Smoking and Sudden Infant Death Syndrome (SIDS):
A Selected Annotated Bibliography

This bibliography provides information about the effects of smoking, tobacco, and nicotine on the death of infants, including perinatal death and sudden infant death. Also see the Resource Center bibliography on air pollution.

These articles have been selected by Resource Center staff from PubMed, a service of the National Library of Medicine that includes over 19 million citations from MEDLINE and other life science journals for biomedical articles back to 1948. PubMed includes links to full text articles and other related resources.

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Duncan JR, Garland M, Myers MM, Fifer WP, Yang M, Kinney HC, Stark RI.
Prenatal nicotine-exposure alters fetal autonomic activity and medullary neurotransmitter receptors: implications for sudden infant death syndrome.
J Appl Physiol. 2009 Nov;107(5):1579-90. Epub 2009 Sep 3.

During pregnancy, exposure to nicotine and other compounds in cigarette smoke increases the risk of the sudden infant death syndrome (SIDS) two- to fivefold. Serotonergic (5-HT) abnormalities are found, in infants who die of SIDS, in regions of the medulla oblongata known to modulate cardiorespiratory function. Using a baboon model, we tested the hypothesis that prenatal exposure to nicotine alters 5-HT receptor and/or transporter binding in the fetal medullary 5-HT system in association with cardiorespiratory dysfunction. At 87 (mean) days gestation (dg), mothers were continuously infused with saline (n = 5) or nicotine (n = 5) at 0.5 mg/h. Fetuses were surgically instrumented at 129 dg for cardiorespiratory monitoring. Cesarean section delivery and retrieval of fetal medulla were performed at 161 (mean) dg for autoradiographic analyses of nicotinic and 5-HT receptor and transporter binding. In nicotine-exposed fetuses, high-frequency heart rate variability was increased 55%, possibly reflecting increases in the parasympathetic control of heart rate. This effect was more pronounced with greater levels of fetal breathing and age. These changes in heart rate variability were associated with increased 5-HT(1A) receptor binding in the raphé obscurus (P = 0.04) and increased nicotinic receptor binding in the raphé obscurus and vagal complex (P < 0.05) in the nicotine-exposed animals compared with controls (n = 6). The shift in autonomic balance in the fetal primate toward parasympathetic predominance with chronic exposure to nicotine may be related, in part, to abnormal 5-HT-nicotine alterations in the raphé obscurus. Thus increased risk for SIDS due to maternal smoking may be partly related to the effects of nicotine on 5-HT and/or nicotinic receptors.

Möllborg P, Alm B.
Sudden infant death syndrome during low incidence in Sweden 1997-2005.
Acta Paediatr. 2009 Oct 29. [Epub ahead of print]

Abstract Background: Following the change from prone to supine in preferred sleeping position, the incidence of Sudden Infant Death Syndrome (SIDS) in Sweden fell from 1.1 per 1000 live births in 1992 to 0.41 in 1995. After a further small decline, we have been experiencing a plateau at around 0.25 since 2000. Aim: To identify the changes that have occurred in the epidemiology of SIDS since the end of the Nordic Epidemiological SIDS Study in 1995. Methods: Data from the Medical Birth Register of Sweden, covering the years 1995-2005, were used. Sleeping position is not included in the register. Results: The incidence of SIDS has remained low in Sweden. Independent risk factors were smoking during early pregnancy, parents not living together, low maternal age, high parity and short gestational age. The odds ratio for smoking has continued to increase and the median age of death has continued to decrease since the previous study. We found no signs of seasonality in the current material. Conclusions: Age at death continued to decrease. The high incidence during weekends persisted. Seasonality was not significant. There was no evidence of a changing effect from risk factors in the studied period.

Blood-Siegfried J, Bowers MT, Lorimer M.
Is shock a key element in the pathology of sudden infant death syndrome (SIDS)?
Biol Res Nurs. 2009 Oct;11(2):187-94. Epub 2008 Dec 28.

In developed countries, sudden infant death syndrome (SIDS) is the most common cause of death for infants between 1 month and 1 year of age. The etiology of SIDS is likely to be multifactorial, and current paradigms often describe three overlapping elements of risk. Those elements are a critical developmental period, a vulnerable infant, and one or more exogenous stressors. In the triple-risk model, SIDS infants are described as having an underlying vulnerability in cardiorespiratory control in the central nervous system during a critical period when autonomic control is developing. This vulnerability might affect the response to exogenous stressors, including prone sleeping position, hypoxia, and increased carbon dioxide. In the common bacterial hypothesis and fatal triangle, the focus is on the stressors. In the first, a combination of common respiratory infections can cause SIDS in an infant during a developmentally vulnerable period. This theory also includes 3 factors of vulnerability: a genetic predisposition, a vulnerable developmental age, and infectious stressors. In the fatal triangle theory, infection, inflammation, and genetics each play a role in triggering a SIDS fatality. From our work in an animal model, we have found that rat pups die from a combination of infectious insults during a critical time of development. This is exacerbated by perinatal nicotine exposure, a condition shown to alter the autonomic response in exposed offspring. We are proposing that shock and cardiovascular collapse is a key element that links these theories.

Rogers JM.
Tobacco and pregnancy.
Reprod Toxicol. 2009 Sep;28(2):152-60. Epub 2009 Apr 9.

