ajog.

org Oral Plenary I

infected fetuses and postnatal therapy is only available for the most
severe cases of infection due to substantial safety concerns. We
showed that valnoctamide (VCD), a mood stabilizer, effectively
blocks CMV. Here we investigate CMV infection in the developing
auditory system of newborn mice and the potential benefits of VCD
on long-term hearing outcomes.
STUDY DESIGN: Pups inoculated i.p. with CMV (750 PFU) on the day
of birth received VCD (n¼8) or vehicle (VEH, n¼8) daily (1.4mg/
mL) from p1 to p21. Brain development of newborn mice parallels
that of an early 2nd trimester human fetus. Uninfected animals
served as controls (n¼8). CMV load and distribution in the cochlea
and central auditory regions were assessed by qPCR and histo-
chemistry at multiple time-points post-infection. Hearing was
investigated blindly with respect to the experimental group using
Auditory Brainstem Responses in 7 week-old mice. Statistical sig-
nificance was determined by mixed-model ANOVA with repeated
measures.
RESULTS: CMV was detected in the cochlea as early as 2 dpi, with
viral load peaking at p16-21 and viral particles still measurable at
p50. CMV-infected cells were identified in several areas of the
inner ear, including the stria vascularis, the temporal bone, and
the cochlea, where selective loss of outer hair cells was evident by
p12. CMV+ cells were also recognized in central components of
the auditory system, such as cochlear nuclei, inferior colliculus, 6 The impact of the HYPITAT I trial on obstetric
and auditory cortex. Infected mice showed increased hearing management and outcome for gestational
thresholds at multiple frequency tone stimuli. VCD substantially hypertension and preeclampsia in the Netherlands
reduced CMV load in the cochlea (Fig. 1) and the brain, and Catherine de Sonnaville1, Ben Willem Mol2, Henk Groen3,
ameliorated hearing development with restoration of normal Floortje Vlemmix4, Joke Schutte5, Chantal Hukkelhoven6,
auditory responses (Fig. 2). Marielle van Pampus1
CONCLUSION: VCD effectively blocks CMV infection in the devel- 1
OLVG, Amsterdam, Netherlands, 2University of Adelaide, Adalaide,
oping auditory system and rescues virally induced hearing impair- Australia, 3University Medical Centre Groningen, Groningen, Netherlands,
4
ment. VCD is approved for treatment of neuropsychiatric disorders Academic Medical Centre, Amsterdam, Netherlands, 5Isala klinieken,
and lacks teratogenic activity. Thus, it may merit consideration as Zwolle, Netherlands, 6Perined, Utrecht, Netherlands
a novel approach in treating CMV-mediated deafness during OBJECTIVE: In 2009, the HYPITAT I study showed that in women
development. with pregnancy induced hypertension or preeclampsia at term, in-
duction of labor reduces maternal morbidity compared with
expectant management, without compromising neonatal outcome or
cesarean section rate. We aimed to evaluate the impact of the
HYPITAT I trial results on obstetric management and subsequent
maternal and neonatal outcomes in the Netherlands, five years after
the trial, as compared to before the trial.
STUDY DESIGN: We studied aggregated data from the Dutch National
Perinatal Registry from 2000 to 2014. We studied women with hy-
pertension in pregnancy or preeclampsia and a singleton fetus in
cephalic position between 36 to 41 weeks’ gestation. Outcome
measures were induction of labor, mode of delivery and the occur-
rence of maternal and neonatal complications. We compared the
proportions of the period before the trial (2000-2005) to the period
after the trial (2008-2014). We also compared outcomes to a refer-
ence group of women without hypertensive disorders in pregnancy.
RESULTS: We evaluated data of 55 780 women before to 70 890 after
the trial (Table 1). Induction of labor increased from 51.1% to
64.2% (RR 1.26 (95 %CI 1.24-1.27)). This increased rate was more
pronounced in HYPITAT I participating hospitals compared to non-
participating hospitals (participating: 48.5% to 64.5% (RR 1.33; 95%
CI 1.31-1.35); non-participating: 53.4% to 63.9% (RR 1.20; 95% CI
1.18-1.21)). A reduction was observed in the instrumental delivery
rate after the trial compared to the period before the trial (16.5% to
13.1%; RR 0.79; 95% (CI 0.77-0.81)). Spontaneous delivery rates

