Acta Pædiatrica ISSN 0803-5253
REVIEW ARTICLE
Smoking during pregnancy affects foetal brain development Mikael Ekblad ([email protected])1, Jyrki Korkeila2,3, Liisa Lehtonen1 1.Department of Pediatrics, Turku University Hospital, and University of Turku, Turku, Finland 2.Department of Psychiatry, University of Turku, Turku, Finland 3.Department of Psychiatry, Harjavalta Hospital, Satakunta Hospital District, Harjavalta, Finland
Keywords Diffusion tensor imaging, Foetal development, Nicotine, Tobacco, Volumetric magnetic resonance imaging Correspondence Mikael Ekblad, MD, PhD, Department of Pediatrics, Turku University Hospital and University of Turku, Kiinanmyllynkatu 4-8, 20520 Turku, Finland. Tel: +358405457613 | Email: [email protected]
ABSTRACT Environmental factors such as maternal smoking can significantly modulate genetically programmed brain development during foetal life. This review looks at how prenatal smoking exposure modulates brain development, including new evidence on the effects of smoking on foetal brain development and function. Conclusion: Smoking during pregnancy exposes the foetus to thousands of healththreatening chemicals, restricting foetal body and head growth. Alterations in brain structure and function have been seen in children exposed to prenatal smoking.
Received 29 March 2014; revised 12 July 2014; accepted 25 August 2014. DOI:10.1111/apa.12791
INTRODUCTION Environmental factors can significantly modulate genetically programmed brain development during foetal life, and one harmful factor is maternal smoking. Despite increasing knowledge about the adverse effects of smoking during pregnancy on the developing foetus, between 5% and 26% of pregnant women continue to smoke during pregnancy in the United States and Europe (1,2). Women who are single, young, have not had a previous delivery or have low socioeconomic status are more likely to smoke during pregnancy than others (3). The highest smoking rates during pregnancy have been seen in teenagers, with as many as half of them smoking (3). There is also increasing knowledge of the potential harm that smoking during pregnancy can have on a child’s later psychological development, and this can extend into adulthood, as shown in recent literature (4). It is important that professionals working in maternal and antenatal care are aware of the risks of smoking during pregnancy, so that they can use that knowledge to increase their success in encouraging women to stop smoking if they are pregnant or planning a pregnancy. This review will also discuss new knowledge about the mediating mechanisms of smoking on foetal brain development.
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MECHANISMS OF FOETAL EFFECTS Tobacco smoke contains thousands of health-threatening chemicals, (5) and many of these ingredients are potentially toxic to foetal development. The major components in tobacco smoke that have been shown to interfere with foetal brain development are nicotine and carbon monoxide (6). Nicotine has been shown to cross the placenta, enter the foetal circulation and accumulate in the foetal compartments from as early as 7 weeks of gestation, in both active and passive smokers. (7,8). The concentrations of nicotine have been shown to be even higher in the foetuses, and to last longer, than in their smoking mothers (8). The possible mediating mechanisms and outcomes of prenatal
Key notes
Smoking during pregnancy predisposes the fetus to thousands of health threatening chemicals. Prenatal smoking exposure restricts both fetal body and head growth. Compared to unexposed children, alterations in brain structure and function have been seen in children exposed to prenatal smoking.
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Smoking during pregnancy and foetal brain
Figure 1 The mediating mechanisms and outcomes of prenatal smoking exposure on foetal brain development.