This paper will review the epidemiology of the impact of cigarette smoking and other forms of tobacco exposure on human development. Sources of exposure described include cigarettes and other forms of smoked tobacco, secondhand (environmental) tobacco smoke, several forms of smokeless tobacco, and nicotine from nicotine replacement therapy. Exposure is immense and worldwide, most of it due to smoking, but in some parts of the world and in some populations, smoking is exceeded by smokeless tobacco use. Nicotine and carbon monoxide exposure are of large concern, but cigarette smoke contains over 4000 chemical constituents and additives including known carcinogens, toxic heavy metals, and many chemicals untested for developmental toxicity. The impact of tobacco on human development will be reviewed. Fertility, conception, survival of the conceptus, most phases and aspects of development studied to date, as well as postnatal survival and health are adversely impacted by maternal tobacco use or exposure. Effects in surviving offspring are probably life-long, and are still being elucidated. It is hoped that this review will serve to keep a focus on the critical and continuing problem of tobacco use impacting human development.

Lavezzi AM, Casale V, Oneda R, Weese-Mayer DE, Matturri L.
Sudden infant death syndrome and sudden intrauterine unexplained death: correlation between hypoplasia of raphé nuclei and serotonin transporter gene promoter polymorphism.
Pediatr Res. 2009 Jul;66(1):22-7.

This study, besides to delineate the cytoarchitecture and the localization in the brainstem of the human raphé nuclei, aims to evaluate the correlation between neuropathological raphé defects and serotonin transporter gene (5-HTT) promoter region polymorphisms in a cohort of 28 SIDS victims, 12 sudden intrauterine unexplained deaths (SIUD), and 17 controls. Hypoplasia of one or more nuclei of both the rostral and caudal raphé groups was found in 57% of SIDS, in 67% of SIUD, and only in 12% of controls. Furthermore, a significant correlation among 5-HTT Long (L) allele, hypoplasia of the raphé nuclei, and maternal smoking in pregnancy was observed in sudden fetal and infant deaths. The presence of the L allele represents a predisposing factor for sudden fetal and infant death in association with morphologic developmental defects of the raphé nuclei and prenatal smoke exposure. A further consideration of the authors is that SIUD should not be regarded as a separate entity from SIDS, given the potentially shared neuropathological and genetic bases.

Lavezzi AM, Corna M, Mingrone R, Matturri L.
Study of the human hypoglossal nucleus: Normal development and morpho-functional alterations in sudden unexplained late fetal and infant death.
Brain Dev. 2009 Jun 22. [Epub ahead of print]

This study evaluated the development and the involvement in sudden perinatal and infant death of the medullary hypoglossal nucleus, a nucleus that, besides to coordinate swallowing, chewing and vocalization, takes part in inspiration. Through histological, morphometrical and immunohistochemical methods in 65 cases of perinatal and infant victims (29 stillbirths, 7 newborns and 29 infants), who died of both unknown and known cause, the authors observed developmental anomalies of the hypoglossal nucleus (HGN) in high percentage of sudden unexplained fetal and infant deaths. In particular, HGN hypoplasia, hyperplasia, positive expression of somatostatin and absence of interneurons were frequently found particularly in infant deaths, with a significant correlation with maternal smoking.

Thiriez G, Bouhaddi M, Mourot L, Nobili F, Fortrat JO, Menget A, Franco P, Regnard J.
Heart rate variability in preterm infants and maternal smoking during pregnancy.
Clin Auton Res. 2009 Jun;19(3):149-56. Epub 2009 Mar 3.

OBJECTIVE: Tobacco smoke exposure increases the risk of premature birth and of dying of sudden infant death syndrome (SIDS). Prematurity significantly increases the risk of dying of SIDS, but mechanisms underlying this epidemiological finding are unclear. The cumulated effect of both prematurity and prenatal exposure to nicotine on autonomic heart rate control has not been studied. METHODS: Using coarse-graining spectral analysis, we compared heart rate variability (HRV) indices of preterm newborns at 33-34 weeks post-conceptional age from smoking (n = 19) and non-smoking (n = 21) mothers. Assessment of tobacco exposure relied on maternal reports and newborns cotinine analysis. We observed how indicators of HRV depended on gestational age at birth. RESULTS: At 33-34 weeks postconceptional age, the newborns from smoking mothers had lower HRV low frequency power normalised to the total spectral power (LF/TP) than the control group (median values: 8% vs. 15% respectively, p < 0.02). In the non-smoking group, RR-interval values and total HRV power were correlated with gestational age at birth, with a shorter RR and a lower total HRV power in lesser gestational ages (rho = 0.67, p = 0.03, rho = 0.71, p = 0.003 respectively). This correlation was not observed for RR values in the group with smoking mothers.

Shao XM, Feldman JL.
Central cholinergic regulation of respiration: nicotinic receptors.
Acta Pharmacol Sin. 2009 Jun;30(6):761-70.

