Episodic exposure to nicotine – caffeine – amphetamines trigger malfunctions in the fetal brain


If pregnant women take significant amounts of the psychostimulants coffee, nicotine, and amphetamine during pregnancy, their children have a higher risk of developing neurological and psychiatric problems later in life.

Researchers at MedUni Vienna’s Center for Brain Research have now successfully identified the regions of the brain that act as “hot spots” for psychostimulants and discovered that the mother’s reactions to these substances are substantially different from those of their baby.

This study has now been published in the multidisciplinary journal PNAS.

Drug abuse during pregnancy carries considerable risk and negatively impacts fetal development.

Even though the mother does not react particularly strongly to certain psychostimulants, these drugs can nonetheless permanently affect brain development of her baby or child.

The precise areas of the brain that are affected by maternal drug consumption were hitherto unknown.

The recent study conducted by MedUni Vienna’s Center for Brain Research, working in conjunction with the Swedish Karolinska Institute, has now shown that episodic exposure to amphetamine, nicotine or caffeine during pregnancy triggers an extensive malfunction in the fetal brain, which specifically affects the development of the indusium griseum (IG).

The IG is a cerebral area that reacted to all psychostimulants tested in a mouse model.

“In the indusium griseum, we found a new type of neuron that is affected by psychostimulants, in that they greatly inhibit its development so that the baby is born with neurons still in a fetal-like state.

A major consequence of this is that these cells are no longer able to integrate appropriately into the brain in the long term,” explains principal investigator Tibor Harkany from MedUni Vienna’s Center for Brain Research.

For their analysis, the researchers combined conventional neuroanatomy with the very latest RNA sequencing techniques to show how molecular impairments occur in neurons of the indusium griseum.

“In particular, the level of a certain protein, secretagogin, is reduced.

This deficiency impairs the mechanism by which neurons are able to process information. This has also been proven in genetic models.

Mice that do not have this protein respond to psychostimulants such as methamphetamine more strongly and with an increased risk of developing epilepsy,” explains lead author of the study Janos Fuzik from MedUni Vienna’s Center for Brain Research.

The result: Children could also develop an increased risk of neurological complications later on, because the anatomical structure of the indusium griseum is also present as a thin layer of gray matter in the human brain.

Neuronal population in the human IG documented for the first time

According to Harkany, a “surprising observation” was that there is any neuronal population in the indusium griseum of men at all.

“Up until now, science believed that there are no neurons, or only a tiny numbers of neurons, in this area,” he says. Whether the function of these neurons in the human brain is equivalent to those of mice needs further study, though.

The precise areas of the brain that are affected by maternal drug consumption were hitherto unknown.

“However, this at least shows that brain networks are more complex than previously thought, and that coordination of brain functions is much more diverse than we might have expected,” says Thomas Hokfelt of the Karolinska Institute, who is an adjunct professor at MedUni Vienna’s Center for Brain Research.

Since these neurons are involved in cognitive networks and probably facilitate cognition, when their networks become damaged by psychostimulants during their developmental phase, life-long deficiencies can be expected.

Maternal smoking during pregnancy (MSDP) remains an intractable public health problem. Despite pervasive medical and societal sanctions against smoking during pregnancy, 10 to 30% of women continue to smoke in the US (Curtin & Matthews, 2016Tong et al., 2013U.S. Department of Health and Human Services, 2014).

Although national health statistics show rates of 10% based on maternal/birth certificate reports, studies involving biochemical verification and those conducted in poor, young, and less-educated populations reveal rates as high as 25-30% (Bardy et al., 1993Dietz et al., 2011Mathews, 2001Tong et al., 2015). Although rates of spontaneous quitting are increasing, approximately 50% of pregnant smokers continue to smoke into the last trimester (Ockene et al., 2002Pirie, Lando, Curry, McBride, & Grothaus, 2000Tong et al., 2013).

Further, new and emerging tobacco products including electronic cigarettes and hookah are proliferating among youth and reproductive age women with potential to increase rates of infants born exposed to nicotine/tobacco (England et al., 2016U.S. Department of Health and Human Services, 2016Villanti, Cobb, Cohn, Williams, & Rath, 2015).

MSDP is associated with numerous adverse offspring outcomes. In particular, evidence in support of associations between MSDP and neonatal morbidity and mortality is so strong as to be considered causal by the 2014 Surgeon General’s Report (U.S. Department of Health and Human Services, 2014).

Infants exposed to MSDP are at more than double the risk for low birthweight, show an average 200 gram reduction in continuous birth weight, and have 2-4× increased rates of sudden infant death syndrome (SIDS), the leading cause of death in the first year (Dietz et al., 2010MacDorman, Cnattingius, Hoffman, Kramer, & Haglund, 1997Martin et al., 2007Polakowski, Akinbami, & Mendola, 2009).

