Prenatal Programming of Brain Development: The Role of Maternal Stress and Stress Biology
February 14, 2023Information
YCSC Grand Rounds February 14, 2023
Claudia Buss, PhD, Professor, Institute of Medical Psychology, Charité, Berlin
ID9485
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- 00:00So I was able to look at associations
- 00:04between maternal stress and brain phenotypes.
- 00:08So this was very exciting,
- 00:10but the one thing I wasn't so happy
- 00:13about was that we looked at the
- 00:16children's brain at 7 years age.
- 00:18And of course there's a lot happening
- 00:20in the post Natal period and
- 00:22there's a lot of interaction and
- 00:24also continuity in terms of free
- 00:26Natal stress and post Natal stress.
- 00:28So we don't really know if we
- 00:29look at something at 7 years age,
- 00:31is it something that's really related
- 00:33to the prenatal environment or is it
- 00:35really the post Natal environment that
- 00:37shapes this or at least moderates this?
- 00:38So I thought.
- 00:40I actually.
- 00:43I have to confirm something here. Got
- 00:46it that it's recorded but I
- 00:49don't see my cursor. We still
- 00:51have somebody who can.
- 00:52Karen, can you help me?
- 00:55See it's. Oh, I see. See the
- 00:59cursor is there on mission.
- 01:03There we go. OK. Thank you
- 01:07so much. So I thought.
- 01:14Umm.
- 01:18Moving forward, no. No. OK.
- 01:21I just wanted to get you to talk.
- 01:25Thank you. So I thought if we really wanted
- 01:28to see what our prenatal influences were,
- 01:30supposed Natal influences,
- 01:31what we should do is try to characterize
- 01:34the brain phenotypes shortly after
- 01:36birth because at this time point
- 01:38post Natal influences cannot yet
- 01:40have exerted their influences.
- 01:41So this is. This is what we set
- 01:45up together with my colleagues.
- 01:46Pathik, what ones on your entringer at
- 01:48the University of California, Irvine.
- 01:50We had this pregnancy cohort
- 01:53that where we did extremely.
- 01:57Deep phenotyping in terms of
- 01:59their stress and stress biology,
- 02:00applying ecological momentary or stress
- 02:04momentary assessments of stress in their
- 02:07home environment across four days in
- 02:10their home environment and we took,
- 02:12we collected a lot of biological
- 02:15samples and then we followed up these
- 02:18children and my specific focus was brain
- 02:21development based on multimodal MRI
- 02:24and also cognitive function whereas.
- 02:27Uh, my colleague Sonia entering ahead
- 02:29more focus on body composition and um,
- 02:32cellular aging.
- 02:33So this is like a pretty well characterized
- 02:36cohort and I will be mainly talking
- 02:38about results from this cohort today.
- 02:40Umm, where we have roughly, yeah,
- 02:44between, depending on the outcome,
- 02:46100 and 114 Mother,
- 02:4814 Mother child diets.
- 02:51We do have several other cohorts now.
- 02:54We are part of the ECHO consortium here in
- 02:57the US and contributed 2 cohorts to that.
- 03:01And we also have a pregnancy cohort
- 03:03in Berlin.
- 03:04And we are trying to harmonize our
- 03:06data collection in ways that we can
- 03:09eventually merge these cohorts.
- 03:10For either for mega analysis or at
- 03:13least for replication purposes and
- 03:15this is something that we will be
- 03:18focusing on to really address the
- 03:20replication crisis and and see where we
- 03:24stand with some of these initial findings.
- 03:28So when I started this work,
- 03:30there was quite a bit of evidence
- 03:33from epidemiological studies showing
- 03:35that there was an association between
- 03:37maternal stress during pregnancy and
- 03:39higher risk for neurodevelopmental
- 03:41disorders and psychiatric disorders,
- 03:43as well as cognitive impairment.
- 03:45But anything we knew about really changes
- 03:48in the brain was based on animal models.
- 03:51So as Kieran said earlier,
- 03:53we did publish the first study.
- 03:56Now 13 years ago,
- 03:58showing associations between maternal
- 04:00pregnancy specific anxiety and
- 04:02reductions in Gray matter volume
- 04:04in the children at 7 years age.
- 04:07And as you can see here,
- 04:09especially these pronounced reductions in
- 04:11Gray matter volume in the prefrontal cortex,
- 04:14but here also in the in the temporal cortex.
- 04:18And this is interesting because these
- 04:20are brain regions that support some of
- 04:22these cognitive functions that have
- 04:24been shown in epidemiological studies.
- 04:26To be associated with maternal stress.
- 04:28We then later when the sample was.
- 04:32Larger also looked at cortical thickness
- 04:34and whether there were associations,
- 04:36associations between maternal
- 04:38depressive symptoms during pregnancy
- 04:40and cortical thickness.
- 04:41And as you can see in blue are
- 04:44several regions in the brain where
- 04:46the cortex was thinner in children
- 04:48whose mothers had higher depressive
- 04:50symptoms during pregnancy.
- 04:52Again,
- 04:52very pronounced are the
- 04:54reductions here in the prefrontal
- 04:56cortex, and this is also
- 04:59what mediated an association,
- 05:01the association between.
- 05:02Maternal depressive symptoms and
- 05:04externalizing problems in her children.
- 05:07So this is something we have also
- 05:10started looking at in our newborns.
- 05:12In this other cohort, I told about,
- 05:14I talked about and here's one example
- 05:16where we were able to show that
- 05:19there is an association between
- 05:20higher perceived stress levels
- 05:22in the mother during pregnancy
- 05:24and smaller hippocampal volumes.
- 05:25And we of course also interested in
- 05:28whether this has done any kind of
- 05:30implications for cognitive function
- 05:32cognitive development later on.
- 05:33And interestingly,
- 05:34we didn't see a main effect
- 05:36of hippocampal volume.
- 05:38The birth and cognitive function
- 05:39here in this case at six months age,
- 05:41but it was an interaction with the
- 05:43environment and those children who
- 05:45had a larger hippocampal volume
- 05:47were better able to benefit from
- 05:49an enriched environment.
- 05:50So it really shows this concept
- 05:52of conditional probability.
- 05:54So certain phenotypes get established
- 05:56by certain experiences and then will
- 05:59determine how future experiences
- 06:01can shape further development,
- 06:04which I think is this is a
- 06:07nice example of that.
- 06:09And then this is some work I'm I'm
- 06:12working on with Kieran currently
- 06:15the the UCI children we have done
- 06:19gene DNA methylation analysis,
- 06:22longitudinal DNA methylation analysis
- 06:24that we are currently analyzing and
- 06:27something we have started looking
- 06:29into is we have generated this
- 06:31wholly epigenetic risk score that is
- 06:35supposedly based on this paper indicates.
