1 | INTRODUCTION
Twin pregnancies are associated with a threefold to sevenfold increase
in perinatal morbidity and mortality compared to singleton
pregnancies,1 mainly due to higher rates of preterm
birth and discordant growth.2 Intertwin size
discordance has been reported to be an independent risk factor for
stillbirth and short-term adverse neonatal outcomes especially the
smaller twin of birthweight discordance of 20 % or more suffering from
a neurodevelopmental disadvantage.3
Twin birth weight (BW) discordance is attributable to various genetic or
environmental factors containing differences in nutrient supply
associated with variation in placental mass, placental insufficiency and
umbilical cord insertion. These impact one twin more than the other in a
sub-optimal intrauterine environment, which of twins contributed to
short- 4 and long-term perinatal
outcomes,5,6 especially the effects on neural
development (e.g. induced
neurological morbidity).7
Several studies have assessed the link between metabolic alterations
with BW discordance and abnormal infant neurodevelopment. However, most
have focussed on circulating factors in blood– often highly dynamic and
not reflective of the cumulative time in
utero .8,9 A downregulation of amino acids, including
valine, tryptophan, isoleucine, and proline, occurred in the cord blood
plasma of selective fetal growth restriction (FGR) in
monochorionic-diamniotic (MCDA) twins.10 Disrupted
essential amino acids, such as methionine, phenylalanine and tyrosine in
cord plasma were correlated with phenotypic growth discordance of
selective FGR.11 Gut microbial dysbiosis and variation
in the faecal metabolome of neonatal twins have also been correlated
with long-term neurobehavioural development in selective
FGR.12
The concentration of endogenous compounds and environmental compounds in
hair samples is maintained in an ordered temporal manner as hair grows
and therefore the neonatal hair metabolome is considered reflective of
the time in utero . Maternal exposure in the hair metabolome has
been explored to reflect the lower language ability in offspring with
373 infant-mother included.13
We previously demonstrated the feasibility of using the neonatal hair
metabolome to accurately generate a longitudinal picture of the
intrauterine environment over pregnancy.14 However, to
date, no study has attempted to identify specific metabolic differences
in the newborn hair metabolome associated with discordant in
utero growth in dichorionic (DC) twin pregnancies, or explored the link
between metabolic variation in hair at birth with later
neuro-developmental outcomes.
This study aimed to define hair metabolic perturbations associated with
intrauterine growth discordance of DC twin pregnancies and to assess the
link between metabolic variation in the hair at birth with infant
neurodevelopment at 2-3 years of age.
2 |
MATERIALS AND METHODS
2.1 |
Experimental Design
This is a cohort-based case-control study, within a twin cohort
recruited at the Peking University Third Hospital (Clinicaltrials.gov
Identifier: NCT03220750) between September 2017 and December 2018.
Chorionicity was established at booking ultrasound prior to 14 weeks’
gestation. A total of 201 DCDA twin pregnancies were recruited between
14-28 weeks of gestational age. The exclusion criteria included maternal
factors, such as chronic diseases, obstetric complications and delivery
complications; fetal factors included major congenital anomalies, or
major fetal structural anomalies, or aneuploidy, other adverse twin
pregnancy outcomes, and those lost to follow-up. DC twin neonates were
classified into DCDA-C (DCDA twins with birth weight concordance) and
DCDA-D (DCDA twins with birth weight discordance) according to
consensus-based diagnostic criteria of a within-pair difference in BW
exceeding 25%, with one twin <10th
centile.15 The gross examination of placenta was
executed carefully by our obstetricians immediately after delivery
including discerning the intertwin membrane to confirm chorionicity
(determined by antenatal ultrasound), the placental territory and cord
insertions attributed to each twin. Maternal and fetal clinical
characteristics were measured within 24 hours after delivery.