Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT03389178 |
| Other study ID # |
FELICITy |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
December 22, 2017 |
| Last updated |
January 2, 2018 |
| Start date |
July 1, 2016 |
| Est. completion date |
June 30, 2020 |
Study information
| Verified date |
January 2018 |
| Source |
Technische Universität München |
| Contact |
Silvia Lobmaier, MD |
| Phone |
00498941405417 |
| Email |
silvia.lobmaier[@]tum.de |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational [Patient Registry]
|
Clinical Trial Summary
The investigators´ main hypothesis is that prenatal stress (PS)- induced programming during
fetal and postnatal development is reflected in epigenetic and autonomic nervous system (ANS)
biomarkers which can be harnessed for early detection and follow-up of affected children. By
integrating multiple non-invasively obtainable sources of information using novel epigenetic,
electrophysiologic and statistical approaches, the trial could yield progress in
maternal-fetal medicine, offering a more precise and truly personalized prediction and new
possibilities for designing interventions to improve neurodevelopmental outcomes of pregnancy
affected by PS.
Description:
Rationale:
A cohort of the population of women attending the center of perinatology at the Department of
Obstetrics and Gynecology at the Klinikum rechts der Isar of the Technische Universität
München (TUM) for having birth will fall in the group of persons with higher perceived stress
levels that might concomitantly carry fetuses that show altered sympathetic and vagal
activity.
Experimental design:
This study will be conducted at the Department of Obstetrics and Gynecology at the Klinikum
rechts der Isar of the Technische Universität München (TUM) a tertiary center of Perinatology
of high complexity located in Munich, Germany and that serves about 2000 mothers/newborns per
year. TUM obstetricians will identify prospective subjects according with the inclusion
criteria of the study, consistent on singleton pregnant women between 18 to 45 years of age
in their third trimester (at least 28 weeks gestation) and without a) serious placental
alterations; b) fetal malformations; c) maternal severe illness during pregnancy (i.e.
preclampsia), d) maternal drug or alcohol abuse, e) preterm birth (less than 37 weeks) and f)
Cord blood pH<7,10.
Prospective participants will be referred to attend an informational session, when procedures
will be explained, formal enrollment will be completed and the consent forms from the
participants themselves and parental consent for their infants will be obtained. These
protocols are in strict accordance with the Committee of Ethical Principles for Medical
Research from TUM and has the approval of the Ethics Committee of the Hospital " Klinikum
rechts der Isar". Upon acceptance participants will enter to Phase I-IV.
Phase I: Screening:
In this initial stage, the investigators will collect demographic information from consented
women and participants will be categorized as stressed or controls after scoring the Cohen
Perceived Stress Scale-10 (PSS-10). This questionnaire measures the degree to which
situations in one's life are appraised as stressful and is a widely used psychological
instrument to measure nonspecific perceived stress. The PSS predicts objective biological
markers of stress and increased risk for disease among persons with higher perceived stress
levels. In particular, PSS scores were used to relate prenatal stress, anxiety, and
depressive symptoms as predictors of intention to breastfeed and to examine correlates of
perceived stress in pregnant women. Increased maternal prenatal stress, measured as PSS and
anxiety, was associated with temperamental variation of young infants and may represent a
risk factor for psychopathology later in life. The PSS-10 has been validated in German
speaking populations and will be a quick tool for screening stress among prospective
subjects. For the purposes of the current study, a participant with a PSS-10 score ≥19 will
be categorized as stressed and entered into Phase II. For every consented subject categorized
as stressed, the next screened participant matching for maternal and gestational age with a
PSS-10 score < 19 will be entered into Phase II as control. Recruitment will continue until
reaching the aimed cohort of n=75 subjects/group.
Phase II: Maternal psychological evaluation and fetal prenatal recordings:
1. Questionnaires: In the context enrolled participants entering this phase will be asked
to complete a widely used and validated self-rating questionnaire in order to assess
concerns related to pregnancy. The participants will have to complete the Prenatal
Distress Questionnaire (PDQ-12) designed to assess specific worries and concerns
pertaining to pregnancy and includes items on concerns regarding medical problems,
physical symptoms, parenting, relationships, bodily changes, labour and delivery, and
the health of the baby. This instrument has been previously applied in numerous studies
involving pregnant women from diverse cultural and socio-economic backgrounds and is an
effective instrument to assess pregnancy related stress. PDQ-12 has been translated into
German and was validated. Additionally participants will fill in a questionnaire about
their education level, socio-economic situation, ethnicity and clinical history.
2. ANS assessment: During the same visit the fetal heart rate (FHR) will be measured by a
routine cardiotocography (CTG) and simultaneously by transabdominal electrocardiography
(transabdominal-fetal ECG). The electrophysiological signal contains the maternal ECG
(mECG), fetal ECG (fECG) and noise, it will be recorded using 5 disposable electrodes.
The five disposable electrodes will be placed on the maternal abdomen in a standardized
manner. Before placing the electrodes, skin impedance will be reduced by using abrading
paper at the electrode placement site. Data will be analyzed off line after computer
download. For the case that signal loss is high with fECG method, which is a known
problem (more frequent between 28 to 32 gestational weeks, but also might occur after
that period), conventional external CTG will be performed simultaneous using an
ultrasound transducer placed on the maternal Abdomen. The investigators will analyze the
impact of PS on ANS activity by deploying advanced methods of FHR monitoring:
phase-rectified signal averaging (PRSA), multidimensional FHR variability analysis and
assessment of maternal-fetal heart rate synchronization FECG registrations as well as
CTG registrations will be performed once during pregnancy for at least 40 minutes to get
fetal activity status. During labour conventional CTG and if possible fECG and mECG will
be performed simultaneously.