- 06:38Exposure to glucocorticoids during
- 06:41fetal development and what we did,
- 06:45we created this polygenetic risk
- 06:47score and actually showed that
- 06:49it was associated with maternal
- 06:51depressive symptoms during pregnancy
- 06:53and also that it then predicted
- 06:55hippocampal volume in the newborn.
- 06:57So this is just an initial attempt
- 06:59to try to understand potential some
- 07:02of the epigenetic underpinnings of
- 07:04some of the associations we observe.
- 07:07Umm.
- 07:10I told you that when I started this work,
- 07:12Umm,
- 07:12we were the first who who published on this.
- 07:16But this has changed dramatically
- 07:18in the last decade.
- 07:20There are a lot of studies now in
- 07:22humans showing associations between
- 07:24various types of maternal distrust
- 07:27during pregnancy, depression,
- 07:29anxiety,
- 07:30but also perceived stress levels and.
- 07:34Sorry,
- 07:35it's too loud.
- 07:38The various forms of maternal
- 07:40distress levels and brain outcomes,
- 07:42and this has been work has been
- 07:44done in in fetuses and newborns,
- 07:46infants, children and also
- 07:48adolescents and young adults.
- 07:49And so there is accumulating
- 07:52evidence for this for sure.
- 07:54But the picture is very heterogeneous
- 07:56because people are suffering
- 07:58different types of stress,
- 07:59different brain outcomes.
- 08:00They are using different pipelines
- 08:03for analyzing the MRI data.
- 08:04So I think we don't have a.
- 08:07Very good picture in terms of
- 08:09what replicates and what is like
- 08:10a true effects and I think we are
- 08:12getting there and and and I will
- 08:14be talking about some of the steps
- 08:16that we need to take but at least I
- 08:18think what we what we can establish
- 08:20that there is from different
- 08:22independent research groups quite a
- 08:23bit of evidence for an association
- 08:26between maternal distress during
- 08:28pregnancy and brain development and.
- 08:31We are of course very interested
- 08:33in what is it that the fetus
- 08:35actually receives in terms of the
- 08:37the signal of maternal stress.
- 08:39Because I often get asked what kind of
- 08:42stress should we be paying attention to.
- 08:44And I think any kind of stress
- 08:46we should be paying attention to
- 08:49because we don't know what in an
- 08:51individual actually leads to the
- 08:54translation into a biological signal.
- 08:57So there might be coping strategies.
- 08:59There might be like, like.
- 09:01Certain other resilience factors
- 09:02that lead to the mother coping with
- 09:05stress well and not increasing like
- 09:08different stress biology components,
- 09:10but others where this might be the case.
- 09:12And here are some mechanisms that
- 09:14we think are really important and of
- 09:16course on the one hand it is cortisol.
- 09:19We know that maternal cortisol
- 09:21can pass through the placenta.
- 09:23There is an enzyme 11 beta HSD two
- 09:25that converts active cortisol into
- 09:27inactive cortisone and protects
- 09:29the fetus from an overexposure.
- 09:32It's just a partial barrier and
- 09:34a certain percentage of cortisol
- 09:35passes through.
- 09:36And something that Kieran has
- 09:38actually shown and has very early
- 09:40work is that this enzyme seems to
- 09:41be stress sensitive.
- 09:43So not only is there more cortisol
- 09:45when the mother is stressed,
- 09:47but potentially more of this
- 09:48higher levels can.
- 09:49Pass through and this will lead
- 09:52to an increase in cortisol in the
- 09:55fetal compartment.
- 09:56And then also there's placenta CRH.
- 10:00Placenta CRH is identical to the
- 10:02peptide produced by the hypothalamus,
- 10:05but there is one very important difference,
- 10:07and that is that it underlies
- 10:09a positive feedback loop.
- 10:10So when cortisol is high,
- 10:12it produces CRH production in
- 10:14the placenta and will further
- 10:16stimulate the maternal HP access,
- 10:19but also the fetal HP a access.
- 10:20So under levels of under
- 10:22conditions of chronic stress,
- 10:23this can lead to this feed forward.
- 10:26Cycle of elevated cortisol concentrations.
- 10:29We are also really interested in
- 10:32cytokines and inflammatory markers,
- 10:34not only because of the like very good
- 10:40evidence for infections during pregnancy,
- 10:43increasing risk for psychopathology
- 10:45and we have been of course now worried
- 10:48during the pandemic also what COVID-19,
- 10:51how COVID-19 infections during
- 10:53pregnancy might do to the fetal.
- 10:56Features and feature development,
- 10:59but these these these immune
- 11:02mediators are also stress sensitive.
- 11:04And This is why we are
- 11:05very interested in them.
- 11:06And there are some debate whether
- 11:08they can actually pass the placenta.
- 11:10I don't think the evidence
- 11:12is very convincing.
- 11:13But what definitely happens
- 11:16is that there's systemic,
- 11:18systemic inflammation in the mother.
- 11:20It will lead to inflammation in the placenta,
- 11:22and the placenta itself will produce
- 11:26cytokines into the fetal compartment and
- 11:29inflammatory mediators will be elevated.
- 11:33This is what I will be talking
- 11:34about on the next slides,
- 11:35variation of maternal cortisol and
- 11:37interleukin 6 concentrations and how
- 11:39it affects fetal brain development.
- 11:41But we've also done work on metabolic
- 11:45factors like free fatty acids.
- 11:47We have characterized insulin
- 11:49and glucose and we have looked
- 11:51at conditions like maternal pre
- 11:53pregnancy BMI and we also see that
- 11:55this has the capability of programming
- 11:57fetal brain development and there
- 11:59we have focused specifically on
- 12:01brain regions that are important.
- 12:03Our energy homeostasis and see
- 12:05associations for example between
- 12:07maternal pre pregnancy BMI and
- 12:10elevated free fatty acid concentrations
- 12:12and hypothalamic development and
- 12:14hypothalamic integrity that then
- 12:16predicts body composition and
- 12:19fat gain in the infant.
- 12:22So this is just another summary
- 12:24how we're thinking about it,
- 12:26that various conditions during
- 12:30early life in the mother when she
- 12:33is pregnant or even before she
- 12:35was pregnant can affect maternal
- 12:38placental fetal stress biology and
- 12:40thereby affect all the fundamental
- 12:43processes of brain development.
- 12:46And um,
- 12:46then affect cognitive and
- 12:48affective processes as well,
- 12:50as well as mental health outcomes.
- 12:53So Umm,
- 12:54I want to share some findings
- 12:56with you on the variation in
- 13:00maternal cortisol concentrations.
- 13:01And here in Michelle volume
- 13:03and seven-year old children,
- 13:05this was the first cohort again that
- 13:08I've referred to and what we saw was.