Nicotinic acetylcholine receptors (nAChRs) are expressed in brainstem and spinal cord regions involved in the control of breathing. These receptors mediate central cholinergic regulation of respiration and effects of the exogenous ligand nicotine on respiratory pattern. Activation of alpha4* nAChRs in the preBötzinger Complex (preBötC), an essential site for normal respiratory rhythm generation in mammals, modulates excitatory glutamatergic neurotransmission and depolarizes preBötC inspiratory neurons, leading to increases in respiratory frequency. nAChRs are also present in motor nuclei innervating respiratory muscles. Activation of post- and/or extra-synaptic alpha4* nAChRs on hypoglossal (XII) motoneurons depolarizes these neurons, potentiating tonic and respiratory-related rhythmic activity. As perinatal nicotine exposure may contribute to the pathogenesis of sudden infant death syndrome (SIDS), we discuss the effects of perinatal nicotine exposure on development of the cholinergic and other neurotransmitter systems involved in control of breathing. Advances in understanding of the mechanisms underlying central cholinergic/nicotinic modulation of respiration provide a pharmacological basis for exploiting nAChRs as therapeutic targets for neurological disorders related to neural control of breathing such as sleep apnea and SIDS.

Campos M, Bravo E, Eugenín J.
Respiratory dysfunctions induced by prenatal nicotine exposure.
Clin Exp Pharmacol Physiol. 2009 May 19. [Epub ahead of print]

1. Maternal tobacco smoking is the principal risk factor associated to the Sudden Infant Death Syndrome (SIDS), a leading cause of death of infants under 1 year old. Victims of SIDS show a higher incidence of respiratory control abnormalities including central apnoeas, delayed arousal responses, and diminished ventilatory chemoreflexes. 2. Nicotine is likely the link between maternal tobacco smoking and SIDS. Prenatal nicotine exposure can alter the breathing pattern and can reduce hypoxia- and hypercarbia-induced ventilatory chemoreflexes. In vitro approaches have revealed that prenatal nicotine exposure impairs central chemosensitivity, switching the cholinergic contribution from a muscarinic to a nicotinic receptor based drive. In addition, serotonergic, noradrenergic, GABAergic, glycinergic, and glutamatergic, among other systems, are affected by prenatal nicotine. 3. Here we propose that prenatal nicotine affects the respiratory network through two main processes: reorganization of neurotransmitter systems and remodelling of neural circuits. These changes make breathing more vulnerable to fail in the early postnatal life, which could be related to the pathogenesis of SIDS.

Richardson HL, Walker AM, Horne RS.
Maternal smoking impairs arousal patterns in sleeping infants.
Sleep. 2009 Apr 1;32(4):515-21.

OBJECTIVE: Impairment of the arousal process from sleep is thought to be involved in the pathogenesis of sudden infant death syndrome (SIDS). We hypothesized that a greater propensity for cortical arousal in the prone position may, in a normal infant, be a protective mechanism to promote complete arousal in a vulnerable sleeping position, a protection that is absent in SIDS victims. We aimed to examine the arousal process in a group of infants exposed to maternal smoking, who are thus at higher risk for SIDS. DESIGN: Twelve healthy, full-term infants born to smoking mothers were studied using daytime polysomnography at 2 to 4 weeks, 2 to 3 months and 5 to 6 months postnatal age. Data were compared with 13 healthy infants born to nonsmoking mothers. Arousal was induced by pulsatile air-jet stimulation to the nostrils during active and quiet sleep, in both supine and prone positions. For each stimulus, physiologic and electroencephalogram changes were visually assessed and arousal responses were classified as sub-cortical activation or cortical arousal. RESULTS: In smoke-exposed infants, the progression from sub-cortical activation to cortical arousal was depressed at 2 to 4 weeks and 5 to 6 months. There was no effect of maternal smoking observed at 2 to 3 months; however, a significant dose-dependent relationship between cortical activation proportions and urinary cotinine levels was present in both supine and prone positions. CONCLUSION: We have shown that maternal smoking is associated with impaired arousal processes to trigeminal stimulation that may increase the risk for SIDS. This further highlights the importance of public education of the risks of maternal smoking.

Fifer WP, Fingers ST, Youngman M, Gomez-Gribben E, Myers MM.
Effects of alcohol and smoking during pregnancy on infant autonomic control.
Dev Psychobiol. 2009 Apr;51(3):234-42.

Comment in:
* Dev Psychobiol. 2009 Apr;51(3):213-4.
Prenatal exposure to smoking and alcohol increases the risk for Sudden Infant Death Syndrome (SIDS). Physiological changes associated with these exposures are not well studied. Full-term infants were tested within the first 3 days of life. We hypothesized that maternal alcohol consumption and/or smoking during pregnancy would alter autonomic nervous system function. Newborns whose mothers smoked during pregnancy had lower beat-to-beat heart rate variability in quiet sleep. Infants whose mothers consumed alcohol had lower global heart rate variability, but only in active sleep. Unexposed infants demonstrated increases in heart rate with head-up tilt and decreases in heart rate with head-down tilt, but smoking and alcohol-exposed infants showed no significant responses. These results indicate that autonomic function is altered by prenatal exposure to alcohol and smoking. Such markers may provide early identification of infants at greatest risk for SIDS. (c) 2009 Wiley Periodicals, Inc.

Kinney HC.
Brainstem mechanisms underlying the sudden infant death syndrome: evidence from human pathologic studies.
Dev Psychobiol. 2009 Apr;51(3):223-33.

