Prenatal Caffeine Exposure: Association with Neurodevelopmental Outcomes

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In this podcast, we hear from neuroscientist Dr. Peter Manza and Dr. Rui Zhang of the Laboratory of Neuro Imaging, National Institute on Alcohol Abuse and Alcoholism at the National Institutes of Health, Bethesda, Maryland in the USA.

The focus is on their co-authored Open Access JCPP paper ‘Prenatal Caffeine Exposure: Association with Neurodevelopmental Outcomes in 9- to 11- year old children’.

Rui and Peter summarise the paper, provide an insight into the methodology used, as well as share some of the key findings, including the association of prenatal caffeine exposure with externalising problems in children.

Furthermore, we hear Rui and Peter discuss what, in their view, is a safe dose of caffeine for expectant mothers, whether expectant mothers should cut out caffeine altogether, and what are the implications of this study for policymakers and professionals working with young people and their families.

You can listen to this podcast directly on our website or on the following platforms; SoundCloudApple PodcastsSpotifyCastBox, DeezerGoogle Podcasts and (not available in the EU).

Dr. Rui Zhang
Dr. Rui Zhang

Dr. Rui Zhang studied psychology at the University of Marburg and received her Ph.D. in cognitive neuroscience from the Technical University of Dresden in Germany. After Ph.D., Rui joined LNI as a special volunteer with research fellowship from German Research Foundation in November 2018 and became a postdoctoral IRTA fellow afterwards. Her research focuses on the role of sleep in drug addiction using multimodal imaging techniques (e.g. fMRI, EEG). She is currently working on sex differences in sleep and how this is affected by drug use. (Bio from National Institute on Alcohol Abuse and Alcoholism)

Dr. Peter Manza
Dr. Peter Manza

Dr. Peter Manza joined the LNI as a postdoctoral IRTA fellow in February 2017. He studied psychology and biology at the University of Rochester and earned his Ph.D. in integrative neuroscience from Stony Brook University in December 2016. Pete is interested in how dopamine influences cognitive control in health and neuropsychiatric disease. He is currently working on combining fMRI, PET, and neuropsych measures to understand how negative emotionality and stress influence brain functions that support cognitive control in drug addiction. (Bio from National Institute on Alcohol Abuse and Alcoholism)


[00:00:27.200] – Jo Carlowe: Welcome to a different type of in conversation podcast from the Association for Child and Adolescent Mental Health, ACAMH, where we will look at the paper ‘Prenatal Caffeine Exposure: Association with Neurodevelopmental Outcomes in 9- to 11- year old children’, recently published in the JCPP. I’m Jo Carlowe, a freelance journalist with a specialism in psychology, and I have with me neuroscientist Dr. Peter Manza and Dr. Rui Zhang of the Laboratory of Neuro Imaging, National Institute on Alcohol Abuse and Alcoholism at the National Institutes of Health, Bethesda, Maryland in the USA.

[00:01:03.380] Rui and Peter are co-authors of the paper that we’ll be discussing today. If you’re a fan of our In Conversation series, please subscribe on iTunes or your preferred streaming platform. Let us just know how we did with a rating or review and do share with friends and colleagues. Rui and Peter welcome. Can you start by introducing yourselves?

[00:01:22.270] – Dr. Rui Zhang: Thank you, Jo. Thank you for having us. My name is Rui Zhang as you introduced. I’m currently a post doctor fellow at the National Institute on Alcohol Abuse and Alcoholism. I had my training in cognitive neuroscience and clinical psychology in Germany and the focus of my research is on substance use and sleep circadian rhythms. So we all know that caffeine is the most consumed psycho-stimulant worldwide and can strongly affect our sleep. So as a neuroscientist I’m very curious to know how caffeine effects our brain and also I’m a coffee-lover myself.

[00:01:55.780] So I enjoy my morning coffee very much. That’s also further enhanced my research interest in studying caffeine.

[00:02:04.300] – Jo Carlowe: Brilliant, and Peter over to you.

[00:02:04.300] – Dr. Peter Manza: My name is Pete Manza. I’m a research fellow in the same group in NIAAA and I did my training in cognitive neuroscience as well at Stony Brook University of New York and my research focuses on how drugs impact the dopamine system, stimulants, how those drugs can change our brain and our behaviour. I’m also completely hooked on caffeine.

[00:02:25.320] – Jo Carlowe: As mentioned in the intro you co-authored the paper ‘Prenatal Caffeine Exposure Association with Neuro-developmental Outcomes in 9- to 11- year old children’ published in the JCPP. Can you give us a summary of the paper? What did you look at?

