SRI Supplement to Reproductive Sciences - Volume 25 Number 1 - March 2018 - 58A

58A

Reproductive Sciences Vol. 25, Supplement 1, March 2018

in the hippocampus. Reduced levels of methionine cycle metabolites in
the maternal hippocampus and plasma supports our hypothesis. In fetuses,
elevated metabolite levels in the hippocampus and plasma are contrary to
our hypothesis and do not involve altered gene expression of methionine
cycle enzymes. Increased placental expression of methionine and folate
transporters may indicate increased methyl-donor transfer, but this was
only observed in male fetuses. This is clinically relevant as disturbances
in the fetal methionine cycle can significantly affect patterns of DNA
methylation and gene expression in the developing brain.

O-004
Maternal Obesity is Associated with Altered Cardiac Structure
and Function in Neonates: UPBEAT TEMPO Heart Study. Ellie
Battersby†, 1 Matias Costa Vieira†,1 Faith Miller†,1 Paul T Seed,1
Dharmintra Pasupathy,1 Lucilla Poston*,1 Alan Groves,2 Paul D Taylor*.1
1
King's College London, London, United Kingdom; 2Weill Cornell Medical
College, New York, NY, United States.
INTRODUCTION: Epidemiological and animal studies suggest that
maternal obesity may result in deleterious consequences for offspring
cardiovascular development, morbidity and mortality. Fetuses of obese
mothers have decreased HRV antenatally, associated with adverse neurodevelopmental outcomes in childhood. We hypothesized that in a mother/
child cohort study, maternal obesity would be associated with altered
offspring cardiac structure and function in newborns.
METHODS: In a case-cohort study of neonates born to obese women
(BMI ≥ 30kg/m2, n=10) recruited into the UPBEAT RCT, we evaluated
parameters of cardiovascular function in comparison with newborn
infants of lean control women (BMI, 20-25kg/m2, n=13) recruited
contemporaneously, and matched for age and ethnicity. MRI scans were
performed in sleeping swaddled neonates after feeding and within 72
hours of delivery (neonatal 3.0T Philips Achieva MRI scanner). Segment
analyses were computed blinded to maternal BMI. Electrocardiograph
(ECG) recordings were also taken to obtain measures of heart rate
variability (HRV) during sleep.
RESULTS: Neonates born to obese women had a reduced mean end
systolic volume compared with lean controls (ESVI [ml/kg] 0.78 (0.68 to
0.89) vs 0.96 (0.82 to 1.11) % difference 0.18 (0.004 to 0.36), P=0.045)
whilst ejection fraction (EF [%] 68.9 (65.3 to 72.5) vs 64.3 (61.3 to 67.3)
% difference: -4.63 (-9.01 to -0.25) P= 0.0394) and cardiac output index
(COI [min/kg] 0.22 (0.20 to 0.23) vs >0.19 (0.18 to 0.21) % difference:
-0.025 (-0.047 to -0.0023) P= 0.032) were increased in neonates born
to obese women. All other parameters of cardiac structure and function
including left ventricular mass index (LVMI) showed no apparent
difference between maternal BMI catagories. Sleeping neonates born to
obese women demonstrated reduced HRV as indicated by significantly
lower SDNN-i (mean: 26.3<36.6; risk ratio: 0.72; p= 0.008)
CONCLUSION: The findings from this current study indicate that
markers of cardiovascular dysfunction are already present in neonates
born to obese women. Enhanced sympathetic drive in these infants, as
indicated by heart rate variability analysis during sleep state, is associated
with altered cardiac structure and function. This study suggests that makers
of future cardiovascular dysfunction may already be present at birth.

O-005
Conditional Xbp1 Deletion Ameliorates Maternal Diabetes-Induced
ER Stress and Neural Tube Defects through Restoration of miR-17
Expression. Penghua Yang*, Peixin Yang*. University of Maryland
School of Medicine, Baltimore, MD, United States.
INTRODUCTION: Our previous studies have demonstrated that
pregestational maternal diabetes induces neural tube defects (NTD)
through activating endoplasmic reticulum (ER) stress, oxidative stress, and
neuroepithelial cell apoptosis. However the precise mechanism whereby
ER stress mediates the teratogenicity of maternal diabetes needs be further
elucidated. We aim to determine whether conditional deletion of the Xbp1
gene, an ER stress sensor, in the neuroepithelium ameliorates maternal
diabetes-induced NTDs.
METHODS: The Xbp1 gene was deleted in the neuroepithelium using
the Cre-Flox (f) recombination approach by crossing XBP1f/+;nestin-Cre