Supplement to JANUARY 2018 American Journal of Obstetrics & Gynecology S5

slightly increased from 65.0% to 66.7% (RR 1.03 (95%CI 1.02- 7 Maternal administration of melatonin for
1.04)). Emergency caesarean section rates were 12.8% and 14.4% prevention of preterm birth and fetal brain injury
respectively (RR 1.12; 95% (CI 1.09-1.16)). Maternal mortality ratio associated with premature birth in a mouse model
reduced from 3.5 to 1.2 per 100 000 live births. Perinatal death Ji Yeon Lee1,2, Eunna Kim3, Jong Yun Hwang4, Hang Seok Song5
reduced from 0.49% to 0.27% (RR 0.54 (95% CI 0.45-0.65)). The 1
Department of Obstetrics and Gynecology, CHA Bundang Medical Center,
reduction in perinatal mortality over time was greater in women CHA University School of Medicine, Seongnam, Korea, Republic of,
2
with hypertension compared to women without hypertensive dis- Integrated Research Center for Fetal medicine, Department of Gynecology
orders (Figure 1). and Obstetrics, Johns Hopkins University, Baltimore, MD, 3Department of
CONCLUSION: HYPITAT I lead to an increased induction of labor rate Pathology, Asan Medical Center, University of Ulsan College of Medicine,
in women with a hypertensive pregnancy at term. This was associ- Seoul, Korea, Republic of, 4Department of Obstetrics and Gynecology,
Kangwon national university school of medicine, Chuncheon, Korea,
ated with significant reductions in maternal morbidity and mortal-
Republic of, 5Department of Biomedical Science, College of Life Science,
ity, and perinatal mortality.
CHA University, Seongnam, Korea, Republic of
OBJECTIVE: Many studies have suggested that intrauterine infections
may be a cause of preterm birth. Melatonin exhibits immunomod-
ulatory effects in many inflammatory conditions. We hypothesized
that melatonin may decrease the rate of preterm birth and protect
fetal brain through changes in the anti-inflammatory and regulatory
milieu.
STUDY DESIGN: A mouse model was used with the following
groups: (1) control; (2) LPS group, inflammation by an intra-
peritoneal(IP) injection of lipopolysaccharide (LPS); and (3) LPS
with melatonin group, IP injection of LPS and pretreatment with
melatonin at E17. Inflammation was analyzed in the uterus,
placenta, and fetal brain using real-time RT-qPCR or immuno-
histochemistry. Immunofluorescent staining was used to examine
the morphological condition of neurons in fetal brain. We per-
formed western blotting to characterize the expression and ac-
tivity of silent information regulator transcript-1 (SIRT1) and
nuclear factor-erythroid 2-related factor 2 (Nrf2) in uterine
strips.
RESULTS: Melatonin decreased the rate of preterm birth compared
with that in the LPS group (30 vs. 100%, P<0.01). Latency period
from LPS injection to delivery was longer in LPS with melatonin
group than LPS group(42 vs. 10h, P<0.01). Coadministration of
melatonin was associated with decreased proinflammatory cyto-
kines in the uterus and placenta. In LPS group, layers of the fetal
brain are indistinguishable (fig. 1C) and polarity of normal
migration of neuroblasts was destroyed. Cortical plate became
thinner and neutrophils were seen (fig. 1D). In LPS with melatonin
group, all layers of the cortex maintain well (fig. 1E). Neuronal
differentiation is accelerated in the cortical plate (fig. 1F). Mela-
tonin inhibited LPS-induced neurotoxicity (fig. 2; cortical neuronal
primary culture). Western blot analysis in the uterine strips showed
that relative integrated densities for SIRT1 and Nrf2 were increased
significantly in the melatonin group, compared with other groups
(P<0.05).
CONCLUSION: Maternally administered melatonin appears to
modulate the maternal and fetal immune response to intrauterine
inflammation and decreases the frequency of preterm birth and
fetal brain injury. Current results suggest that melatonin could be
a new therapeutic agent to prevent preterm birth and fetal brain
injury.

S6 American Journal of Obstetrics & Gynecology Supplement to JANUARY 2018