Comment in:
* Dev Psychobiol. 2009 Apr;51(3):213-4.
The brainstem hypothesis is one of the leading hypotheses concerning the sudden infant death syndrome (SIDS). It states that SIDS, or an important subset of SIDS, is due to abnormal brainstem mechanisms in the control of respiration, chemosensitivity, autonomic regulation, and/or arousal which impairs the infant's response to life-threatening, but often occurring, stressors during sleep (e.g., hypoxia, hypercarbia, asphyxia, hyperthermia) and leads to sudden death in a vulnerable developmental period. In this review, we summarize neuropathologic evidence from SIDS cases that support this hypothesis, beginning with the seminal report of subtle brainstem gliosis three decades ago. We focus upon recent neurochemical studies in our laboratory concerning the neurotransmitter serotonin (5-HT) and its key role in mediating protective responses to homeostatic stressors via medullary circuits. The possible fetal origin of brainstem defects in SIDS is reviewed, including evidence for adverse effects of prenatal exposure to maternal cigarette smoking and alcohol upon the postnatal development of human brainstem 5-HT pathways. (c) 2009 Wiley Periodicals, Inc.

Einarson A, Riordan S.
Smoking in pregnancy and lactation: a review of risks and cessation strategies.
Eur J Clin Pharmacol. 2009 Apr;65(4):325-30. Epub 2009 Jan 24.

BACKGROUND: Despite documented evidence of harm to fetus and infant, a substantial number of women continue to smoke during pregnancy and lactation. OBJECTIVE: To examine the literature regarding smoking during pregnancy and breastfeeding to ascertain adverse effects as well as the efficacy of interventions to enable women to stop smoking in the perinatal period. STUDY DESIGN: A comprehensive literature search was undertaken to identify all published studies reporting on smoking in pregnancy and lactation. MEDLINE, EMBASE, PUBMED, and Web of Science databases were searched for studies published in English from 1966 to 2008 that reported on smoking in pregnancy and breastfeeding, with information on adverse effects and on all forms of smoking cessation, including behavioral interventions, nicotine replacement therapy, and pharmacotherapy such as antidepressants. RESULTS: There is evidence that smoking in pregnancy and lactation may cause many adverse affects in the perinatal period, childhood, and up to adulthood. These adverse effects include infertility, ectopic pregnancy, spontaneous abortion, placenta insufficiency, low birth weight, fetal growth restriction, preterm delivery, orofacial clefts, SIDS, craniosynostosis, clubfoot, childhood respiratory disease, attention deficit disorder, and some childhood cancers. A number of strategies have been developed to assist pregnant women in quitting smoking, including both behavioral interventions and pharmacological therapies, such as nicotine replacement and antidepressant therapy. CONCLUSIONS: Behavioral interventions report only modest success rates. Nicotine replacement therapy and antidepressants appear to be safe to use in pregnancy, but do not achieve a substantially higher success rate for quitting.

Machaalani R, Say M, Waters KA.
Serotoninergic receptor 1A in the sudden infant death syndrome brainstem medulla and associations with clinical risk factors.
Acta Neuropathol. 2009 Mar;117(3):257-65. Epub 2008 Dec 4.

Comment in:
 * Acta Neuropathol. 2009 Mar;117(3):247-55.
The immunoreactivity of the serotoninergic receptor subtype 1A (5HT(1A)R) was quantitatively analyzed in the human infant brainstem medulla (caudal and rostral levels). We hypothesized that immunoreactivity of 5HT(1A)R would be reduced in infants diagnosed with sudden infant death syndrome (SIDS). In particular that those infants with known clinical risk factors (including cigarette smoke exposure, bed sharing and sleep position) would have greater changes than those without clinical risks. Comparing SIDS (n = 67) to infants who died suddenly with another diagnosis (non-SIDS, n = 25), we found decreased 5HT(1A)R immunoreactivity in the majority of the nuclei studied at the rostral medulla level including dorsal motor nucleus of the vagus (DMNV), nucleus of the solitary tract, vestibular, and inferior olivary nucleus (ION). There was a significant relationship with all risk factors for 5HT(1A)R, especially for DMNV, suggesting that 5HT(1A)Rs are highly vulnerable to various insults within the SIDS DMNV. This study not only provides further evidence of abnormalities within the brainstem serotoninergic system of SIDS infants, but also shows that these changes may be associated with exposure to clinical risk factors.

Duncan JR, Paterson DS, Kinney HC.
The development of nicotinic receptors in the human medulla oblongata: inter-relationship with the serotonergic system.
Auton Neurosci. 2008 Dec 15;144(1-2):61-75. Epub 2008 Nov 5.

Maternal cigarette smoking during pregnancy adversely affects fetal development and increases the risk for the sudden infant death syndrome (SIDS). In SIDS we have reported abnormalities in the medullary serotonergic (5-HT) system, which is vital for homeostatic control. In this study we analyzed the inter-relationship between nicotinic receptors (nAChRs), to which nicotine in cigarette smoke bind, and the medullary 5-HT system in the human fetus and infant as a step towards determining the mechanisms whereby smoking increases SIDS risk in infants with 5-HT defects. Immunohistochemistry for the alpha4 nAChR subunit and 5-HT neurons was applied in fetal and infant medullae (15-92 postconceptional weeks, n=9). The distribution of different nAChRs was determined from 39-82 postconceptional weeks (n=5) using tissue autoradiography for 3H-nicotine, 3H-epibatidine, 3H-cytisine, and 125I-bungarotoxin; the findings were compared to laboratory 5-HT1A and 5-HT transporter binding data, and 5-HT neuronal density. Alpha4 immunoreactivity was ubiquitously expressed in medullary nuclei related to homeostatic functions from 15 weeks on, including rhombic lip germinal cells. At all ages, alpha4 co-localized with 5-HT neurons, indicating a potential site of interaction whereby exogenous nicotine may adversely affect 5-HT neuronal development and function. Binding for heteromeric nAChRs was highest in the inferior olive, and for homomeric nAChRs, in the vagal complex. In the paragigantocellularis lateralis, 5-HT1A receptor binding simultaneously increased as alpha7 binding decreased across infancy. This study indicates parallel dynamic and complex changes in the medullary nicotinic and 5-HT systems throughout early life, i.e., the period of risk for SIDS.