smoking exposure on foetal brain development are shown in Figure 1. The neurotoxic effects of smoking are supported by withdrawal symptoms, and these also commonly occur in newborns (9,10). The first of these two studies focused on full-term newborn infants, using self-reports of maternal smoking exposure and saliva cotinine measurements. It found that the newborns who had been exposed to smoking were more hypertonic and excitable, showed more stress signs and required more handling than unexposed newborns (9). The second study reported that withdrawal symptoms decreased in exposed newborn infants during the first 5 days of life (10). However, it did not report whether the alleviation of these symptoms could have been as a result of nicotine exposure through breast milk. In addition, prenatal smoking exposure has been shown to lead to long-term alterations in blood pressure control mechanisms and heart rate responses in infants (11). The nicotinic acetylcholine receptors (nAChRs) are crucial during foetal brain development, as they modulate axonal pathfinding, synapse formation and cell survival (12,13). The presence of nAChRs can be detected in the human brain and spinal cord from 4 to 5 weeks of gestation (14). The activation of nAChRs triggers acetylcholine neurotransmission postsynaptically and the release of other catecholaminergic neurotransmitters, such as serotonin, dopamine and epinephrine, presynaptically (15). Chronic exposure to exogenous nicotine leads to a high affinity and desensitisation of the nAChR, causing long-term changes in the function of the receptor (13,16). Loss of function of the specific subtype of nAChRs caused by prenatal nicotine exposure has been linked to poor neonatal outcomes, including growth restriction, unstable breathing and impaired arousal in animals (16). In addition, the brain reward system can be affected by chronic nicotine exposure, by altering dopamine release (13,17). Nicotine exposure during pregnancy has been shown to affect brain cell replication and differentiation, leading to changes in brain structure, such as impaired growth of the rat forebrain (18,19). Carbon monoxide also crosses the placenta, where it binds with haemoglobin in blood circulation and produces carboxyhaemoglobin, which limits oxygen delivery to the tissues (20). In addition, prenatal nicotine exposure
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has been shown to affect the contractility of the uterine arteries, leading to decreased uterine blood flow in animals (21). Therefore, exposure to maternal smoking may lead to foetal hypoxia and ischaemia, which affect brain development. This model is supported by the findings of Verhagen et al. (22), who found that preterm infants exposed to smoking during pregnancy had lower cerebral oxygen saturation during the first week of life than unexposed infants. In recent years, knowledge of epigenetic programming during pregnancy has emerged. Maternal smoking during pregnancy has been associated with alterations in deoxyribonucleic acid (DNA) methylation and dysregulation of microRNA expression (23), but the role of these epigenetic mechanisms is not yet fully understood. One study found that DNA methylation in leucocytes was increased in adult women exposed to prenatal smoking, but not in unexposed women (24). The activity of genes that are important for normal brain development, such as the brain-derived neurotrophic factor (BDNF) gene, is regulated by DNA methylation (25). BDNF is important for the growth of new neurons and synapses and helps the survival of the existing neurons. A study by ToledoRodriquez et al. (26) showed that adolescents who had been exposed to prenatal smoking demonstrated increased DNA methylation of the BDNF gene, potentially leading to long-term downregulation of BDNF expression. The reduction in BDNF mRNA and protein was found to contribute to the behavioural alterations in male mice exposed to smoking (27). It has been suggested that epigenetic changes may underlie long-lasting modifications of the development and plasticity of the brain, resulting in later neurodevelopmental problems, and that these effects may transfer beyond the next generation (23,26,27). It is challenging to prove or disprove the causal link between maternal smoking and foetal and child health problems, because of the numerous factors related to both the women who smoke during pregnancy and to child outcomes. Women who continue to smoke during pregnancy are less likely to engage in important health-related behaviours, such as abstaining from alcohol or drug use or following nutritional recommendations (28). On the other hand, women who continue to smoke may have stronger nicotine dependence and may use smoking to alleviate their anxiety or attention disorders, which may have a genetic
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background. If so, the associations between smoking during pregnancy and long-term foetal development may be explained by common genetic and psychosocial factors (29,30).
THE CLINICAL EFFECTS OF PRENATAL SMOKING EXPOSURE ON FOETAL HEAD GROWTH AND BRAIN Head growth Normal head growth during, and after, pregnancy reflects normal brain growth. Infants exposed to prenatal smoking have been shown to display reduced head growth compared to unexposed infants (31–40). As part of this study, we carried out a meta-analysis of nine papers (31–40), based on the assessment method of maternal smoking, that include information on prenatal smoking exposure and head circumference at birth. These are summarised in Figure 2. The meta-analysis included three studies with an unselected population (31–33) and six studies that just comprised fullterm infants (34–40). The study-specific estimate was pooled using random-effect meta-analysis. On average, the head circumference of the infants exposed to maternal smoking during pregnancy was 0.5 cm smaller than the unexposed infants. The studies using cotinine verification of maternal smoking showed an even greater effect on head circumference than those that only used maternal selfreports. In addition, a Swedish study with a large birth cohort of 1 362 169 infants found that those who had been exposed to smoking had a 60% higher risk of having a head circumference below 32 cm and an 8% higher risk of having a head circumference below 2.0 standard deviations at birth than unexposed infants (41).
Figure 2 The mean difference of head circumference (cm) at birth in newborns exposed to maternal smoking during pregnancy, compared to unexposed newborns (forest plot) (31–40).