- 13:10Sorry,
- 13:10I don't know if you can see my
- 13:13cursor doesn't work very well that
- 13:15higher levels of maternal cortisol
- 13:16concentrations during pregnancy
- 13:17were associated with larger McKellar
- 13:19volumes and there was a sex specific effect.
- 13:22We only saw those in girls and not in boys.
- 13:24And these larger amygdala volumes
- 13:27also mediated and association between
- 13:29maternal cortisol and effective symptoms.
- 13:31And these seven-year old girls,
- 13:34when we looked at the newborns,
- 13:36there was a tendency for exactly the
- 13:38same effect on larger amygdala volumes.
- 13:40Only young girls, but not in boys.
- 13:42It was not quite significant,
- 13:44but.
- 13:44And what we did find was that elevated
- 13:47maternal cortisol was associated
- 13:49with stronger amygdala connectivity
- 13:52to brain regions involved in
- 13:55sensory processing and integration.
- 13:57And very specifically,
- 13:58for example,
- 13:59a stronger connectivity between
- 14:01amygdala and the anterior insula
- 14:04and this higher connectivity.
- 14:09Actually this is yet another another network
- 14:13where we see a stronger connectivity to
- 14:16the supramarginal gyrus and mediated the
- 14:19association between maternal cortisol
- 14:22concentrations and internalizing problems
- 14:24when the children were two years old.
- 14:27So I think this is really important that.
- 14:30We do see that the variation in
- 14:33brain phenotypes in the newborn
- 14:36actually do predict later behavior,
- 14:39later cognitive function,
- 14:39and I'll show you some more of that.
- 14:41So this variation that we see
- 14:44does seem to be meaningful.
- 14:47So, Umm, we did find that elevated
- 14:50material cortisol concentrations
- 14:51are associated with larger amygdala
- 14:53volumes and this was associated
- 14:55with more effective symptoms and
- 14:57also with increased the mitella
- 14:59connectivity with cortisol with
- 15:01cortical structures that were associated
- 15:04with higher internalizing problems.
- 15:06And this may support higher vigilance
- 15:08and offspring of mothers who experience
- 15:10high stress during pregnancy and
- 15:12therefore could increase the risk
- 15:14for effective and anxiety disorders,
- 15:16although eventually this might have.
- 15:18Or if an evolutionary purpose to
- 15:21prepare these children to a potential
- 15:24stressful extrauterine environment.
- 15:26Umm,
- 15:27we did see these interesting sex
- 15:30specific effects and we are not
- 15:33really clear why this is and we
- 15:35cannot say that in general females
- 15:37are more susceptible than males.
- 15:40There are a lot of examples where
- 15:42it seems like for certain exposure
- 15:44and certain outcomes males seem
- 15:45to be more susceptible.
- 15:47But what we continuously see when
- 15:49we look at variational cortisol,
- 15:51it seems like females are more
- 15:54susceptible and some reasons.
- 15:56Um could be, for example,
- 15:58that there are sex differences in
- 16:00the timing of glucocorticoid receptor
- 16:01expression in the fetal brain,
- 16:03and there is also sex differences in
- 16:06placental glucocorticoid receptor
- 16:07functioning.
- 16:08And also it has been shown in adults
- 16:10that chronic stress had different has
- 16:13different effects in males and females.
- 16:15So dendritic expansion in females
- 16:17but retraction in males.
- 16:19So we don't know yet why this is,
- 16:22but it's something that we consistently see.
- 16:25I will now talk about some of
- 16:28our findings in association with
- 16:31variation in maternal interleukin
- 16:346 concentrations and I already want
- 16:36to say we we looked at.
- 16:38Whether there is any moderation by
- 16:40fetal sex as well, and there was not.
- 16:42So here males and females seem to
- 16:45be equally affected by higher levels
- 16:47of interleukin 6 concentrations.
- 16:49So yeah,
- 16:50I already said a higher inflammatory
- 16:52measure is a risk factor for various
- 16:55neurodevelopmental disorders.
- 16:56And like various conditions like
- 17:00obesity and infection,
- 17:01as well as psychological stress are
- 17:04associated with higher interleukin
- 17:056 concentrations. Umm.
- 17:07It seems like Interleukin six really
- 17:10plays an important role because in
- 17:12an animal model, if you block Interleukin 6,
- 17:17if you give an sorry,
- 17:18if you give an interleukin 6 antibody,
- 17:21it blocks the effect of maternal
- 17:23immune activation.
- 17:24So it it really does seem to be
- 17:26to play a very specific role.
- 17:29As I said earlier,
- 17:30Interleukin 6,
- 17:31there's some evidence that it
- 17:32can pass the placenta,
- 17:33but there's definitely much more
- 17:35evidence that it will induce inflammation
- 17:36in the placenta and the placenta.
- 17:38Itself produces cytokines.
- 17:40And then of course there's
- 17:43really a lot of evidence,
- 17:45preclinical evidence for maternal
- 17:47immune activation during pregnancy,
- 17:49altering fetal brain development.
- 17:50So all I'm going to show
- 17:53you now is in the newborns.
- 17:55And again, we found our larger mikalah
- 18:00volume in those newborns whose mothers
- 18:03had higher interleukin 6 concentrations.
- 18:06And as I said earlier,
- 18:07there was no sex specific effect here.
- 18:10Umm. We also looked at a metal icon
- 18:14activity here and there was a stronger
- 18:18bilateral amygdala connectivity to brain
- 18:20regions involved in sensory processing,
- 18:23like the fusiform,
- 18:25the somatosensory cortex,
- 18:26the thalamus.
- 18:28Also brain areas involved in salience
- 18:32detection like the anterior insula,
- 18:35as well as learning and memory like
- 18:37the cottage and parahippocampal gyrus.
- 18:40And this is just to show you a scatter
- 18:45plot of one of these connections.
- 18:48This is the amygdala anterior
- 18:51insula connection and how it is
- 18:54associated with varying levels of
- 18:56interleukin 6 during pregnancy.
- 18:57And I should say I'm sorry
- 18:59I haven't said that yet.
- 19:01Here we are looking at average
- 19:03interleukin 6 concentrations.
- 19:04We collected maternal samples three times
- 19:07during pregnancy and because interlocken.
- 19:106 concentrations were so highly
- 19:13correlated across pregnancy,
- 19:14we calculated an average.
- 19:15We felt we are not really in the
- 19:18position of looking at timing specific
- 19:21effects because they are so highly
- 19:23correlated and we only have this
- 19:25one time measure in the newborn.
- 19:27So trying to draw any kind of conclusions
- 19:30of time specific effects I don't
- 19:33think would be warranted with this
- 19:35design and what the data looked like.
- 19:38And Umm,
- 19:39I have done all this,
- 19:41all this work with my collaborators
- 19:45Damien Fair and Alice Graham at back then,
- 19:48which is you,
- 19:51Damien Ferris now in Minnesota and.