Jarvie JA, Malone RE.
Children's secondhand smoke exposure in private homes and cars: an ethical analysis.
Am J Public Health. 2008 Dec;98(12):2140-5. Epub 2008 Oct 15.

Comment in:
* Am J Public Health. 2009 Jul;99(7):1158-9; author reply 1159.
Secondhand smoke (SHS) exposure is a known cause of disease among nonsmokers, contributing to lung cancer, heart disease, and sudden infant death syndrome, as well as other diseases. In response to the growing body of scientific literature linking SHS with serious diseases, many countries, states, and cities have established policies mandating smoke-free public spaces. Yet thousands of children remain unprotected from exposure to SHS in private homes and cars. New initiatives targeting SHS in these spaces have raised ethical questions about imposing constraints on private behavior. We reviewed legislation and court cases related to such initiatives and used a principlist approach to analyze the ethical implications of policies banning smoking in private cars and homes in which children are present.

Viskari-Lähdeoja S, Hytinantti T, Andersson S, Kirjavainen T.
Heart rate and blood pressure control in infants exposed to maternal cigarette smoking.
Acta Paediatr. 2008 Nov;97(11):1535-41. Epub 2008 Aug 6.

AIM: Exposure to maternal cigarette smoking is a major risk factor for sudden infant death syndrome (SIDS). Foetal and postnatal smoke-exposure may alter cardiovascular control in infants. We studied heart rate (HR) and blood pressure (BP) responses in smoke-exposed infants. METHODS: Eleven infants exposed to maternal cigarette smoking were studied at the age of 12 +/- 2.1 (range 10-16) weeks. Twenty healthy, age-matched infants from non-smoking families served as controls. During confirmed slow-wave sleep (NREM3), 3-5 sec side motion and 45 sec 45 degrees head-up tilt tests were performed. RESULTS: Control infants showed consistent biphasic HR and BP responses to side motion, with an initial 2-5% increase followed by a 2% decrease (p < 0.0001). In smoke-exposed infants, the initial HR (p = 0.009) and BP responses (p < 0.0001) were markedly reduced, and the subsequent decrease in BP was more prominent (systolic blood pressure, SBP, p = 0.005; diastolic blood pressure, DBP, p = 0.03). No differences were observed between the groups in tilt test results, HR variability or HR responses to spontaneous arousals. CONCLUSION: Maternal cigarette smoking may alter vestibulo-mediated cardiovascular control in early infancy. This may contribute to increased SIDS risk.

Cohen G, Vella S, Jeffery H, Lagercrantz H, Katz-Salamon M.
Cardiovascular stress hyperreactivity in babies of smokers and in babies born preterm.
Circulation. 2008 Oct 28;118(18):1848-53. Epub 2008 Oct 13.

BACKGROUND: Being born preterm, small, and to a mother who smokes are common perinatal complications with major public health implications. Evidence suggests that each affects the body's structure and function in ways that could increase susceptibility to cardiovascular dysfunction later in life. Here, we used 2 routine stress reactivity tests to identify incipient "silent" programming of cardiovascular dysfunction associated with adverse perinatal events. METHODS AND RESULTS: We studied 29 control babies born at term to nonsmokers, 18 term-born babies of mothers who smoked throughout pregnancy (mean, 15 cigarettes a day), and 31 babies born preterm to nonsmokers. All infants were compared at the same age after conception (ie, at 40 to 42 weeks), during sleep. We analyzed blood pressure (BP) and heart rate responses to breathing 4% CO(2) for 4 minutes or to passive head-up tilt to 60 degrees . BP was measured continuously from a wrist cuff. CO(2) exposure raised heart rate and BP in controls by 10%, and tilt increased their BP by 5%. CO(2) elicited the expected BP but no heart rate response from preterm infants but a much-greater-than-expected BP and heart rate response from babies of smokers. Tilt elicited a 3- to 4-fold greater rise in BP from preterm and tobacco-exposed babies. CONCLUSIONS: Vascular, cardiac, and blood pressure reactivity is heightened in babies born preterm or to smokers. The findings are consistent with in utero and early postnatal "programming" of human cardiovascular dysfunction by adverse circumstances. This incipient dysfunction may be an early manifestation of processes that lead to other problems or complications later on (eg, higher BP or sudden infant death syndrome).

Schneider J, Mitchell I, Singhal N, Kirk V, Hasan SU.
Prenatal cigarette smoke exposure attenuates recovery from hypoxemic challenge in preterm infants.
Am J Respir Crit Care Med. 2008 Sep 1;178(5):520-6. Epub 2008 Jun 19.