In addition, suggestive associations have also been shown between MSDP and long-term neurobehavioral deficits in children—particularly, disruptive behaviors/conduct disorder, attention deficits/attention deficit hyperactivity disorder, and risk for smoking/nicotine dependence (Gaysina et al., 2013Huang et al., 2018Ruisch, Dietrich, Glennon, Buitelaar, & Hoekstra, 2018Shenassa, Papandonatos, Rogers, & Buka, 2015U.S. Department of Health and Human Services, 2014).

Effects of MSDP on long-term neurobehavioral outcomes were initially demonstrated in large birth cohort studies that did not include adequate measures of exposure, maternal factors, context, or offspring phenotypes leaving questions of causality unresolved. Because MSDP cannot be randomly assigned, the field then incorporated genetically-informative designs (e.g., discordant sibling pairs) to address familial confounding.

Findings have been inconsistent. Studies using genetically informative designs revealed attenuated or no effects on long-term neurobehavioral outcomes; however, measures of exposure and offspring phenotype were limited (D’Onofrio et al., 2010Ellingson, Goodnight, Van Hulle, Waldman, & D’Onofrio, 2014Estabrook et al., 2016Skoglund, Chen, D’Onofrio, Lichtenstein, & Larsson, 2014).

Mechanistic studies with detailed measures of exposure and animal models where exposure is randomly assigned revealed more consistent effects of prenatal nicotine/tobacco on offspring neurobehavior (Estabrook et al., 2016Hall et al., 2016Harrod, Lacy, & Morgan, 2012Wakschlag, Pickett, Cook, Benowitz, & Leventhal, 2002).

Prospective, developmentally sensitive studies are needed with rigorous measures of exposure and context, and coherent measures of behavior and regulation in infancy to delineate early pathways that may cascade to long-term deficits from MSDP (Estabrook et al., 2016Wakschlag, Leventhal, Pine, Pickett, & Carter, 2006).

Our group conducted some of the first studies of associations between MSDP and infant neurobehavior using the NICU Network Neurobehavioral Scale (NNNS, behavior exam designed to be sensitive to subtle deficits in substance-exposed infants) and rigorous measures of MSDP including prospective measures of timing, quantity, and biomarkers of exposure (Law et al., 2003L. Stroud et al., 2009Stroud, Papandonatos, Rodriguez, et al., 2014Stroud, Papandonatos, Salisbury, et al., 2016L. R. Stroud, R. L. Paster, M. S. Goodwin, et al., 2009).

We found decreased ability to self-regulate reactions to environmental stimuli (self-regulation/need for external handling), decreased ability to attend to stimuli (attention), and altered motor activity (lethargy) in MSDP-exposed vs. comparison infants (Law et al., 2003Stroud, Papandonatos, Salisbury, et al., 2016Stroud, Paster, Papandonatos, et al., 2009). Additional studies have found increased odds of MSDP exposure in NNNS profiles characterized by altered arousal, activity, muscle tone, attention, and signs of stress (Appleton et al., 2016Liu et al., 2010).

Our group also found altered cortisol stress response in MSDP-exposed infants, suggestive of altered biological response to daily stressors (Stroud, Papandonatos, Rodriguez, et al., 2014). Studies by other research groups and utilizing alternative neurobehavioral exams have also supported effects of MSDP on infant neurobehavior and cortisol (Eiden et al., 2015Espy, Fang, Johnson, Stopp, & Wiebe, 2011Schuetze, Lopez, Granger, & Eiden, 2008Stroud, Paster, Goodwin, et al., 2009Yolton et al., 2009).

Over the last two decades, a large body of human and animal research has highlighted the profound importance of the fetal environment in “programming” a host of postnatal neurobehavioral and medical outcomes (Alexander, Dasinger, & Intapad, 2015Barker, 2002Moisiadis & Matthews, 2014Xiong & Zhang, 2013). Changes to fetal physiological stress systems are believed to help the infant adapt in the short-term to a stressful postnatal environment, but may predispose offspring to disease over the long-run (Cao-Lei et al., 2017Maccari et al., 2003Meaney, Szyf, & Seckl, 2007Seckl, 1998). For example, our group has shown the importance of programming of biological stress pathways in short and long-term effects of MSDP (Stroud, Papandonatos, Rodriguez, et al., 2014Stroud, Papandonatos, Shenassa, et al., 2014)

However, despite emphasis on the critical importance of the fetal period in programming of long-term disease and disorders, measurement of offspring behavior in studies of MSDP and other prenatal insults typically begins after birth. Yet, “the explosive rate of growth and development that occurs during the period before birth is unparalleled at any other point in the lifespan. In just 266 days, a single fertilized cell develops into a sentient human newborn infant” (J. DiPietro, 2010).