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In the second half of pregnancy, foetal growth mostly depends on nutrition and oxygen supply and foetal brains should be protected by blood flow redistribution if these are poor (42). However, it appears that when foetuses are exposed to smoking, the brain’s protective mechanisms are counteracted by adverse neuronal effects. As a result, smoking exposure reduces foetal growth both in the head and in other organs after the first half of pregnancy. Jaddoe et al. found no association between maternal smoking and foetal head growth in mid-pregnancy using repeated ultrasound examinations in 7098 pregnant women in the Generation R Study, a Dutch population-based prospective cohort study. This study found that from 25 gestational weeks onwards, the exposed foetuses had significantly smaller head growth, abdominal circumferences and femur lengths than the unexposed foetuses. Importantly, the head growth was normal in foetuses whose mothers stopped smoking in early pregnancy (40), which suggests that smoking throughout pregnancy restricts both foetal head and body growth. Foetal brain volumes Two studies have examined the effects of prenatal smoking exposure on brain volume during the foetal period. Firstly, Roza et al. studied a cohort of 7042 pregnant women, which included 545 women who stopped smoking in early pregnancy and 1199 who continued to smoke throughout pregnancy. Foetuses who were exposed to continued smoking had a significantly smaller transcerebellar diameter than unexposed foetuses and also had a smaller lateral ventricle width, measured by repeated ultrasound examinations during pregnancy. No difference was found between foetuses that were not exposed to smoking or whose mothers stopped smoking in early pregnancy (43). Secondly, Anblagan et al. examined the effect of prenatal smoking exposure on foetal organ growth during pregnancy, in a case–control study that used magnetic resonance imaging (MRI) to measure brain volumes at approximately 24 and 35 weeks of gestation. Although no difference in foetal brain size was observed in mid-pregnancy, there was a significant difference in brain size between the unexposed and exposed foetuses in late pregnancy (277.5 vs. 246.5 cm3, p = 0.03) (44). Brain volumes in preterm infants Smoking exposure does not appear to have the same adverse effects on head circumference on preterm infants as it does on full-term infants (45,46), and this is likely to be due to shorter exposure during pregnancy. Kayemba-Kay’s et al. found no effect of maternal smoking exposure on head circumference and other growth in preterm infants born at 24–32 weeks of gestation. However, infants born at term age to mothers who had smoked during pregnancy had significantly smaller head circumferences, birth weights and length than unexposed full-term infants (45). Our study of 232 very preterm infants focused on the effects of prenatal smoking exposure on measured brain volumes in preterm infants. Post-natal factors such as
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environmental smoking exposure were unlikely to interfere with the findings, as the MRIs were carried out at term equivalent age. The findings showed that the frontal lobe and cerebellar volumes were significantly smaller in the preterm infants exposed to smoking than in the unexposed infants. However, no differences were found in head growth during the first 2 years of life (46). This study suggests that the frontal lobe and cerebellum could be the most vulnerable brain regions affected by smoking exposure in the early developmental stages. The important message is that regional volumetric changes can occur even when there are no changes in head circumference. Brain volumes in children Full-term infants could be more vulnerable to prenatal smoking because they are exposed for longer periods in the womb than very preterm infants, but there are no volumetric studies on smoking exposure in full-term, newborn l et al. estimated cerebral mass in newborn infants. Kro infants using a calculation based on head circumference. They found that smoking exposure, verified by cotinine measurements, affected head circumference and that cerebral mass was estimated to be 48 g lower in infants exposed to prenatal smoking than in unexposed infants (296 vs. 344 g) (47). In conclusion, a smaller head circumference in full-term infants exposed to smoking throughout pregnancy might reflect a global reduction in brain volumes. The volumetric effects of smoking exposure should also be evaluated in full-term infants. In adolescents exposed to smoking, the volumetric changes associated with prenatal smoking exposure include thinner frontal, temporal and parietal lobes and smaller cerebral cortex grey matter and corpus callosum volumes (48). In addition, adolescents exposed to prenatal smoking have been reported to have smaller amygdala (49) and pallidum volumes (50) than unexposed adolescents. Paus et al. (51) showed that the genetic variation in a specific potassium channel modulates the effects of smoking exposure on brain development. Therefore, it is likely that gene– environmental interactions play a role in modulating the effects of prenatal smoking exposure. A recent study examined the effects of prenatal smoking exposure on brain volumes and later child behaviour. El Marroun et al. examined 113 children exposed to smoking together with their matched, unexposed controls. When MRI scans were carried out at 6–8 years of age, they showed that the children who had been exposed to prenatal smoking throughout pregnancy had smaller total brain volume and cortical grey matter volumes than the controls and thinner superior frontal, superior parietal and precentral cortices. Exposed children also showed more affective problems at 6 years of age, assessed by the Child Behaviour Checklist, which was explained by the observation of cortical thinning (52). In addition, a graded pattern for prenatal smoking exposure on brain volumes was found in a longitudinal case–control study that focused on children with attention deficit hyperactivity disorder (ADHD) and healthy controls. The children with ADHD and smoking