RATIONALE: The effects of prenatal cigarette smoke (CS) exposure and hypoxemia on cardiorespiratory control have been investigated in full-term infants. However, few data are available in preterm infants, who form a particularly vulnerable population, with developmentally immature cardiorespiratory control. OBJECTIVES: To investigate the effects of prenatal CS exposure on the duration and recovery of breathing pauses and oxygen saturation levels under baseline and hypoxemic conditions in preterm infants. Methods: The study was performed on 22 (12 born to smoking and 10 to nonsmoking mothers) spontaneously breathing preterm infants between 28 and 36 weeks' gestation. Cardiorespiratory variables were recorded under baseline normoxemic and hypoxemic conditions. MEASUREMENTS AND MAIN RESULTS: Breathing pauses, pause indices, time to recovery, percent pause recovery, oxygen saturation (Sp(O2)), periods of wakefulness, and cardiorespiratory rates were compared between the two groups. Spontaneous recovery of breathing pauses (P = 0.03) and Sp(O(2)) levels (P = 0.017) were attenuated in CS-exposed infants as compared with the control group during the hypoxemic and posthypoxemic periods, respectively. The episodes of wakefulness during the hypoxemic challenge were similar between the two groups. Furthermore, CS-exposed infants showed a greater increase in heart rate (P < 0.001) during the hypoxemic challenge when compared with control infants. CONCLUSIONS: We provide evidence of how prenatal CS exposure and hypoxemic episodes affect the duration and recovery of breathing pauses in preterm infants. These observations could help explain why these infants are at a particularly high risk for sudden infant death syndrome.

Pinho AP, Aerts D, Nunes ML.
Risk factors for sudden infant death syndrome in a developing country.
Rev Saude Publica. 2008 Jun;42(3):396-401.

OBJECTIVE: To analyze whether previously identified risk factors for sudden death syndrome have a significant impact in a developing country. METHODS: Retrospective longitudinal case-control study carried out in Porto Alegre, Southern Brazil. Cases (N=39) were infants born between 1996 and 2000 who died suddenly and unexpectedly at home during sleep and were diagnosed with sudden death syndrome. Controls (N=117) were infants matched by age and sex who died in hospitals due to other conditions. Data were collected from postmortem examination records and questionnaires answers. A conditional logistic model was used to identify factors associated with the outcome. RESULTS: Mean age at death of cases was 3.2 months. The frequencies of infants regarding gestational age, breastfeeding and regular medical visits were similar in both groups. Sleeping position for most cases and controls was the lateral one. Supine sleeping position was found for few infants in both groups. Maternal variables, age below 20 years (OR=2, 95% CI: 1.1; 5.1) and smoking of more than 10 cigarettes per day during pregnancy (OR=3, 95% CI: 1.3; 6.4), significantly increased the risk for the syndrome. Socioeconomic characteristics were similar in both groups and did not affect risk. CONCLUSIONS: Infant-maternal and socioeconomic profiles of cases in a developing country closely resembled the profile described in the literature, and risk factors were similar as well. However, individual characteristics were identified as risks in the population studied, such as smoking during pregnancy and maternal age below 20 years.

Dwyer JB, Broide RS, Leslie FM.
Nicotine and brain development.
Birth Defects Res C Embryo Today. 2008 Mar;84(1):30-44.

Preclinical studies, using primarily rodent models, have shown acetylcholine to have a critical role in brain maturation via activation of nicotinic acetylcholine receptors (nAChRs), a structurally diverse family of ligand-gated ion channels. nAChRs are widely expressed in fetal central nervous system, with transient upregulation in numerous brain regions during critical developmental periods. Activation of nAChRs can have varied developmental influences that are dependent on the pharmacologic properties and localization of the receptor. These include regulation of transmitter release, gene expression, neurite outgrowth, cell survival, and synapse formation and maturation. Aberrant exposure of fetal and neonatal brain to nicotine, through maternal smoking or nicotine replacement therapy (NRT), has been shown to have detrimental effects on cholinergic modulation of brain development. These include alterations in sexual differentiation of the brain, and in cell survival and synaptogenesis. Long-term alterations in the functional status and pharmacologic properties of nAChRs may also occur, which result in modifications of specific neural circuitry such as the brainstem cardiorespiratory network and sensory thalamocortical gating. Such alterations in brain structure and function may contribute to clinically characterized deficits that result from maternal smoking, such as sudden infant death syndrome and auditory-cognitive dysfunction. Although not the only constituent of tobacco smoke, there is now abundant evidence that nicotine is a neural teratogen. Thus, alternatives to NRT should be sought as tobacco cessation treatments in pregnant women.

Milei J, Ottaviani G, Lavezzi AM, Grana DR, Stella I, Matturri L.
Perinatal and infant early atherosclerotic coronary lesions.
Can J Cardiol. 2008 Feb;24(2):137-41.

OBJECTIVE: Because the fetal origin of coronary artery lesions is controversial, early atherosclerotic coronary artery lesions in late fetal stillborns and infants, as well as the possible atherogenic role of maternal cigarette smoking, were studied. METHODS: Twenty-two fetal death and 36 sudden infant death syndrome victims were examined by autopsy. In 28 of 58 cases, the mothers were smokers. Serially cut sections of coronary arteries were stained for light microscopy and immunotypified for CD68, CD34, alpha-smooth muscle actin, proliferating cell nuclear antigen, c-fos and apoptosis. RESULTS: Multifocal coronary lesions were detected in 10 of 12 fetuses and in 15 of 16 infants whose mothers smoked. Arterial lesions in infants with nonsmoking mothers were observed in only five cases (two of 10 fetuses and three of 20 infants) (P<0.001). Alterations ranged from focal areas with mild myointimal thickening in prenatal life to early soft plaques in infants. Smooth muscle cells infiltrated into the subendothelium. These early lesions demonstrated c-fos gene activation in the smooth muscle cells of the media, and in some of these, positivity for apoptosis was observed, suggesting that c-fos overexpression may promote proliferation, as evidenced by proliferating cell nuclear antigen-positive cells. CONCLUSIONS: Early intimal alterations of the coronary arteries are detectable in the prenatal and infancy period, and may be significantly associated with maternal smoking.