- 19:55So they have really let all the efforts
- 19:57on the resting state analysis and
- 19:59then anything related to diffusion
- 20:01tensor imaging that I will be talking
- 20:04about as well as the brain anatomy
- 20:06we have done in collaboration with
- 20:08Martin Steiner and John Gilmore at
- 20:10the University of North Carolina.
- 20:11And the next slide I'm going to
- 20:14show you was really mainly led by by
- 20:17Damien and here we looked at whole
- 20:19brain connectivity in association
- 20:21in the new ones and association
- 20:23with higher maternal interleukin 6.
- 20:25Concentrations during pregnancy and
- 20:27saw associations within networks
- 20:30again and the salience network,
- 20:33the dorsal attention network as
- 20:34well as the visual network,
- 20:36but also various between network connections,
- 20:40as you can see here below.
- 20:43As an additional modality,
- 20:45we looked at diffusion tensor
- 20:46imaging and we were specifically
- 20:48interested in this track,
- 20:49the unsigned fasciculus,
- 20:51which is a pathway that connects
- 20:53the temporal lobe with the inferior
- 20:55frontal gyrus and has us by the
- 20:58amygdala and the hippocampus.
- 21:00And we did analysis along this tract
- 21:03of different diffusion parameters
- 21:05as you can see here.
- 21:07So this is the tract and what we
- 21:10saw bilaterally was that higher
- 21:12maternal interleukin.
- 21:13Six was associated with lower
- 21:16fracture anisotropy which is a
- 21:18measure of lower maturation of
- 21:20this tract and this was
- 21:22very specifically where around the track
- 21:24where it passes by the amygdala and I think
- 21:29this is interesting because it's it's a
- 21:33bilateral and this is just a scatter plot.
- 21:37This is here you can see what the tracks
- 21:39look like and what the results look like.
- 21:42So it's it's. It's really a pretty nice
- 21:46linear association and unfortunately only
- 21:48in a really small subgroup here we had
- 21:52repeated MRI scans at 12 month age as well.
- 21:56So we looked at whether there is also an
- 21:59association between maternal interleukin 6
- 22:01concentrations and these diffusion measures,
- 22:03so 12 month age, which was not the case,
- 22:05it was not significant anymore.
- 22:06But what had happened is that the
- 22:09there was accelerated maturation
- 22:10now over the first year of life,
- 22:13which I mean it's.
- 22:14Very small sample and it needs
- 22:15to be replicated.
- 22:16But I think it is really interesting
- 22:18in the if we think about like what
- 22:21we know about this brain overgrowth,
- 22:24for example in the context of autism
- 22:27spectrum disorders that has been shown.
- 22:29So there might be like an initial delay
- 22:32and then an overcompensation and maybe
- 22:35this is something that we see here.
- 22:39So this is a summary of the various
- 22:41findings with variation and maternal
- 22:43interleukin 6 concentrations.
- 22:45And for all these outcomes that
- 22:49we have looked at,
- 22:49we see associations with behavioral
- 22:52or cognitive function in the
- 22:54first two years of life.
- 22:56So this,
- 22:57it makes a lot of connectivity was
- 22:59associated with a measure of executive
- 23:02function response inhibition when
- 23:03the children were two years old.
- 23:06Does it make a lot of connectivity
- 23:08and especially this accelerated
- 23:09increase also during the first year
- 23:11of life was associated with cognitive
- 23:13impaired cognitive development
- 23:14based on the Bayley scales of infant
- 23:17development at one year age and the
- 23:20whole brain functional connectivity
- 23:22was predictive of working memory
- 23:24function that two years age.
- 23:26And because we had these various
- 23:29cognitive aspects that were altered in
- 23:33association with maternal interleukin.
- 23:36Six we wanted to see,
- 23:38although again it was like a
- 23:40small sample at four to five years
- 23:43whether we we have like for a very
- 23:46general cognitive measure here it's
- 23:48fluid intelligence and association
- 23:50between maternal and telekin.
- 23:526 And this measure of fluid intelligence
- 23:54which was the case and this was
- 23:57after adjusting from many variables
- 24:00that would like be qualified,
- 24:02would be indicators of the quality of
- 24:04the post Natal environment like the home.
- 24:06Environment maternal sensitivity,
- 24:08for example,
- 24:09and we also try to see whether we can
- 24:13identify some structural variation
- 24:15and in brain structure that might
- 24:18underlie this association and saw
- 24:21that potentially specifically again
- 24:23here in the prefrontal cortex,
- 24:25the horse triangularis might play
- 24:28a role in this association.
- 24:31There is more evidence now also
- 24:35from other groups,
- 24:37showing that maternal immune activation,
- 24:40here also in humans,
- 24:42is associated with neonatal brain
- 24:45connectivity here specifically
- 24:47the the salience network.
- 24:49This is an interesting study because
- 24:51it's a it's a real longitudinal
- 24:54study looking at maternal cytokine
- 24:56concentrations during pregnancy and brain
- 24:59circuitry 45 years later in adults.
- 25:02There is also evidence,
- 25:05at least in terms of neurodevelopmental
- 25:08delay from like very impressive
- 25:11Scandinavian birth records,
- 25:14and also some interesting.
- 25:17Studies in nonhuman primates.
- 25:21So to conclude,
- 25:22there is evidence for prenatal
- 25:24conditions like various forms
- 25:26of stress but also cortisol and
- 25:28inflamed inflammatory medias like
- 25:30interleukin 6 to be associated
- 25:32with fetal brain development.
- 25:33And showed you evidence for associations
- 25:35with the size of the hippocampus
- 25:37and amygdala as well as structural
- 25:39and functional connectivity of
- 25:41the amygdala and as well as global
- 25:44cortical volume and thickness
- 25:45and the functional connectome.
- 25:48And it really seems like neural
- 25:50phenotypes are being programmed.
- 25:52Increased risk for neurodevelopmental
- 25:54and psychiatric disorders and
- 25:56that potentially these stress
- 25:59sensitive biological mediators,
- 26:01variation and maternal stress
- 26:02biology do play a role for
- 26:05programming in the fetal brain.
- 26:08I think if we talk about MRI,
- 26:11we have to also acknowledge this paper.
- 26:13This is something that has
- 26:15been published last year and
- 26:17my collaborators Damian Ferron,
- 26:19Ellis Graham and Oscar Miranda Dominguez,
- 26:21who I work with closely,
- 26:22are all involved in this and.
- 26:25So I think there is a crisis,
- 26:29a replication crisis,
- 26:30something similar that has
- 26:32affected a genomics a while ago,
- 26:36where this study really suggests that if
- 26:38we want to look at brain wide associations,
- 26:41especially with certain phenotypes,
- 26:43especially when it's complex phenotypes
- 26:45like mental health outcomes,
- 26:47we need very large sample sizes
- 26:49because effect sizes are small and
- 26:51probably most studies that have been
- 26:53published are underpowered and they.