[00:02:41.550] – Dr. Rui Zhang: Here maybe I start with our motivation to study prenatal caffeine exposure. So we know that the capacity of women to metabolise caffeine is markedly reduced during pregnancy. The half-life of caffeine in non-pregnant woman is roughly between four to six hours. While in pregnant women this could be six to 16 hours, so we can see a huge differences here. Also, the capacity of faders to metabolise caffeine is very limited, like almost zero. So as caffeine can be passed to the faders through the placenta and when we think about this, it’s very likely that pre-natal caffeine exposure can lead to accumulation of caffeine inside the brain.

[00:03:20.300] So in this study we look at associations of pre-natal caffeine exposure and with various developmental outcomes, and to understand the effect of caffeine we are particularly interested in using neuro imaging tools to exam related brain changes in children. So until now there are very limited neuroimaging studies on pre-natal caffeine exposure, and we knew almost nothing about how exposure to caffeine in utero affects our brain. So here we’re trying to fill in some piece of information that is missing in the scientific literature.

[00:03:54.250] – Jo Carlowe: And what methodology did you use for the research?

[00:03:57.390] – Dr. Peter Manza: We were using a large data set from the Adolescent Brain and Cognitive Development Study. This is also called the ABCD Study, and for those who may not know about it this is the largest long-term study of brain development and child health in the US, and this is funded by the NIH. It’s a very ambitious project. We’re tracking over 11,000 children ages nine to ten, and we’re following up with them for over ten years and getting measures of their biological and behavioural development.

[00:04:27.990] And the ABCD study is still ongoing. So it’s really just at the beginning of the project. So we’re using the baseline data here for those nine to ten year old children, and in our study we looked at children and excluded those who were exposed to other drugs of abuse in utero like tobacco, alcohol and other illicit drugs, which left us with roughly 10,000 children that we were able to study here. And we looked at prenatal caffeine exposure, which was assessed by the parents retrospective reports and we had various neurodevelopmental outcomes.

[00:05:03.630] There were interviews, there were questionnaires, there were physical exams, we had different cognitive tasks to assess things like memory function, for instance. Then there were brain scans so that we could look at if there were any possible differences in brain structure between children who were and who were not exposed to caffeine in utero.

[00:05:24.330] – Jo Carlowe: Great. It sounds very comprehensive. Can you share some of the key findings from the paper?

[00:05:30.260] – Dr. Rui Zhang: Yeah. We found that prenatal caffeine exposure was associated with some but not all developmental outcomes and also interestingly in a dose dependent manner. So more into details, we found associations with greater externalising problems, and that was even observed for the recommended safe dose. While the associations with greater BMI and greater soda consumption will only see with high dose exposures. And in contrast, we did not find associations with birth outcomes, sleep problems or internalising problems, cognitive performance. And in terms of brain correlates we see greater cortical signals in brain posterior regions and lower cortical signals in frontal regions.

[00:06:18.400] And we also see changes in sulcal depths which we mainly see in posterior regions.

[00:06:23.460] – Jo Carlowe: As you mentioned there prenatal caffeine exposure, including safe dose was associated with structural changes in the brain and greater externalising problems. Before we explore these findings in more detail, what is the recommended safe dose and is there a universal safe dose?

[00:06:41.620] – Dr. Peter Manza: Right. In 2015, the European Food Safety Authority delivered a scientific opinion on the safety of caffeine and they concluded that habitual caffeine consumption of up to 200 milligrams per day by pregnant women does not give rise to safety concerns for the foetus and 200 milligrams of caffeine roughly corresponds to two cups of coffee. The same recommendation is made by the American College of Obstetricians and Gynaecologists, and they suggest the same thing that less than 200 milligrams per day does not cause miscarriage or preterm birth, but of note, both recommendations are based on studies that just looked at pregnancy and birth outcomes.

[00:07:19.640] And in line with those previous studies we didn’t find any increased risk for birth. Poor birth outcomes associated with this dose of caffeine being under 200 milligrams, but we think it’s important to look beyond just birth outcomes and see if prenatal caffeine exposure affects kids as they age. We think this is an important question that shouldn’t be overlooked, and that was part of the motivation for the study.

[00:07:42.840] – Jo Carlowe: Let’s return to the findings. You talked about structural changes, what structural changes were seen, and can you explain to the lay person the significance of these changes?

[00:07:53.860] – Dr. Peter Manza: It’s important to mention that these brain changes that Rui was describing earlier, they were associated with the behavioural changes in children. So we can see a correlation between greater externalising problems in these children and greater BMI in association, that’s Body Mass Index, in association with these brain structural changes. So we’re operating on the theory that prenatal caffeine exposure may be causing some brain changes in the children. So differences in the thickness of the cortex and that this might be leading to their behavioural changes.