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exposure had the smallest cerebellum volumes; the unexposed children with ADHD in between and unexposed healthy controls had the largest volumes (53). These studies suggest that smoking exposure has long-term effects on behaviour, mediated through altered brain development. Brain microstructure Two studies have used diffusion tensor imaging to examine the association between prenatal smoking exposure and the white matter microstructure. Jacobsen et al. examined 67 adolescent smokers and non-smokers with retrospective information of prenatal smoking exposure. The groups had several similar background factors, including educational attainment and symptoms of inattention. Prenatal smoking exposure, together with smoking during adolescence, was associated with increased fractional anisotropy in the anterior cortical brain region, which is an important region for normal auditory processing (54). The fact that the study included adolescents who smoked complicates the interpretation of the true effect of prenatal smoking exposure on white matter microstructure. Another study used diffusion tensor imaging to investigate the effect of prenatal smoking exposure on the microstructure of the corpus callosum. The study included 23 exposed and 17 unexposed adolescents, who were also tested for sensation-seeking patterns. Smoking exposure during pregnancy was associated with decreased fractional anisotropy in the regions of the corpus callosum containing fibres to the premotor cortex. Decreased fractional anisotropy in these areas was related to more sensation seeking in those individuals exposed to maternal smoking during pregnancy (50). Brain function The effects of prenatal smoking exposure on brain function can be studied in newborn infants, for example by measuring auditory brainstem responses. Peck et al. examined the neuroelectrical activity of the auditory nerve in 2-day-old newborn infants. Newborns exposed to maternal smoking, verified by maternal cotinine measurements, were four times more likely to respond to a sound stimulus than unexposed newborns (55). Similar findings have been reported in infants at 6 months of age (56). A greater response to sound stimulus indicates an impaired ability to process auditory information, which may also impair reading and language development during childhood. Three studies of adolescents, reviewed by Bublitz and Stroud (48), used functional MRI to demonstrate the adverse effects of prenatal smoking exposure on brain function. In summary, adolescents exposed to prenatal smoking showed a lack of coordination across a large, diverse set of brain regions, including frontal, temporal and parietal lobes and cerebellum during information and auditory processing, when they were compared to unexposed adolescents. However, these studies were limited by € ller the small number of participants. A larger study by Mu et al. of 177 adolescents exposed to prenatal smoking showed a weaker response in the ventral striatum during
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reward anticipation in exposed adolescents than in a group of matched, unexposed controls (57). The authors speculated that this alteration may increase the risk of substance abuse or addiction later in life.
NICOTINE REPLACEMENT THERAPY DURING PREGNANCY A Cochrane Database Systematic Review concluded that the effectiveness and safety of nicotine replacement therapy (NRT) during pregnancy are unclear (58). NRT can be used during pregnancy to prevent exposing the foetus to the other potentially toxic ingredients of tobacco smoke. However, nicotine has been shown to be one of the major components of tobacco smoke that interferes with foetal development, as confirmed in this review. The foetus might be exposed to nicotine for a longer period of time, and even be exposed to higher amounts, if the mother uses combinations of different NRTs or combines them with smoking, rather than just smoking. There are no official international guidelines on the use of NRT in pregnant women. The national Finnish guidelines (59) suggest that NRT can be considered for women who are motivated to stop smoking, but cannot do it by themselves and who suffer from physical withdrawal symptoms. The use of methods that provide intermittent nicotine exposure, such as gums and sprays, is preferred when it comes to avoiding long-lasting exposure to nicotine.
FUTURE In the future, 3D-ultrasound scans may provide a new way of studying the effects of smoking exposure on the early developmental stages of foetal brain development (60). Functional MRI might provide the opportunity to study brain function in newborn infants, especially the executive functions of the brain. More active use of cotinine would yield more objective data on the amount of prenatal smoking exposure and could, therefore, enable the evaluation of dose–response relationships. Current human studies are struggling with attempts to adjust for the wide-range of confounding environmental factors linked with smoking during pregnancy, and these should be studied using thorough methodology. The links between genetic susceptibilities and environmental risks, including smoking exposure, are a new field of research. It is also important to study the gene–environmental interactions of smoking exposure on brain development and later psychiatric problems.
CONCLUSIONS Prenatal smoking exposure affects brain growth, specific regional brain volumes and the microstructure of the newborn brain. In addition, alterations in neurophysiological functions and overall brain function have been demonstrated using functional MRI. The mechanisms that mediate these effects include nicotine modulating axonal pathfinding, synapse formation in neurons and carbon monoxide leading to foetal hypoxia and interfering with
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foetal brain development. The epigenetic mechanisms alter the reading of human genomes. The effects of prenatal smoking exposure can extend up to adulthood and even on to the next generation. This review emphasises the importance of preventing smoking during pregnancy and also shows that early cessation of smoking during pregnancy can prevent adverse effects on brain growth.
FUNDING This work was supported by the Turku University Hospital Research Foundation.