- 26:55Like,
- 26:56I think they showed the evidence for
- 26:58this very impressively in this study.
- 27:01They also did acknowledge that
- 27:03there are phenotypes where the
- 27:06associations are stronger,
- 27:07like cognitive phenotypes for example.
- 27:10But in general,
- 27:11I mean this raises really the question,
- 27:13what can we do with these smaller
- 27:15sample sizes and can we still,
- 27:17are they still worth it,
- 27:18can we still trust the results?
- 27:20And Umm.
- 27:20So we have of course done a lot
- 27:24of thinking and.
- 27:25What we what we feel about what
- 27:27we have published so far and what
- 27:30we can do going forward.
- 27:31And so I I still believe that we
- 27:35have a very good conceptual model
- 27:38and there's a lot of preclinical
- 27:41evidence kind of supporting the
- 27:43kind of analysis we have done
- 27:45and also like in support of the
- 27:48specific findings we have.
- 27:50But in the future we should
- 27:53still see whether we can do.
- 27:55Better whether there are
- 27:58opportunities for replication,
- 28:00whether we can work together more
- 28:02closely in terms of the specific
- 28:04protocols not only for data
- 28:06collection but especially also
- 28:08for processing the data they are,
- 28:11I think there are a lot of
- 28:14opportunities for collaboration.
- 28:15And there is this fetal infant
- 28:17toddler on your imaging group that
- 28:20that has been founded that really
- 28:23addresses some of these issues
- 28:27and were people who work in the
- 28:30field of Infinera imaging,
- 28:31come together and share their
- 28:33experiences and bring their protocols
- 28:35together. There's a lot of progress
- 28:38in freely available processing
- 28:41pipelines and a lot of advances.
- 28:43Then there are several.
- 28:45Consortia are trying to bring in,
- 28:47bring together the various infant samples.
- 28:49There are like this origin consortium
- 28:52that is led by Rebecca Nikaya in
- 28:55Michigan or also the Echo consortium.
- 28:57And then of course there are larger
- 29:01representative developmental in
- 29:02your imaging studies like the
- 29:04Baby Connectome project and very
- 29:06importantly coming up the HBCD
- 29:08study that I think would be very,
- 29:10very informative.
- 29:13Something that we have also
- 29:15think about is how can we huge,
- 29:17how can we use the larger consortia that
- 29:21are available right now to potentially
- 29:24inform the results in our smaller cohorts.
- 29:26And one of the things that we are trying
- 29:29to do now is to use the larger consortia
- 29:32like for example the ABC D study to
- 29:35calculate polling euro risk scores.
- 29:37So really in the sample of
- 29:40several thousand like ABC D.
- 29:43Um, look at associations with a certain
- 29:45outcome that we are interested in,
- 29:47like internalising problems,
- 29:48and then look at the functional connectivity
- 29:52that is associated with this outcome
- 29:54and then apply the weights from this
- 29:57larger consortium to our smaller samples.
- 30:00So really a very similar approach to
- 30:02polygenic risk scores and this is
- 30:04something we are currently working on and.
- 30:06We have done this for it makes a lot of
- 30:09connectivity and internalizing problems and
- 30:12we're actually able to then use this Poly.
- 30:16Pulling your risk score to predict
- 30:19emotional regulation and our infant cohort.
- 30:21So this is work in progress but this
- 30:24is and this is led by by Oscar Randos
- 30:29Dominguez and he he has yeah we I
- 30:32think we are making good progress to
- 30:35to see how we can utilize these larger
- 30:37cohorts and another example is for
- 30:40example these brain charts for human
- 30:42for the human lifespan that has been
- 30:44recently published based on like 100.
- 30:461000 individuals,
- 30:47something similar to growth charts so that
- 30:50you can see where does your data fall,
- 30:52how representative is it,
- 30:54and then you get percentiles
- 30:56based on the larger population,
- 30:58which I think probably is a good way of
- 31:01correcting your smaller sample sizes.
- 31:02So this is something we are
- 31:05currently working on.
- 31:07And I'm happy to discuss this further later.
- 31:10But before I come to the end,
- 31:12I want to talk about this 4th
- 31:14area that I wanted to address,
- 31:16which is maternal preconceptional
- 31:20stress experiences and specifically.
- 31:23Now it doesn't work again.
- 31:30This slide.
- 31:35Maybe I stay very long.
- 31:38Thank you so. The UM,
- 31:42maternal child adverse childhood experiences
- 31:44and how these might potentially get
- 31:48transmitted to the next generation.
- 31:51And so, I mean we're thinking of different
- 31:56forms of neglect and abuse experiences and.
- 32:01As we all know, this is a huge problem
- 32:03because prevalence rates are really,
- 32:05really high.
- 32:06I think it's also really important that
- 32:09people working and and and perinatal
- 32:12medicine know that this is like such
- 32:15a high prevalence and that they will
- 32:17encounter many women who have made
- 32:20these kind of experiences and that
- 32:22potentially 1/3 of the women that they
- 32:25see could have these kind of risk factors.
- 32:29What we know from like many studies
- 32:31is that there is an increased risk
- 32:35in the exposed individual for higher.
- 32:37For psychiatric disorders as well As
- 32:40for somatic disorders and metabolic
- 32:43function like obesity,
- 32:45and we also understand some of the
- 32:47mechanisms.
- 32:47We know that there are alterations
- 32:50in the endocrine stress system,
- 32:52but also a very well replicated
- 32:55finding is increased systemic
- 32:56inflammation in individuals exposed
- 32:59to childhood maltreatment.
- 33:01And what is accumulating more and more
- 33:03is that also the offspring of these
- 33:05mothers who themselves have not been.
- 33:08Victims of abuse also have a higher
- 33:11risk for neurodevelopmental disorders,
- 33:13behavioral problems,
- 33:14but also adverse birth outcomes and.
- 33:20Also obesity, for example,
- 33:22and what we have done in in the ongoing
- 33:27ECHO cohort is because several studies in
- 33:31smaller or larger samples have addressed
- 33:34the association between maternal childhood
- 33:37maltreatment and single health outcomes.
- 33:39And what these studies do not allow to
- 33:42address is what is the potential effect
- 33:45on comorbidity across disorder, so.
- 33:48We took advantage of this echo cohort
- 33:51where we had information on up to 4000
- 33:56Mother child diets and we're about like.
- 33:59A little more than a third of those
- 34:03mothers did report that they had been
- 34:05exposed to childhood maltreatment.
- 34:07And then we looked at these six outcomes,
- 34:10internalizing problems, asthma, obesity,
- 34:13autism spectrum disorders, ADHD analogy.