[00:08:32.600] But it’s really important to know that this is cross sectional data, meaning that we can’t establish causality for sure with this data. These are correlations, and this is a very large study. It’s great to have a really comprehensive study and a lot of kids that helps us to really feel solid about these associations. We think that they’re a real effect here, but at the same time we can’t demonstrate causality for sure. So an important next step is to understand how prenatal caffeine exposure actually leads to these brain structural changes that we’re seeing in a more causal way.

[00:09:13.680] So we hope that by understanding this we might be able to come up with targeted interventions to prevent these negative consequences that we think are may be induced by prenatal caffeine exposure.

[00:09:25.570] – Jo Carlowe: You point to a small but significant association of prenatal caffeine exposure with externalising, but not internalising problems in children. How do you account for this association with externalising behaviours?

[00:09:40.120] – Dr. Rui Zhang: That’s a very important question. So let me break this question into two parts. So first, why associations with externalising problems but not with internalising problems and the current signings of greater associations with externalising problems are also in line with previous studies, both done in humans and in animals. So the short answer to this question is that we still don’t know and to make this whole picture more complex we also see sex differences in our study. What we found is that boys and girls they showed different profiles for associated externalising problems, such that boys showed greater externalising problems in general, while girls reported greater conduct problems specifically, and further, girls, but not boys, with prenatal caffeine exposure had greater somatic complaints which is one of the internalising problems.

[00:10:39.110] So this is really interesting and suggests that prenatal caffeine exposure might affect boys and girls through different pathways. And another relevant point that worth discussing here is that the small effect size, which is also observed in other ABCD publications as well. So in part this might be due to the over representation of high functioning families included in the ABCD study. We know that high functioning family and also social environment could buffer negative consequences, and what should also be mentioned here that the effect size of association with externalising problems observed in the current study was comparable to previous ABCD publications on prenatal alcohol and prenatal cannabis exposure.

[00:11:29.610] So this is quite surprising and also to us when we look at the results for the first time and this really makes us rethink the importance of studies on prenatal caffeine exposure. As in our society there is greater awareness of alcohol and cannabis use during pregnancy, than caffeine used during pregnancy.

[00:11:49.170] – Jo Carlowe: As you explained earlier the study also suggested dose dependent association with maternal caffeine consumption during pregnancy and higher BMI during childhood. Can you elaborate on this finding?

[00:12:02.180] – Dr. Rui Zhang: Oh, correct. We found a greater BMI was only associated with high dose exposure in our sample with children at age nine to 11 years. So a prospective cohort study from Norway they also show the same results when they look at children at age eight years. However, very interesting, they demonstrated those by age effects. So in that study they measured outcomes of children at different ages, and when they look at the data from earlier time points like at age three and five years the association with higher BMI was found even for low dose exposure.

[00:12:42.210] So one potential explanation could be that when children get older, such as at nine to eleven years in our sample, the social and environmental factors such as a score attendance, care influence start to play a growing role in children’s lives, which could dampen the associations with prenatal caffeine exposure. What I also want to mention that our BMI findings is independent of children’s birth weight, socioeconomic status of the family or educational level of the parents, and as I just mentioned, that the same results can be seen across different social and cultural context in both the US and European samples.

[00:13:23.730] So this indicates that there might be biological pathways and through which prenatal caffeine exposure can affect fat metabolism in off-spring, as there’s already some suggestive evidence from animal studies.

[00:13:37.690] – Jo Carlowe: Thank you, and Rui and Peter is anything else in the paper that you’d like to highlight?

[00:13:42.360] – Dr. Rui Zhang: I think what could also be interesting to our audience is that in this study we explored the mother’s characteristics associated with high caffeine consumption during pregnancy. What we found is that women who are older, white, and who had higher level of psychopathology and also who consumed tobacco and alcohol before pregnancy appeared to have more caffeine intake during pregnancy and in contrast, women with higher education and higher income they had moderate caffeine intake with weekly or less than weekly use. And also important there was association between earlier awareness of pregnancy and less caffeine intake.

[00:14:24.320] This is consistent with previous findings showing that pregnant women tend to reduce their caffeine consumption compared to pre pregnancy which reflects to some extent of awareness of caffeine intake amount [inaudible].

[00:14:37.660] – Jo Carlowe: You conclude by saying you conclude in the paper by saying the recommended safe dose of caffeine during pregnancy should be reassessed. Is that happening, and in the interim what advice do you have for expectant mothers? What, in your view, is a safe dose?

[00:14:55.280] – Dr. Rui Zhang: I think the good news is that research interests and studies in the field have been growing and we have good hope that the guideline will be updated soon with more evidence accumulating and to the question what the safe dose is and whether there is a safe dose at all. So combine all the literatures in the field, as far as I can say, is that less is better, since there is no evidence showing that prenatal caffeine exposure has beneficial effects on children. However, there could be some medical concerns, especially withdrawal systems when stopping caffeine use all of a sudden.