CONFLICT OF INTEREST The authors have no conflict of interests to declare.
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REVIEW ARTICLE
Smoking during pregnancy affects foetal brain development Mikael Ekblad ([email protected])1, Jyrki Korkeila2,3, Liisa Lehtonen1 1.Department of Pediatrics, Turku University Hospital, and University of Turku, Turku, Finland 2.Department of Psychiatry, University of Turku, Turku, Finland 3.Department of Psychiatry, Harjavalta Hospital, Satakunta Hospital District, Harjavalta, Finland
Keywords Diffusion tensor imaging, Foetal development, Nicotine, Tobacco, Volumetric magnetic resonance imaging Correspondence Mikael Ekblad, MD, PhD, Department of Pediatrics, Turku University Hospital and University of Turku, Kiinanmyllynkatu 4-8, 20520 Turku, Finland. Tel: +358405457613 | Email: [email protected]
ABSTRACT Environmental factors such as maternal smoking can significantly modulate genetically programmed brain development during foetal life. This review looks at how prenatal smoking exposure modulates brain development, including new evidence on the effects of smoking on foetal brain development and function. Conclusion: Smoking during pregnancy exposes the foetus to thousands of healththreatening chemicals, restricting foetal body and head growth. Alterations in brain structure and function have been seen in children exposed to prenatal smoking.
Received 29 March 2014; revised 12 July 2014; accepted 25 August 2014. DOI:10.1111/apa.12791
INTRODUCTION Environmental factors can significantly modulate genetically programmed brain development during foetal life, and one harmful factor is maternal smoking. Despite increasing knowledge about the adverse effects of smoking during pregnancy on the developing foetus, between 5% and 26% of pregnant women continue to smoke during pregnancy in the United States and Europe (1,2). Women who are single, young, have not had a previous delivery or have low socioeconomic status are more likely to smoke during pregnancy than others (3). The highest smoking rates during pregnancy have been seen in teenagers, with as many as half of them smoking (3). There is also increasing knowledge of the potential harm that smoking during pregnancy can have on a child’s later psychological development, and this can extend into adulthood, as shown in recent literature (4). It is important that professionals working in maternal and antenatal care are aware of the risks of smoking during pregnancy, so that they can use that knowledge to increase their success in encouraging women to stop smoking if they are pregnant or planning a pregnancy. This review will also discuss new knowledge about the mediating mechanisms of smoking on foetal brain development.
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MECHANISMS OF FOETAL EFFECTS Tobacco smoke contains thousands of health-threatening chemicals, (5) and many of these ingredients are potentially toxic to foetal development. The major components in tobacco smoke that have been shown to interfere with foetal brain development are nicotine and carbon monoxide (6). Nicotine has been shown to cross the placenta, enter the foetal circulation and accumulate in the foetal compartments from as early as 7 weeks of gestation, in both active and passive smokers. (7,8). The concentrations of nicotine have been shown to be even higher in the foetuses, and to last longer, than in their smoking mothers (8). The possible mediating mechanisms and outcomes of prenatal
Key notes
Smoking during pregnancy predisposes the fetus to thousands of health threatening chemicals. Prenatal smoking exposure restricts both fetal body and head growth. Compared to unexposed children, alterations in brain structure and function have been seen in children exposed to prenatal smoking.
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Figure 1 The mediating mechanisms and outcomes of prenatal smoking exposure on foetal brain development.