Shea AK, Steiner M.
Cigarette smoking during pregnancy.
Nicotine Tob Res. 2008 Feb;10(2):267-78.

Maternal smoking during pregnancy is associated with several adverse developmental outcomes in the offspring. These include preterm delivery, spontaneous abortion, growth restriction, increased risk of sudden infant death syndrome (SIDS), as well as long-term behavioral and psychiatric disorders. However, the underlying physiological mechanisms for these ill-effects are not fully understood. The aim of this paper is to review the animal and human data to date, linking in utero smoke exposure to negative neurodevelopmental outcomes. It is known that nicotine from cigarette smoke exerts its effects by affecting placental vasculature, and also by nicotinic acetylcholine receptor binding in fetal membranes. Thus, subsequent consequences involve a cascade of events causing not only dysregulation of the nicotinic and muscarinic, but also catecholaminergic and serotonergic neurotransmitter systems. These observations provide some insight into how smoking can impair neurodevelopment, but the long-term neurotransmitter involvement in dysregulation of emotion and attention awaits further elucidation. It is important that pregnant women are warned of the detrimental effects of smoking, and encouraged to abstain for healthy fetal development.

Machaalani R, Waters KA.
Neuronal cell death in the Sudden Infant Death Syndrome brainstem and associations with risk factors.
Brain. 2008 Jan;131(Pt 1):218-28.

Immunoreactive expression of three cell death markers was quantitatively analysed in the human infant brainstem medulla. We assessed active caspase-3, TUNEL and single-stranded DNA (ssDNA) in a cohort of 92 infants, and analysed for: (i) variations in the immunoreactive expression with development; (ii) comparison of infants diagnosed with the Sudden Infant Death Syndrome (SIDS, n = 67) to infants who died suddenly with another diagnosis (non-SIDS, n = 25); and (iii) correlations with known clinical risk factors for SIDS. Five nuclei from the brainstem medulla (caudal and rostral levels) were studied, including the hypoglossal (XII), dorsal motor nucleus of the vagus (DMNV), the dorsal column nuclei (gracile and cuneate) and the arcuate nucleus. Our main hypothesis was that neuronal cell death would be increased in SIDS compared to non-SIDS infants, and the increase would correlate with risk factors such as prone sleeping and cigarette smoke exposure. Comparing SIDS to non-SIDS, there was an increase in caspase-3 in the rostral DMNV (P = 0.01), and a trend to increased TUNEL in the arcuate nucleus (P = 0.1), which was statistically significant when comparing the male SIDS to male non-SIDS cohort (P = 0.04). No major changes for ssDNA immunoreactivity were found. Moreover, TUNEL expression was affected by post-conceptional age, by sleep-related risk factors (predominantly affecting the dorsal column nuclei), and by cigarette smoke exposure in the rostral DMNV and arcuate nucleus. Active caspase-3 was affected by post-conceptional age but only in the XII, while gender-related differences were seen in the arcuate nucleus. This study provides further evidence of increased apoptosis in the brainstem of SIDS infants, but shows for the first time that these changes are also affected by age and gender, and by clinical risk factors such as the sleep position and cigarette smoke exposure.

Duncan JR, Randall LL, Belliveau RA, Trachtenberg FL, Randall B, Habbe D, Mandell F, Welty TK, Iyasu S, Kinney HC.
The effect of maternal smoking and drinking during pregnancy upon (3)H-nicotine receptor brainstem binding in infants dying of the sudden infant death syndrome: initial observations in a high risk population.
Brain Pathol. 2008 Jan;18(1):21-31. Epub 2007 Oct 9.

The high rate of the sudden infant death syndrome (SIDS) in American Indians in the Northern Plains (3.5/1000) may reflect the high incidence of cigarette smoking and alcohol consumption during pregnancy. Nicotine, a neurotoxic component of cigarettes, and alcohol adversely affect nicotinic receptor binding and subsequent cholinergic development in animals. We measured (3)H-nicotine receptor binding in 16 brainstem nuclei in American Indian SIDS (n = 27) and controls (n = 6). In five nuclei related to cardiorespiratory control, (3)H-nicotinic binding decreased with increasing number of drinks (P < 0.03). There were no differences in binding in SIDS compared with controls, except upon stratification of prenatal exposures. In three mesopontine nuclei critical for arousal there were reductions (P < 0.04) in binding in controls exposed to cigarette smoke compared with controls without exposure; there was no difference between SIDS cases with or without exposure. This study suggests that maternal smoking and alcohol affects (3)H-nicotinic binding in the infant brainstem irrespective of the cause of death. It also suggests that SIDS cases are unable to respond to maternal smoking with the "normal" reduction seen in controls. Future studies are needed to establish the role of adverse prenatal exposures in altered brainstem neurochemistry in SIDS.

Markowitz S.
The effectiveness of cigarette regulations in reducing cases of Sudden Infant Death Syndrome.
J Health Econ. 2008 Jan;27(1):106-33. Epub 2007 Apr 8.