Scientific Abstracts

nondiabetic male mice with XBP1f/f nondiabetic and diabetic female
mice. Maternal diabetes was induced through tail vein streptozotocin
(STZ) injections. Xbp1 gene deletion specifically in the developing
neuroepithelium was confirmed by XBP1 immunofluorescence. NTDs
was recorded by morphological examination and histological sectioning
of embryonic day 10.5 (E10.5). Chromatin immunoprecipitation (ChIP)
was used to determine XBP1 binding to the promoter of the Mir17 gene.
Furthermore we generated a neuroepithelium-specific miR-17 transgenic
(Tg) mouse line driven by the promoter of the neural stem cell marker
nestin to investigate whether restoring miR-17 expression suppressed by
maternal diabetes would reduce NTD formation.
RESULTS: Only 3.7% (1 out of 27 embryos) NTDs were observed in
Xbp1 null (XBP1f/f;Nestin-Cre+) embryos exposed to maternal diabetes,
whereas embryos without the Xbp1 gene deletion exhibited 37.9% NTDs
(11 out of 29 XBP1f/f;Nestin-Cre- embryos) and 32.1% NTDs (9 out
of 28 XBP1f/+;Nestin-Cre- embryos). Heterozygous Xbp1 deleting
embryos (XBP1f/+;Nestin-Cre+ genotype) had an NTD rate of 29.6%
(8 out of 27 embryos) in diabetic pregnancy, which was comparable to
those in embryos without the Xbp1 gene deletion. We found that XBP1
was significantly enriched in the promoter region of the Mir17 gene, and
deleting the Xbp1 gene restored miR-17 expression suppressed by maternal
diabetes. Comparing to the NTD rate of 52.4% (22 out of 42 embryos)
in wild-type embryos in diabetic pregnancy, miR-17 overexpression in
the neuroepithelium significantly reduced the NTD rate from 52.4% to
8.1% (3 out of 37 embryos).
CONCLUSION: Our findings support the hypothesis that the unfolded
protein response mediator and ER stress sensor XBP1 mediates the
teratogenic effect of maternal diabetes leading to NTDs by suppressing
miR-17 expression, which is essential for normal neurulation.

O-006
Immediate Perioperative Predictors of Survival in TTTS. Jessica
Ehrig†, Nicholas Behrendt, Megan Lagueux, Kenneth W Liechty, Michael
V Zaretsky, Timothy M Crombleholme, Henry L Galan*. University of
Colorado School of Medicine, Aurora, CO, United States.
INTRODUCTION: Survival rates following fetoscopic laser
photocoagulation (FLP) have improved over the past 20 years. Published
survival data vary considerably in part because complicating variables may
or may not be included. Some fetal centers use these as exclusion criteria
for FLP. We sought to determine if single or combined perioperative
factors predict overall survival or survival of one or both twins affected
by twin twin transfusion syndrome (TTTS) who undergo FLP.
METHODS: All TTTS patients who underwent FLP at a single site
from 2012-2017 were included in this retrospective study. We evaluated
perioperative risk factors identified prior to procedure through POD #5.
The perioperative risk factors included gestational age (GA), location
of the placenta, cervical length < 2.5cm, and selective intrauterine
growth restriction (sIUGR). Each perioperative risk factor was evaluated
individually and in combination. We evaluated survival of one or both
twins, double survival and overall survival at time of delivery. Chi-square
and fisher's exact tests were used with p< 0.05 taken as significant.
RESULTS: Of 235 TTTS cases reviewed, 209 had survival data. Table
1 shows the survival rates by the number and type of complications. In
patients without any of the 4 complications, the overall survival rate was
89.7%, survival for one or both 96.5% and double survival was 82.8%.
Of pregnancies with one complicating factor, the lowest survival rate
was observed in two groups, GA < 18 wks (75%) and sIUGR (75%).
For paired complications, either a short cervix and sIUGR or anterior
placenta and GA < 18wk, had the lowest survival rates (56.3%). The
addition of any complication decreased the overall survival rate (fig
1). Some categories (e.g. all 4 complications) had too few twin pairs to
accurately calculate survival.
CONCLUSION: The survival rates for the entire population were
comparable to previously published data. Knowing that the absence
of major perioperative complications increases survival rate and the
cumulative effect of each complication decreases survival rate is important
in counseling patients prior to FLP.
*Figure(s) will be available online.

Table of Contents for the Digital Edition of SRI Supplement to Reproductive Sciences - Volume 25 Number 1 - March 2018