smoking exposure on foetal brain development are shown in Figure 1. The neurotoxic effects of smoking are supported by withdrawal symptoms, and these also commonly occur in newborns (9,10). The first of these two studies focused on full-term newborn infants, using self-reports of maternal smoking exposure and saliva cotinine measurements. It found that the newborns who had been exposed to smoking were more hypertonic and excitable, showed more stress signs and required more handling than unexposed newborns (9). The second study reported that withdrawal symptoms decreased in exposed newborn infants during the first 5 days of life (10). However, it did not report whether the alleviation of these symptoms could have been as a result of nicotine exposure through breast milk. In addition, prenatal smoking exposure has been shown to lead to long-term alterations in blood pressure control mechanisms and heart rate responses in infants (11). The nicotinic acetylcholine receptors (nAChRs) are crucial during foetal brain development, as they modulate axonal pathfinding, synapse formation and cell survival (12,13). The presence of nAChRs can be detected in the human brain and spinal cord from 4 to 5 weeks of gestation (14). The activation of nAChRs triggers acetylcholine neurotransmission postsynaptically and the release of other catecholaminergic neurotransmitters, such as serotonin, dopamine and epinephrine, presynaptically (15). Chronic exposure to exogenous nicotine leads to a high affinity and desensitisation of the nAChR, causing long-term changes in the function of the receptor (13,16). Loss of function of the specific subtype of nAChRs caused by prenatal nicotine exposure has been linked to poor neonatal outcomes, including growth restriction, unstable breathing and impaired arousal in animals (16). In addition, the brain reward system can be affected by chronic nicotine exposure, by altering dopamine release (13,17). Nicotine exposure during pregnancy has been shown to affect brain cell replication and differentiation, leading to changes in brain structure, such as impaired growth of the rat forebrain (18,19). Carbon monoxide also crosses the placenta, where it binds with haemoglobin in blood circulation and produces carboxyhaemoglobin, which limits oxygen delivery to the tissues (20). In addition, prenatal nicotine exposure
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has been shown to affect the contractility of the uterine arteries, leading to decreased uterine blood flow in animals (21). Therefore, exposure to maternal smoking may lead to foetal hypoxia and ischaemia, which affect brain development. This model is supported by the findings of Verhagen et al. (22), who found that preterm infants exposed to smoking during pregnancy had lower cerebral oxygen saturation during the first week of life than unexposed infants. In recent years, knowledge of epigenetic programming during pregnancy has emerged. Maternal smoking during pregnancy has been associated with alterations in deoxyribonucleic acid (DNA) methylation and dysregulation of microRNA expression (23), but the role of these epigenetic mechanisms is not yet fully understood. One study found that DNA methylation in leucocytes was increased in adult women exposed to prenatal smoking, but not in unexposed women (24). The activity of genes that are important for normal brain development, such as the brain-derived neurotrophic factor (BDNF) gene, is regulated by DNA methylation (25). BDNF is important for the growth of new neurons and synapses and helps the survival of the existing neurons. A study by ToledoRodriquez et al. (26) showed that adolescents who had been exposed to prenatal smoking demonstrated increased DNA methylation of the BDNF gene, potentially leading to long-term downregulation of BDNF expression. The reduction in BDNF mRNA and protein was found to contribute to the behavioural alterations in male mice exposed to smoking (27). It has been suggested that epigenetic changes may underlie long-lasting modifications of the development and plasticity of the brain, resulting in later neurodevelopmental problems, and that these effects may transfer beyond the next generation (23,26,27). It is challenging to prove or disprove the causal link between maternal smoking and foetal and child health problems, because of the numerous factors related to both the women who smoke during pregnancy and to child outcomes. Women who continue to smoke during pregnancy are less likely to engage in important health-related behaviours, such as abstaining from alcohol or drug use or following nutritional recommendations (28). On the other hand, women who continue to smoke may have stronger nicotine dependence and may use smoking to alleviate their anxiety or attention disorders, which may have a genetic
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background. If so, the associations between smoking during pregnancy and long-term foetal development may be explained by common genetic and psychosocial factors (29,30).
THE CLINICAL EFFECTS OF PRENATAL SMOKING EXPOSURE ON FOETAL HEAD GROWTH AND BRAIN Head growth Normal head growth during, and after, pregnancy reflects normal brain growth. Infants exposed to prenatal smoking have been shown to display reduced head growth compared to unexposed infants (31–40). As part of this study, we carried out a meta-analysis of nine papers (31–40), based on the assessment method of maternal smoking, that include information on prenatal smoking exposure and head circumference at birth. These are summarised in Figure 2. The meta-analysis included three studies with an unselected population (31–33) and six studies that just comprised fullterm infants (34–40). The study-specific estimate was pooled using random-effect meta-analysis. On average, the head circumference of the infants exposed to maternal smoking during pregnancy was 0.5 cm smaller than the unexposed infants. The studies using cotinine verification of maternal smoking showed an even greater effect on head circumference than those that only used maternal selfreports. In addition, a Swedish study with a large birth cohort of 1 362 169 infants found that those who had been exposed to smoking had a 60% higher risk of having a head circumference below 32 cm and an 8% higher risk of having a head circumference below 2.0 standard deviations at birth than unexposed infants (41).
Figure 2 The mean difference of head circumference (cm) at birth in newborns exposed to maternal smoking during pregnancy, compared to unexposed newborns (forest plot) (31–40).