- 34:16And as you can see here,
- 34:19across many of these disorders,
- 34:22we see a very significant increase
- 34:24in the risk for these disorders
- 34:26in children whose mothers had been
- 34:28exposed to childhood maltreatment.
- 34:31The highest is for internalizing problems,
- 34:33but also for autism spectrum disorders.
- 34:37It's one.
- 34:38It's a 1.7 fold increase and a more
- 34:42than twofold increase for ADHD.
- 34:44And there's also an increase for asthma.
- 34:47We didn't find any association with allergy,
- 34:50and the only outcome where we found
- 34:53an association that was moderated
- 34:54by sex was obesity.
- 34:56So only female offspring whose mothers
- 34:58had been exposed to childhood trauma were.
- 35:02Had a higher risk for obesity and
- 35:05what was really interesting.
- 35:08Is that these mothers, these,
- 35:12these children clustered into different
- 35:15groups and there was one group that
- 35:18you see here who had who had diagnosis
- 35:21on various of these outcomes,
- 35:24especially the neurodevelopmental outcomes.
- 35:28ADHD,
- 35:28LG,
- 35:29but also asthma and also internalizing
- 35:32problems.
- 35:33And mothers of children in this group
- 35:35were twice as likely to have been exposed
- 35:38to childhood maltreatment then in the
- 35:40other lower risk groups with lower health,
- 35:43with the lower prevalence of health outcomes.
- 35:46And then we also did a latent class
- 35:49analysis to to look at whether different
- 35:52types of exposures of maternal childhood
- 35:55maltreatment were associated with
- 35:56specific outcomes and the child.
- 35:58But what our data suggested
- 36:00was that it was rather,
- 36:02um,
- 36:02a matter of severity,
- 36:04because it was those mothers who
- 36:06had been exposed to more than one
- 36:08type of abuse and neglect whose
- 36:11children had the highest risk of
- 36:13developing these disease outcomes.
- 36:16So this paper was just accepted for
- 36:19publication and will be out next week.
- 36:21Umm, it's not yet out.
- 36:23We are working on it. And so I want to.
- 36:29I'll be quick,
- 36:30I will.
- 36:31I will only talk like I try to finish
- 36:33in like 5 minutes and we'll talk a
- 36:35little bit of the Mecca about the mechanisms,
- 36:37what might underlie this
- 36:40intergenerational transmission.
- 36:41And there has been a lot of focus.
- 36:43On post Natal factors,
- 36:45because women exposed to childhood
- 36:48maltreatment have a higher risk
- 36:51for postpartum depression,
- 36:52they have more often bonding difficulties.
- 36:56They're like impaired maternal,
- 36:59maternal sensitivity,
- 37:00which of course are all risk factors
- 37:03for later pathology and the child.
- 37:06But the case we wanted to
- 37:08make is. And that's because of all
- 37:12the evidence for altered stress
- 37:15biology in the exposed individual.
- 37:17After childhood maltreatment,
- 37:18they will most likely carry
- 37:20those forward to pregnancy.
- 37:21It will not stop once they become pregnant.
- 37:24And I have just shown you that
- 37:25there's a lot of evidence that like
- 37:27variation in these biological mediators
- 37:29can then program the fetal brain.
- 37:31And this is what we're trying
- 37:34what we've tried.
- 37:35To summarize in this review and also
- 37:38recent another recent review how
- 37:40the various sequelae of maternal
- 37:43childhood maltreatment that you see
- 37:45here will affect the biological
- 37:47state during pregnancy and can can
- 37:50affect fetal brain development
- 37:53and even the maternal behavior.
- 37:56The post Natal environment that is
- 37:59being created by that will most
- 38:01likely be affected by stress biology
- 38:04during pregnancy and this is.
- 38:06Something else,
- 38:07uh Kieran and I are working on
- 38:09together whether there could be
- 38:11differences in estrogen sensitivity
- 38:13potentially that will maybe reduce
- 38:15estrogen sensitivity in these
- 38:17mothers who have been exposed to
- 38:19childhood maltreatment that might
- 38:21not allow her brain to adapt to
- 38:23this new situation to prepare for
- 38:26motherhood as well as in individuals
- 38:28with higher estrogen sensitivity.
- 38:30At least this is a working hypothesis
- 38:33that we are examining right now.
- 38:37Umm here's an overview of various
- 38:42associations between maternal
- 38:43childhood maltreatment and variation
- 38:46in stress biology during pregnancy.
- 38:49And so this is what we have
- 38:52contributed to as well.
- 38:53And indeed,
- 38:54there is evidence for higher cortisol
- 38:57concentrations during pregnancy,
- 38:58higher inflammation,
- 39:01steeper increase in this placental
- 39:02CRH over the course of gestation,
- 39:05but also other important.
- 39:06Andrew,
- 39:07current mediators like thyroid
- 39:08hormones that are very important
- 39:10for fetal brain development seem
- 39:13to be associated with higher
- 39:15maternal childhood maltreatment.
- 39:17And to to really make the case that
- 39:19the transmission already occurs
- 39:21prenatally and not just pro postnatally.
- 39:23We wanted to show that already in the
- 39:26neonatal brain we see associations
- 39:28with maternal childhood maltreatment
- 39:29and this was indeed the case.
- 39:31We saw that neonates newborns whose
- 39:34mothers were exposed to childhood.
- 39:37Treatment had actually overall
- 39:38smaller brain volumes and very
- 39:41specifically lower Gray matter volumes.
- 39:43When we looked at whether this was
- 39:45regional specific or more global effect,
- 39:46we really saw it was more of a global
- 39:49effect globally smaller brain.
- 39:51In these newborns whose mothers had
- 39:53been exposed to childhood maltreatment,
- 39:55so really making the point that
- 39:57it's then probably something like
- 40:00the post Natal environment that
- 40:02might also be affected will add
- 40:04on top of this this early already
- 40:07prenatally programmed phenotype.
- 40:09And we were interested in whether
- 40:12total brain volume and newborns
- 40:14was associated with cognitive
- 40:17performance and executive function
- 40:19and did not find any main effect.
- 40:22Um in two years and 4 1/2 years.
- 40:24But again,
- 40:25we saw a really interesting
- 40:27moderation by maternal sensitivity
- 40:29that we observed in a standardized
- 40:32place situation in a way that.
- 40:35Infants with larger brain volumes,
- 40:37we are more able to benefit and
- 40:40be affected by variation in
- 40:42maternal sensitivity,
- 40:43whereas this was reduced
- 40:46and individuals who are born
- 40:47with a smaller brain volume,
- 40:49and this was the case at two
- 40:51years and also a very similar
- 40:53pattern at four to five years.
- 40:57So potentially we want brain
- 40:59volume could be in Europe phenotype
- 41:01that indicates differential
- 41:03susceptibility to the environment.