Further, “there is no other period in development in which the proximal environment is so physiologically entangled” with the offspring (J. A. DiPietro, Costigan, & Voegtline, 2015). Ongoing improvements in ultrasound technology and fetal monitoring have allowed understanding of fetal development to progress from delineating structural and organ development to assessing patterns of fetal movements and fetal heart rate (FHR) to elucidating fetal state and neurobehavior (J. A. DiPietro et al., 2010Groome, Bentz, & Singh, 1995Nijhuis, Martin, & Prechtl, 1984Nijhuis, Prechtl, Martin, & Bots, 1982).

Fetal neurobehavioral assessment has been defined as comprising four domains: FHR, motor behavior and activity level, behavioral state, and responsiveness to environmental stimuli (J DiPietro, 2001J. A. DiPietro et al., 2010).

Assessment of these domains across gestation is believed to provide information about central nervous system (CNS) function and development (J. A. DiPietro, Bornstein, et al., 2002Nijhuis, 1986bPrechtl, 1977). Early in pregnancy, fetal movements appear to be random and uncoordinated (Nasello-Paterson, Natale, & Connors, 1988). As pregnancy advances, fetal movements become increasingly smooth, coordinated, and organized with lengthening and regular periods of rest (quiescence) that lead to observable rest-activity cycles by 28 weeks gestational age (Pillai & James, 1990Pillai, James, & Parker, 1992Robertson, Dierker, Sorokin, & Rosen, 1982).

As gestation advances, more mature behavioral states can be observed (de Vries, Visser, & Prechtl, 19851988J. A. DiPietro, Costigan, & Pressman, 2002Groome et al., 1999). Fetal behavioral states are typically defined by the co-occurrence of somatic movements, eye movements, and specific FHR patterns, and are evident by 32 weeks (Arabin & Riedewald, 1992). Cardiac-somatic coupling–defined as state-independent temporal associations between FHR and fetal movements–also increases over gestation (J DiPietro, 2001J. A. DiPietro, Hodgson, Costigan, Hilton, & Johnson, 1996).

Characterization of fetal behavior utilizing the four domains has been validated through studies showing continuity over gestation, cross-domain associations, and continuity with postnatal behavior (J. A. DiPietro, Bornstein, et al., 2002J. A. DiPietro et al., 2010Gingras & O’Donnell, 1998Salisbury, Fallone, & Lester, 2005).

Specifically, a growing number of studies have shown links between fetal and infant neurobehavior. For example, fetal activity levels are correlated with infant motor activity (J. A. DiPietro et al., 2010) and a higher incidence of fetal cardiac-somatic coupling has been associated with better newborn state regulation and brain auditory evoked potentials (J. A. DiPietro, Bornstein, et al., 2002J. A. DiPietro et al., 2010),

There is evidence of continuity between individual fetal behaviors such as mouthing, yawning, and hand-to-face movements and similar behaviors in newborns (Kurjak et al., 2004).

Our group has also demonstrated links between summary measures of fetal neurobehavior and summary measures of infant neurobehavior, as indicated on the NNNS, including links between fetal quality of movement and newborn self-regulation and excitability (subscales of the NNNS; Salisbury et al., 2005).

In older infants, DiPietro et al. (2000) showed continuity between third trimester FHR and both infant HR and infant HR variability at 1 year. Fetal movements were also found to predict infant temperament at 2 years of age (J. A. DiPietro, Bornstein, et al., 2002J. A. DiPietro et al., 1996).

Behavioral continuity from the pre to postnatal period extends to deviations from typical fetal behavior; deviations in the presence, absence, and patterning of behaviors predict newborn compromise. For example, the absence of fetal breathing movements and rhythmic mouthing movements while in a quiescent state predicted compromised newborn outcomes (Nijhuis, 1986aPillai & James, 19901991Pillai et al., 1992).

Fetal neurobehavioral patterns distinguish high risk fetuses, including fetuses with CNS deficits, intrauterine growth restriction, fetuses born pre-term, and fetuses exposed to maternal medical conditions (e.g., diabetes, pre-eclampsia; Andonotopo & Kurjak, 2006J DiPietro, 2001Kainer, Prechtl, Engele, & Einspieler, 1997Kisilevsky, Gilmour, Stutzman, Hains, & Brown, 2012Kiuchi, Nagata, Ikeno, & Terakawa, 2000Lumbers, Yu, & Crawford, 2003Pillai et al., 1992Salisbury, Ponder, Padbury, & Lester, 2009).

Despite important potential for characterizing markers of risk prior to birth and continuity with infant neurobehavior, only a small number of studies have investigated effects of MSDP exposure on fetal neurobehavior. Initial studies focused on acute fetal responses to smoking. These studies showed decreases in felt movements, fetal FHR, and FHR variability and reactivity following acute exposure to smoking (Goodman, Visser, & Dawes, 1984Graca, Cardoso, Clode, & Calhaz-Jorge, 1991Lehtovirta, Forss, Rauramo, & Kariniemi, 1983Thaler, Goodman, & Dawes, 1980).

