female fetuses should automatically have the same
proportions of SGA or LGA, we used a validated sex-specific birth weight
standard (Olsen) as a reference for the expected rates of SGA and LGA
for each sex.
Our secondary objective was to compare metrics of clinical outcomes and
management according to growth status using sex-neutral versus
sex-specific growth standards in an unselected cohort. To do this, we
used the full eligible cohort. We then compared interventions and
perinatal outcomes between two size classifications: newborns designated
as AGA by both sex-neutral and sex-specific standards, and newborns
whose growth status was reclassified by the sex-specific standard. This
comparison was performed separately for male and female fetuses as well
as for SGA and LGA.
Two types of clinical measures were used to assess the sex-specific
growth standard. First, we assessed a composite of perinatal morbidity,
which was defined as stillbirth occurring ≥ 24 weeks, need for
mechanical ventilation, neonatal death before discharge, NICU stay
> 48 hours, confirmed sepsis, respiratory distress
syndrome, seizures, necrotizing enterocolitis (NEC), and
intraventricular hemorrhage (IVH). Second, we selected measures that
were specific to SGA and LGA to assess the clinical relevance of the
sex-specific standard. Measures specific to SGA included admission to
labor and delivery for FGR, delivery for FGR, clinical suspicion of FGR
before delivery, scheduled labor induction or cesarean without labor
before 39 weeks’ gestational age, and cesarean delivery for
non-reassuring fetal status. Clinical outcomes specific to LGA included
cesarean delivery for arrest of dilation, cesarean for arrest of
descent, shoulder dystocia, and brachial plexus injury. This analysis
was not an effort at internal validation, but rather an exploratory
assessment of whether reclassification from normal to abnormal orvice versa by the sex-specific standard was inappropriate.
Comparisons of SGA and LGA overall, and comparisons of clinical outcomes
and management by SGA and LGA were tested with a chi-square test.
Statistical analysis was performed using SAS software, Version 9.4 of
the SAS System for Windows. Copyright © 2006 SAS Institute Inc. Cary,
NC, USA. Graphics were created using
GraphPad Prism version 9.1.2 for Windows, GraphPad Software, La Jolla
California USA.