- 41:06Umm. And this is something else
- 41:08we have recently been working on.
- 41:11This is diffusion tensor imaging
- 41:14data of our new cohorts that we
- 41:19recently that we recently established.
- 41:22And here what we see is that it
- 41:26seems so we look at diffusion tensor
- 41:29imaging and we look at this measure
- 41:33radial diffusivity where higher
- 41:35scores indicate lower maturity.
- 41:37And, um, we see that different
- 41:39forms of depression seem to be
- 41:42associated with different patterns.
- 41:44So depression depressed mothers who had
- 41:46been exposed to childhood maltreatment,
- 41:49their children at birth seem to have
- 41:52have a phenotype of delayed maturation,
- 41:55whereas those newborns whose mothers had
- 41:58been exposed to childhood maltreatment.
- 42:01But we're not exposed shelter maltreatment,
- 42:05sorry.
- 42:05And we're depressed during pregnancy rather.
- 42:07Go to pattern of accelerated maturation
- 42:10and I think this is this is interesting
- 42:13because we know that both delayed
- 42:15maturation but also accelerated
- 42:17maturation might have negative outcomes.
- 42:19So I think it is really important to
- 42:22consider both ends of the spectrum
- 42:24and that's why I thought this was
- 42:27actually a quite interesting finding.
- 42:30Umm.
- 42:32So this is just in terms of
- 42:34clinical application,
- 42:35this is something we've developed
- 42:38with my colleagues Christina,
- 42:40Hayem and Azania entering at the
- 42:43charity this kind of the cycle of
- 42:46biological embedding of child of
- 42:50adverse childhood experiences and.
- 42:53And also where potential targets could
- 42:56be for intervention to break the
- 42:59cycle after exposure to not even like
- 43:03to prevent the biological embedding.
- 43:05But if it has embedded,
- 43:06if it has already been embedded,
- 43:08is there a potential for reprogramming
- 43:10for compensation so that not like
- 43:13certain phenotypes get established but
- 43:16then I think what we can do in like
- 43:20caring natural care is really try to.
- 43:24Work here.
- 43:25Work on disrupting this vicious
- 43:27cycle of the intergenerational
- 43:29transmission by really trying to
- 43:32focus or identify women at risk.
- 43:36And and see how to support women who have
- 43:39been exposed to childhood maltreatment,
- 43:42and ideally already during the
- 43:44preconceptional period or during pregnancy.
- 43:47But then of course also providing
- 43:49support in the postpartum period.
- 43:52But as always,
- 43:53of course the the earlier the better.
- 43:57I'd like to just.
- 44:00Finished with this quote,
- 44:01it is easier to build strong
- 44:03children than repair broken men,
- 44:05so I think it is really important to
- 44:09understand the very early origins of.
- 44:13Susceptibility for mental health or
- 44:17adverse mental health conditions.
- 44:22Because we can take advantage
- 44:24of the great plasticity of the
- 44:27brain during development and yeah,
- 44:29and deliver targeted interventions to, yeah,
- 44:32take advantage of this high plasticity.
- 44:36I would like to close by of course.
- 44:40Thanking all my collaborators.
- 44:44Without whom, I couldn't have done this work,
- 44:47and I'd also like you for your attention.
- 45:00Thanks so much. Talk to us.
- 45:01Any questions for Doctor
- 45:03bus in the audience?
- 45:07We do have one question already and
- 45:09from zoom and if Lilia Benoit would
- 45:11like to to unmute maybe start your
- 45:14video and always interesting to discuss
- 45:16individual differences and potential
- 45:18moderating influences and Lilia, do you
- 45:20want to pose your question? Yes.
- 45:23Hi. Can you hear me? Yes, yes.
- 45:26OK. Thank you very much for for this talk.
- 45:28It's very, very interesting.
- 45:30And I'm not an expert at all in methylation.
- 45:35I'm Shawna Dawson, psychiatrist.
- 45:37But I'm more interested usually in behavior,
- 45:42family therapy, communication.
- 45:45And so it's always very unsettling
- 45:48for me because I have the
- 45:50impression that sometime sometimes.
- 45:52When we measure the outcome of
- 45:54the adverse childhood experiences,
- 45:56I do not see how we can measure the
- 46:00moderating effects of behaviors.
- 46:03And and the role model effect on the
- 46:06parent behavior toward the child.
- 46:09And so even maybe I'm just very biased
- 46:12because it's an area I don't know much about.
- 46:14But when I read sometimes obesity,
- 46:17ADHD, depression, inflammation,
- 46:18my impression is that all
- 46:20of these outcomes could be,
- 46:23might be directly transmitted
- 46:25just through behaviors like the
- 46:28maternal behavior towards herself.
- 46:30I don't know, using drugs.
- 46:33Being addictions,
- 46:33feeling depressed or the parental
- 46:36behavior towards a child,
- 46:37which is like repeating this
- 46:39circle of trauma.
- 46:40And so it's very puzzling
- 46:43for me because I'm just like,
- 46:45how I can, how can we measure,
- 46:46you know, or how could we compare,
- 46:48should we go back to very biological?
- 46:53Causation or.
- 46:54Or could we just say,
- 46:56oh,
- 46:56maybe it's just the behavior of being
- 46:58transmitted and we are actually
- 46:59measuring something else which is a.
- 47:02And the body signals of it.
- 47:06But actually this is not really
- 47:07the cause of transmission.
- 47:09I don't know if it's clear.
- 47:10I
- 47:10I think it is clear and I
- 47:12don't think it's an either or.
- 47:13I think the behavior that is
- 47:15altered in response to these
- 47:18adverse experiences will actually.
- 47:20Moderate or affect how much her
- 47:23biology is changed in response
- 47:26to childhood maltreatment.
- 47:28This is why I had this one figure.
- 47:30Sorry, I went through it very quickly with
- 47:33these various sequelae like drug exposure,
- 47:35like obesity, other risky behavior,
- 47:38but also her mental health.
- 47:40And it is indeed the case that
- 47:42the more risk factors they have.
- 47:45The higher or the the the the more
- 47:48pronounced are the differences in
- 47:50biological markers during pregnancy.
- 47:52For example,
- 47:53I don't think I mentioned that,
- 47:54but in our studies when we have
- 47:57looked at inflammatory markers
- 47:58during pregnancy in women who had
- 48:01adverse childhood experiences,
- 48:03we see it only elevated in those
- 48:05women who have also depressive
- 48:07symptoms during pregnancy.
- 48:09So I think these like what has
- 48:12established as a consequence,
- 48:14sorry, I'm looking at you,
- 48:15but I should be looking there.