Fetuses also showed greater rates of maladaptive response to the “non-stress test”, a clinical test of fetal well-being (Phelan, 1980) after acute exposure to maternal smoking. In a study by Oncken et al., prior to maternal smoking, 80% of fetuses were reactive to the non-stress test (indicative of fetal well-being); after mothers smoked, only 27% of fetuses were reactive (2002).

More recent studies revealed preliminary evidence for chronic dysregulation of fetal behavior in MSDP-exposed fetuses. Zeskind and Gingras showed lower FHR variability and altered autonomic regulation in MSDP-exposed fetuses (2006). Fetal responsiveness to stimuli (stress response) is a key domain of fetal neurobehavior. Fetal stress response is typically elicited by means of a vibro-acoustic stimulus (VAS; a vibratory and acoustic stimulus applied to the maternal abdomen) shown to consistently differentiate healthy and at-risk fetuses (Kisilevsky, Muir, & Low, 19901992Smith, 1994Smith, Phelan, Broussard, & Paul, 1988). In a study of behavioral habituation to repeated VAS, Gingras et al. (1998) showed reduced habituation in MSDP-exposed vs. cocaine-exposed and comparison fetuses. Cowperthwaite et al. (2007) further demonstrated altered FHR response to maternal voice recognition in early but not late third trimester MSDP-exposed fetuses.

Salisbury and colleagues developed the Fetal Neurobehavioral Coding System (FENS) to synthesize real-time ultrasound with fetal actocardiography monitoring to characterize fetal neurobehavior and stress response (Grant-Beuttler et al., 2011Salisbury, 2010Salisbury et al., 2005).

The FENS builds upon prior work involving a single measurement system for physiology or behavioral observation or only components of both, to incorporating observational data from real-time ultrasound on a full repertoire of fetal behaviors with simultaneous measurement of FHR and fetal activity (FA) data from fetal actocardiography.

The FENS was designed as a standardized assessment to reveal deficits in high-risk (exposed to maternal medical and psychiatric illness) and substance-exposed fetuses (Salisbury, 2010Salisbury et al., 2005Salisbury et al., 2009). Standardized neurobehavioral assessments during gestation and after birth allow for a comprehensive and “seamless” assessment of fetal to infant development in healthy and at-risk infants.

The standardized observation and measurement of neurobehavior from the fetal period through later developmental periods is captured through a lens informed by the conceptual framework of developmental systems theory which posits that development is dependent upon the mutual influences within the maternal-fetal system. (Bertalanffy, 1968Gottleib, 1991)

This includes all levels of shared biology and experience, not simply the shared genetic encoding of proteins, or the impact of maternal biology on the fetus, but also the mother’s experience and responses to the physiology and behaviors of the fetus (Denenberg, 1980Lecanuet, Fifer, Krasenegor, & Smotherman, 1995).

Examining the neurobehavioral system while it is evolving is an opportunity to determine the factors or processes that are most likely to alter developmental trajectories.

For example, fetal responses to mild stimuli test the ability of the fetal sensory systems to detect and attend to the stimulus, as well as the physiological and behavioral responses to the demands of the stimulus. Measurement of responses over time reflects fetal attention and arousal system function and maturation, systems that are central to all developmental processes (Krasnegor et al., 1998).

MSDP is just one of many potential influences on this developing system. To our knowledge, the present study is the first to investigate the impact of MSDP on comprehensive measures of fetal neurobehavior utilizing the FENS. The FENS was administered in the context of a prospective longitudinal study of MSDP and neonatal neurobehavioral development. Fetal neurobehavior was assessed via ultrasound and actocardiography between 32 and 37 weeks gestation.

After delivery, the NICU Network Neurobehavioral Scale was administered 7 times over the first postnatal month. Thus, the first goal of the present study was to investigate the influence of MSDP on fetal neurobehavior measured by the FENS. Our second goal was to explore links between fetal neurobehavior and evolution of neonatal neurobehavior over the first postnatal month and to investigate potential interactions between MSDP and fetal neurobehavior in predicting neonatal neurodevelopment.

Our overarching hypothesis was that fetal behavior and responses to a sensory stimulus, reflecting attention and arousal systems, would be altered by MSDP and be predictive of infant neurobehavioral development over the first postnatal month.

Medical University of Vienna
Media Contacts:
Tibor Harkany – Medical University of Vienna
Image Source:
The image is in the public domain.

Original Research: Closed access
“Brain-wide genetic mapping identifies the indusium griseum as a prenatal target of pharmacologically unrelated psychostimulants”. Janos Fuzik et al.
PNAS doi:10.1073/pnas.1904006116.


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