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In the second half of pregnancy, foetal growth mostly depends on nutrition and oxygen supply and foetal brains should be protected by blood flow redistribution if these are poor (42). However, it appears that when foetuses are exposed to smoking, the brain’s protective mechanisms are counteracted by adverse neuronal effects. As a result, smoking exposure reduces foetal growth both in the head and in other organs after the first half of pregnancy. Jaddoe et al. found no association between maternal smoking and foetal head growth in mid-pregnancy using repeated ultrasound examinations in 7098 pregnant women in the Generation R Study, a Dutch population-based prospective cohort study. This study found that from 25 gestational weeks onwards, the exposed foetuses had significantly smaller head growth, abdominal circumferences and femur lengths than the unexposed foetuses. Importantly, the head growth was normal in foetuses whose mothers stopped smoking in early pregnancy (40), which suggests that smoking throughout pregnancy restricts both foetal head and body growth. Foetal brain volumes Two studies have examined the effects of prenatal smoking exposure on brain volume during the foetal period. Firstly, Roza et al. studied a cohort of 7042 pregnant women, which included 545 women who stopped smoking in early pregnancy and 1199 who continued to smoke throughout pregnancy. Foetuses who were exposed to continued smoking had a significantly smaller transcerebellar diameter than unexposed foetuses and also had a smaller lateral ventricle width, measured by repeated ultrasound examinations during pregnancy. No difference was found between foetuses that were not exposed to smoking or whose mothers stopped smoking in early pregnancy (43). Secondly, Anblagan et al. examined the effect of prenatal smoking exposure on foetal organ growth during pregnancy, in a case–control study that used magnetic resonance imaging (MRI) to measure brain volumes at approximately 24 and 35 weeks of gestation. Although no difference in foetal brain size was observed in mid-pregnancy, there was a significant difference in brain size between the unexposed and exposed foetuses in late pregnancy (277.5 vs. 246.5 cm3, p = 0.03) (44). Brain volumes in preterm infants Smoking exposure does not appear to have the same adverse effects on head circumference on preterm infants as it does on full-term infants (45,46), and this is likely to be due to shorter exposure during pregnancy. Kayemba-Kay’s et al. found no effect of maternal smoking exposure on head circumference and other growth in preterm infants born at 24–32 weeks of gestation. However, infants born at term age to mothers who had smoked during pregnancy had significantly smaller head circumferences, birth weights and length than unexposed full-term infants (45). Our study of 232 very preterm infants focused on the effects of prenatal smoking exposure on measured brain volumes in preterm infants. Post-natal factors such as
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environmental smoking exposure were unlikely to interfere with the findings, as the MRIs were carried out at term equivalent age. The findings showed that the frontal lobe and cerebellar volumes were significantly smaller in the preterm infants exposed to smoking than in the unexposed infants. However, no differences were found in head growth during the first 2 years of life (46). This study suggests that the frontal lobe and cerebellum could be the most vulnerable brain regions affected by smoking exposure in the early developmental stages. The important message is that regional volumetric changes can occur even when there are no changes in head circumference. Brain volumes in children Full-term infants could be more vulnerable to prenatal smoking because they are exposed for longer periods in the womb than very preterm infants, but there are no volumetric studies on smoking exposure in full-term, newborn l et al. estimated cerebral mass in newborn infants. Kro infants using a calculation based on head circumference. They found that smoking exposure, verified by cotinine measurements, affected head circumference and that cerebral mass was estimated to be 48 g lower in infants exposed to prenatal smoking than in unexposed infants (296 vs. 344 g) (47). In conclusion, a smaller head circumference in full-term infants exposed to smoking throughout pregnancy might reflect a global reduction in brain volumes. The volumetric effects of smoking exposure should also be evaluated in full-term infants. In adolescents exposed to smoking, the volumetric changes associated with prenatal smoking exposure include thinner frontal, temporal and parietal lobes and smaller cerebral cortex grey matter and corpus callosum volumes (48). In addition, adolescents exposed to prenatal smoking have been reported to have smaller amygdala (49) and pallidum volumes (50) than unexposed adolescents. Paus et al. (51) showed that the genetic variation in a specific potassium channel modulates the effects of smoking exposure on brain development. Therefore, it is likely that gene– environmental interactions play a role in modulating the effects of prenatal smoking exposure. A recent study examined the effects of prenatal smoking exposure on brain volumes and later child behaviour. El Marroun et al. examined 113 children exposed to smoking together with their matched, unexposed controls. When MRI scans were carried out at 6–8 years of age, they showed that the children who had been exposed to prenatal smoking throughout pregnancy had smaller total brain volume and cortical grey matter volumes than the controls and thinner superior frontal, superior parietal and precentral cortices. Exposed children also showed more affective problems at 6 years of age, assessed by the Child Behaviour Checklist, which was explained by the observation of cortical thinning (52). In addition, a graded pattern for prenatal smoking exposure on brain volumes was found in a longitudinal case–control study that focused on children with attention deficit hyperactivity disorder (ADHD) and healthy controls. The children with ADHD and smoking