- 48:17What has been established in terms of
- 48:20sequella of these adverse experiences
- 48:22are extremely important and these
- 48:25include behavioral alterations because
- 48:27because if certain phenotypes like
- 48:29depression has been established,
- 48:31this will affect her behavior
- 48:33towards her child most likely.
- 48:35And I think This is why it is so
- 48:38important that we identify these women
- 48:40because we cannot change anything
- 48:42about these experiences that the the
- 48:44the mothers or the parents made.
- 48:46But we can of course try to positively
- 48:49affect some of these sequella,
- 48:52and I think this will already this
- 48:54will already be very effective.
- 48:58Sorry. Thank you.
- 49:02That was really fascinating.
- 49:03Thank you so much.
- 49:04I I was wondering about your comment
- 49:07about girls only being affected.
- 49:10With obesity of girls,
- 49:12of these moms, what, what,
- 49:13what sense do you make of that?
- 49:18That that is difficult. I don't think
- 49:23we really know why this might be.
- 49:26It is interesting that also in exposed
- 49:28individuals it seems like that obesity risk
- 49:31is higher and exposed females than males.
- 49:34Umm. I really don't know.
- 49:36We have a good sense of this.
- 49:38I thought it was really interesting that
- 49:40this was the only outcome that we saw
- 49:44differential effects based on offspring sex.
- 49:48But I actually have to pass.
- 49:49I don't have a good idea.
- 49:50I can, I can say that it has been similar
- 49:54things have been shown in the in the
- 49:57as I said in the exposed person but.
- 50:00Yeah, we don't know.
- 50:01I think this is something to really
- 50:03something to really look look into.
- 50:05And I have to say that the
- 50:08few studies there are,
- 50:09they haven't always looked at sex
- 50:12differences and moderation by by sex.
- 50:14So I think we will have to see
- 50:17whether this this gets replicated
- 50:18and try to make sense of this.
- 50:22Thank you so much. Go catch. One
- 50:24last quick question.
- 50:28Yeah, amazing.
- 50:29Amazing talk and fascinating area.
- 50:33Quick question about the
- 50:35studies involving stress.
- 50:36Were you specifically targeting
- 50:38populations of parents with high
- 50:41stress levels due to whatever other
- 50:44factors that might be causing?
- 50:45Or were you targeting sort of
- 50:47more of a general population?
- 50:49And if if so,
- 50:51are they levels of stress that we
- 50:54should be particularly worried about?
- 50:55Can we quantify
- 50:56it? Can we know when to intervene
- 50:59can and when are we dealing
- 51:00with the natural variation?
- 51:03I think that's a it's an important
- 51:05question and very difficult to answer.
- 51:07So the the first part is very easy.
- 51:08So the initial studies we did
- 51:10and the data I presented today
- 51:12was just a normal population,
- 51:15so normal variation and stress
- 51:17our current ongoing work.
- 51:18We have enriched the cohorts for women
- 51:21exposed to childhood maltreatment.
- 51:23So they are slightly higher risk because
- 51:26we want to investigate this further
- 51:28and also start looking further into
- 51:31these the moderating role of these.
- 51:33So we have enriched.
- 51:35Our ongoing cohorts.
- 51:38What are levels that we should
- 51:39be paying attention to?
- 51:40I think this is really difficult
- 51:42because as I said it's not a one-on-one
- 51:45translation and actually there are
- 51:47a lot of studies that don't find
- 51:49associations between variation and
- 51:51psychological stress and biological
- 51:53mediators that they measure.
- 51:55And I think well obviously it doesn't
- 51:57mean that there is no association,
- 51:59I don't think it's it's measured correctly.
- 52:02So something that we have done
- 52:04for example in this but these
- 52:06ecological momentary assessments is.
- 52:08That we see that the intra individual
- 52:11variation in stress is what is
- 52:14associated with cortisol concentrations.
- 52:16Not the inter individual variation,
- 52:18but how much the individual
- 52:21varies around her or herself.
- 52:24Her own mean is what is important.
- 52:28So I think just based on
- 52:31questionnaire measures in screening,
- 52:34it would be hard to say,
- 52:35oh,
- 52:35this is what you should pay attention
- 52:37to and this is what you should not
- 52:39pay attention to because the how it
- 52:41gets translated into signals for the
- 52:43features might be very different based on,
- 52:46as I said,
- 52:47various resilience factors.
- 52:49But of course I think in general
- 52:51we should be paying attention
- 52:53to mental health and stress,
- 52:55especially in the enduring prenatal care.
- 52:58Because even if maybe it's not high
- 53:01enough to affect the fetus in a negative way,
- 53:04I mean you can do something for the mother.
- 53:06And I think in general it's still
- 53:08a problem that mental health issues
- 53:10are not very much the focus or
- 53:12at least are paying attention,
- 53:14being paid attention to enough during
- 53:17prenatal care and similarly the
- 53:20these adverse childhood experiences.
- 53:24I I always say I I really had a
- 53:27very difficult time to establish,
- 53:29um,
- 53:29the study and in Germany because
- 53:31I got a lot of feedback saying you
- 53:33cannot ask pregnant women about
- 53:35adverse childhood experiences.
- 53:37You will read,
- 53:38traumatize them and you should
- 53:39not do that to a pregnant woman.
- 53:41And I really had to argue that
- 53:43I think we're doing something
- 53:45good for the women because these
- 53:48thoughts will get illicit anyway,
- 53:50because now they are becoming parents.
- 53:52They will think about their own childhood.
- 53:54And it is important to do this in a very
- 53:56secure environment and then offer them help.
- 53:58And they are actually papers out
- 54:01there on exactly this topic saying
- 54:03that women would hope to be asked
- 54:06about these experiences,
- 54:08especially,
- 54:08for example,
- 54:09if it has been sexual abuse,
- 54:10because this can really affect
- 54:12a vaginal delivery and it's
- 54:13very important that these women can
- 54:15address these kind of concerns.
- 54:17Early on our studies, for example,
- 54:20we've had these cases and we went
- 54:22to the delivery room with them and.
- 54:24Some of them, it really helped them
- 54:26to prepare for that and sometimes I
- 54:28still have to do a cesarean section
- 54:30and others were then able to really
- 54:31try it and and go through with it.
- 54:33I think it's it's in general I would
- 54:36say we should start paying attention to
- 54:39stress and mental health issues in general.
- 54:43And even if even if it's not like
- 54:45a extremely higher or toxic level
- 54:47that it would affect the fetus,
- 54:49we can do something good for the
- 54:51for the pregnant woman and that
- 54:53will have a positive impact.
- 54:55But I cannot say, well,
- 54:57this is a cut off that you should pay
- 54:59attention to and others you you shouldn't.
- 55:01It's very difficult of course I
- 55:03think you're rallying cry for.
- 55:06The support for pregnant individuals
- 55:07is a great way to end this.
- 55:08Thank you again, Doctor Bush.