[00:15:32.050] Unfortunately, we are not able to give mothers to be a clear answer to what a safe dose is with exact numbers. As we discuss in the paper there are some limitations in our study that restricts our conclusions. So, for example, the prenatal caffeine exposure was assessed by mothers’ respective report, so there might be some memory biases, but as studies keep emerging we believe that we should have the answer to that soon.

[00:15:59.320] – Jo Carlowe: And in the interim, if somebody is listening, who is expecting should they cut out caffeine altogether?

[00:16:06.620] – Dr. Rui Zhang: I would say they should consult with their doctors and really to make the informed decisions and we also think that professionals should also be open-minded and keep up with new evidence from the emerging studies in the field so that they can also help families make more informed decisions.

[00:16:25.120] – Jo Carlowe: Well, talking about professionals, what are the implications of your findings for them? This is the professionals working with young people and their families.

[00:16:33.520] – Dr. Rui Zhang: We feel strongly that both professionals and the families should be informed of potential negative effects of prenatal caffeine exposure on children, so that professionals can really help the families to make more informed decisions.

[00:16:48.400] – Jo Carlowe: What message should policy-makers take from the paper?

[00:16:51.860] – Dr. Peter Manza: As we said earlier, we think it’s important for policy-makers to not only look at studies on pregnancy and birth outcomes, but we need to start taking evidence from a broader array of studies, including those that follow children up for many years and look at their developmental outcomes throughout their childhood and adolescence. For example, in our sample, 58% of mothers used caffeine during pregnancy. So we think that because of this really high prevalence of caffeine use during pregnancy is actually in this sample of about 10,000 kids. We really think it’s important to reassess the guidelines which could be relevant for public health at the population level when you’re looking at these numbers.

[00:17:35.820] – Jo Carlowe: And are you planning some follow-up research that you can share with us?

[00:17:40.040] – Dr. Rui Zhang: One thing we would like to follow-up is to look at how prenatal caffeine exposure correlates with drug use, such as alcohol and nicotine use in children when they transitioning into adolescence. So at baseline, because of the very low use of drugs in children at age nine to ten years, we were only able to extend their soda consumption, which is the main source of caffeine intake for most children. As we know that high caffeine intake itself can also raise concerns for behavioural problems in children. So it could also be important to follow up whether soda consumption or caffeine intake at baseline would increase the risk of future drug use in these children.

[00:18:20.920] – Dr. Peter Manza: We have a lot of projects coming up in the future. As we said, you know, one of the most important things is to the children longitudinally over time and really understand the development from the foetus throughout childhood and adolescence. So as the study continues on and we’re able to look at these associations over time that’s going to be really, really important for determining some of these cause and effect relationships that we want to understand.

[00:18:47.590] – Jo Carlowe: And is there anything else in the pipeline that you’d like to mention?

[00:18:51.220] – Dr. Peter Manza: There are a lot of things in the pipeline of course. I think one of the most interesting things we’ve been talking about is there are advances in acquisition and analysis methods for foetal MRI. So we think it’s going to be really interesting when we can directly look at brain development in utero, we can do scans on the foetus directly, and so with foetal MRI we think that there’s really quite a lot of possibility for understanding the direct impact of drugs like caffeine and how they affect the foetus.

[00:19:26.340] – Dr. Rui Zhang: Yeah, I would echo what Pete said. We think there are really a lot of research possibilities, especially with the advance of acquisition and analysis methods.

[00:19:37.450] – Jo Carlowe: And finally Rui and Pete what are your take home messages for those listening to our conversation.

[00:19:43.340] – Dr. Rui Zhang: In the current study we provide evidence that prenatal caffeine exposure could affect children’s brain and behaviour. So here I would like also to stress is that caffeine intake during pregnancy deserves the same amount of public awareness as other drug use, particularly when we consider the similar effect size compared to prenatal alcohol and prenatal cannabis exposure.

[00:20:06.720] – Dr. Peter Manza: The main take home from this study is that we need to be very careful in what we put into our bodies during pregnancy, and this is a clear example of something where it’s worth taking another look at caffeine. Absolutely.

[00:20:21.700] – Jo Carlowe: Thank you both ever so much. For more details on Dr. Rui Zhang and Dr. Peter Manza, please visit the ACAMH website and Twitter @acamh. ACAMH is spelt ACAMH and don’t forget to follow us on iTunes or your preferred streaming platform. Let us know if you enjoyed the podcast with a rating or review and do share with friends and colleagues.

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