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exposure had the smallest cerebellum volumes; the unexposed children with ADHD in between and unexposed healthy controls had the largest volumes (53). These studies suggest that smoking exposure has long-term effects on behaviour, mediated through altered brain development. Brain microstructure Two studies have used diffusion tensor imaging to examine the association between prenatal smoking exposure and the white matter microstructure. Jacobsen et al. examined 67 adolescent smokers and non-smokers with retrospective information of prenatal smoking exposure. The groups had several similar background factors, including educational attainment and symptoms of inattention. Prenatal smoking exposure, together with smoking during adolescence, was associated with increased fractional anisotropy in the anterior cortical brain region, which is an important region for normal auditory processing (54). The fact that the study included adolescents who smoked complicates the interpretation of the true effect of prenatal smoking exposure on white matter microstructure. Another study used diffusion tensor imaging to investigate the effect of prenatal smoking exposure on the microstructure of the corpus callosum. The study included 23 exposed and 17 unexposed adolescents, who were also tested for sensation-seeking patterns. Smoking exposure during pregnancy was associated with decreased fractional anisotropy in the regions of the corpus callosum containing fibres to the premotor cortex. Decreased fractional anisotropy in these areas was related to more sensation seeking in those individuals exposed to maternal smoking during pregnancy (50). Brain function The effects of prenatal smoking exposure on brain function can be studied in newborn infants, for example by measuring auditory brainstem responses. Peck et al. examined the neuroelectrical activity of the auditory nerve in 2-day-old newborn infants. Newborns exposed to maternal smoking, verified by maternal cotinine measurements, were four times more likely to respond to a sound stimulus than unexposed newborns (55). Similar findings have been reported in infants at 6 months of age (56). A greater response to sound stimulus indicates an impaired ability to process auditory information, which may also impair reading and language development during childhood. Three studies of adolescents, reviewed by Bublitz and Stroud (48), used functional MRI to demonstrate the adverse effects of prenatal smoking exposure on brain function. In summary, adolescents exposed to prenatal smoking showed a lack of coordination across a large, diverse set of brain regions, including frontal, temporal and parietal lobes and cerebellum during information and auditory processing, when they were compared to unexposed adolescents. However, these studies were limited by € ller the small number of participants. A larger study by Mu et al. of 177 adolescents exposed to prenatal smoking showed a weaker response in the ventral striatum during
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reward anticipation in exposed adolescents than in a group of matched, unexposed controls (57). The authors speculated that this alteration may increase the risk of substance abuse or addiction later in life.
NICOTINE REPLACEMENT THERAPY DURING PREGNANCY A Cochrane Database Systematic Review concluded that the effectiveness and safety of nicotine replacement therapy (NRT) during pregnancy are unclear (58). NRT can be used during pregnancy to prevent exposing the foetus to the other potentially toxic ingredients of tobacco smoke. However, nicotine has been shown to be one of the major components of tobacco smoke that interferes with foetal development, as confirmed in this review. The foetus might be exposed to nicotine for a longer period of time, and even be exposed to higher amounts, if the mother uses combinations of different NRTs or combines them with smoking, rather than just smoking. There are no official international guidelines on the use of NRT in pregnant women. The national Finnish guidelines (59) suggest that NRT can be considered for women who are motivated to stop smoking, but cannot do it by themselves and who suffer from physical withdrawal symptoms. The use of methods that provide intermittent nicotine exposure, such as gums and sprays, is preferred when it comes to avoiding long-lasting exposure to nicotine.
FUTURE In the future, 3D-ultrasound scans may provide a new way of studying the effects of smoking exposure on the early developmental stages of foetal brain development (60). Functional MRI might provide the opportunity to study brain function in newborn infants, especially the executive functions of the brain. More active use of cotinine would yield more objective data on the amount of prenatal smoking exposure and could, therefore, enable the evaluation of dose–response relationships. Current human studies are struggling with attempts to adjust for the wide-range of confounding environmental factors linked with smoking during pregnancy, and these should be studied using thorough methodology. The links between genetic susceptibilities and environmental risks, including smoking exposure, are a new field of research. It is also important to study the gene–environmental interactions of smoking exposure on brain development and later psychiatric problems.
CONCLUSIONS Prenatal smoking exposure affects brain growth, specific regional brain volumes and the microstructure of the newborn brain. In addition, alterations in neurophysiological functions and overall brain function have been demonstrated using functional MRI. The mechanisms that mediate these effects include nicotine modulating axonal pathfinding, synapse formation in neurons and carbon monoxide leading to foetal hypoxia and interfering with
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foetal brain development. The epigenetic mechanisms alter the reading of human genomes. The effects of prenatal smoking exposure can extend up to adulthood and even on to the next generation. This review emphasises the importance of preventing smoking during pregnancy and also shows that early cessation of smoking during pregnancy can prevent adverse effects on brain growth.
FUNDING This work was supported by the Turku University Hospital Research Foundation.
CONFLICT OF INTEREST The authors have no conflict of interests to declare.
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