Phase III: Delivery:
1. Maternal cortisol assessment: Cortisol, the hormonal product of activation of the
hypothalamic-pituitary-adrenal (HPA) axis has been suggested as a potential mechanism
linking maternal stress and perinatal outcome. Single blood and /or saliva samples
provides a measure at a single point in time and considering its major physiological
daily fluctuations, may not be the most informative measure to evaluate overall or long
term HPA activity during the prenatal period. Recently, the use of hair cortisol
measurements demonstrated that it provides a retrospective index of integrated cortisol
secretion over periods of several months . It is postulated that cortisol is
incorporated into the emerging hair and slowly grow with it. Therefore the amount of
cortisol in a particular hair segment is assumed to reflect the integrated systemic
steroid hormone concentration over a growth period of a specific hair segment. Hair and
salivary cortisol are highly correlated in non-human primates and it has been
demonstrated increased hair cortisol concentrations in pregnant women. Therefore, hair
cortisol has the potential to serve as an integrated measure of HPA activity over an
extended period of time of up to 3-6 months. On the day of parturition, hair strands (~3
mm diameter) will be collected from the posterior vertex region on the head as close to
the scalp as possible as recommended by the Society of Hair Testing (Soc of Hair
testing, 1997). Based on an approximate hair growth rate of 1 cm per month, the proximal
3 cm long hair segment is assumed to reflect the integrated hormone secretion over the
three-month-period prior to sampling. The 3 cm hair sample will be wrapped in aluminum
foil for protection and stored at room temperature. Hair samples will be sent for
cortisol determination.
2. Maternal blood collection (not part of this study- blood will be stored at the biobank):
A maximum of 20 ml will be collected to provide serum and plasma specimens. The blood
specimens will be stored in 2-4 x 1.8 ml labelled Cryotube vials after one
centrifugation cycle for serum specimens (2750 rpm x 10 min at RT) and stored at -80 °C
and after 10 gentle invertions for plasma specimens and stored at -20 °C. The blood
samples will be processed and frozen within 2-4 h. The time interval between collection
and freezing will be recorded for all specimens.
3. Cord Blood samples: Once the baby is delivered and before placental separation, the cord
is clamped and cord blood samples will be drawn and distributed in two tubes for serum
and plasma specimens following the same procedure as detailed above. A third sample will
be collected in a PAXgene tube, carefully inverted 10 times and left at RT for 5 hs in
an upright position. The tubes will then be stored at -80 °C after 10-16 hs at -20 °C.
(the PAXgene sample is not part of this study- blood will be stored at the biobank)
4. Placenta samples (not part of this study- samples will be stored at the biobank): Once
the placenta is delivered the maternal side will be dissected. Two biopsies will be
taken (approximately 1 cm³) avoiding decidua contamination. The samples are placed in
Cryotube vials and stored immediately at -20 °C.
5. Newborn recordings: Soon after birth, a neonatal specialized midwife will collect a
saliva/buccal samples from the newborns by gentle rubbing the gums on both sides with
the sponge of the Oracollect-DNA kit (DNA Genotek, Canada) and stored at RT. Clinical
data including body metrics pH and APGAR score, will be recorded.
Phase IV: Postnatal recordings:
Following up on the cohort recruited at phase I and mirroring the neurodevelopmental animal
study, we will perform a longitudinal study to explore the feasibility of measuring
biomarkers of PS-induced epigenetic reprogramming.
1. Infant developmental assessment: In the final stage of the study, the mother will be
asked to complete a final questionnaire to assess postpartum depression and breast
feeding that she will receive by mail post. While the current study is focused on
antenatal events, early postnatal care is heavily impacted by maternal depression and
can alter the epigenetic reprogramming of the infant brain. Therefore, the level of
maternal involvement in childcare during the first months could directly affect the
methylation status and will be recorded. Mothers will be asked about feeding and care
routines to complete the postnatal-care assessment.
2. Infants' cognitive development will be assessed by Bayley Scale III of Infant
development (BSID) at 18 months of age. The BSID is composed by a series of tests aimed
at evaluating cognitive, motor and behavioral development on infants from age 0-3 years.
The Mental Development Index and the Psychomotor Development Index components have a
mean score of 100 and a standard deviation of 15 (range of 55 to 145). Scores between
70-84 indicate mildly delayed performance, and scores ≤ 69 indicate significantly
delayed performance. Approximately 13.5 % of tested infants are expected to fall in
those categories. Maternal psychological distress during pregnancy was associated in a
dose-response manner with BSID scores in 2 years-old children. A specialized
Psychologist, who will be blind regarding maternal stress categorization, will
administer the tests, which will last about 40 minutes.
3. A new saliva sample will be collected from the infants at this final visit. The
biomarkers will be quantified from salivary DNA obtained from the young infants. ECG
will be measured for ANS assessment. Methylation levels will be correlated with maternal
stress, depression and anxiety, with infant's cognitive development and ANS capacity to
assess the efficacy of these novel biomarkers.