Sudden Infant Death Syndrome (SIDS) is a leading cause of mortality among infants and is responsible for thousands of infant deaths every year. Prenatal smoking and postnatal environmental smoke have been identified as strong risk factors for SIDS. Given the link between smoking and SIDS, this paper examines the direct effects of cigarette prices, taxes and clean indoor air laws in explaining changes in the incidence of SIDS over time in the United States. State-level counts of SIDS cases are generated from death certificates for 1973-2003. After controlling for some observed and unobserved confounding factors, the results show that higher cigarette prices and taxes are associated with reductions in SIDS cases. Stronger restrictions on smoking in workplaces, restaurants and child care centers are also effective in reducing SIDS deaths.

Salihu HM, Wilson RE.
Epidemiology of prenatal smoking and perinatal outcomes.
Early Hum Dev. 2007 Nov;83(11):713-20. Epub 2007 Sep 19.

During the previous two decades smoking among pregnant women in the developed world declined by about 60-75%. Nevertheless, prenatal smoking remains a common habit and accounts for a significant proportion of fetal morbidity and mortality through both a direct (fetal) and an indirect (placental) effect. The most important smoking-induced placental pathology is placental abruption with reported risk estimates ranging from 1.4 to 4.0. It is almost a consensus that prenatal smoking is a causative factor for placental abruption. Although the evidence is less compelling, smoking mothers are at an increased risk for placenta previa and placenta-previa-accreta combination. There is no association between maternal smoking and the syndrome of idiopathic uterine bleeding. The relationship between maternal smoking and fetal growth is causal, and includes significant reduction in growth of head circumference, abdominal circumference and femur length, with the largest reduction in size observed for femur length. Prenatal smoking is associated with a 20-30% higher likelihood for stillbirth, a 40% elevation in the risk for infant mortality and a 2-fold increase in the incidence of SIDS. CONCLUSION: Despite a temporal decline in maternal smoking, it still accounts for significant feto-infant morbidity and mortality, and efforts to discourage prenatal smoking need to be intensified.

Fleming P, Blair PS.
Sudden Infant Death Syndrome and parental smoking.
Early Hum Dev. 2007 Nov;83(11):721-5. Epub 2007 Sep 18.

Prenatal exposure to tobacco smoke is a major risk factor associated with Sudden Infant Death Syndrome (SIDS) and the risk has increased despite continued advice against this practice. Evidence from the UK suggests the prevalence of maternal smoking during pregnancy has risen amongst SIDS mothers (from 50% to 80%) when the rate amongst expectant mothers in the general population has fallen (from 30% to 20%) confirming pooled estimates from recent studies of a four-fold risk. An additional risk from postnatal exposure has also been identified; increasing with the number of smokers in the household or the daily hours the infant is subjected to a smoke-filled environment. Exposure may lead to a complex range of effects upon normal physiological and anatomical development in fetal and postnatal life that places infants at greatly increased risk of SIDS. Recent legislation prohibiting smoking in public places needs to emphasise the adverse effects of tobacco smoke exposure to infants and amongst pregnant women.

Etzel RA.
Indoor and outdoor air pollution: tobacco smoke, moulds and diseases in infants and children.
Int J Hyg Environ Health. 2007 Oct;210(5):611-6. Epub 2007 Sep 14.

Although outdoor air pollution first brought the issue of air pollution health effects to public attention, it is now indoor air pollution that likely has the greatest impact on children's health. The World Health Organization estimates that the global burden of disease from indoor air pollution is far greater than the burden from outdoor air pollution. This review focuses on two indoor pollutants, one that has been well studied, and another that deserves additional study. There is very strong evidence about the harmful effects of tobacco. Policy to decrease children's tobacco exposure and use should be implemented without delay. The emerging findings linking household inhalation of mould spores and infant pulmonary hemorrhage merit follow-up in other countries, because they may provide clues to some deaths from the sudden infant death syndrome.

Lavezzi AM, Ottaviani G, Mauri M, Matturri L.
Biopathology of the dentate-olivary complex in sudden unexplained perinatal death and sudden infant death syndrome related to maternal cigarette smoking.
Neurol Res. 2007 Sep;29(6):525-32.

OBJECTIVES: The present study was aimed to evaluate the possible presence of cytohistologic and/or biologic modifications of the human dentate-olivary complex in sudden unexplained perinatal and infant deaths. METHODS: We investigated the histologic morphology of the dentate and inferior olivary nuclei, the glial index, the c-fos and apoptotic immunopositivity, as well as the possible effects elicited by maternal cigarette smoking, in 44 cases of perinatal and infant death victims, aged from the 26th gestational week to 10 months of life. RESULTS: We observed subtle alterations of both the medullary inferior olivary nucleus and of the cerebellar dentate nucleus, represented by a significant increase in the reactive astrocyte density and in the neuronal c-fos and apoptotic expression in unexplained death victims, compared with age-matched controls. These alterations were closely related to a maternal cigarette smoking habit. DISCUSSION: We postulate that maternal smoking, besides inducing the previously demonstrated morpho-functional alterations of the autonomic central nervous system, could also exert an adverse influence on the dentate-olivary complex, leading to sudden death in vulnerable periods of perinatal development or early infancy.

Hogberg L, Cnattingius, S.
Influence of maternal smoking habits on the risk of subsequent stillbirth: Is there a causal relation?
BJOG. 2007 Jun; 114(6):699-704.

OBJECTIVE: Maternal smoking has previously been associated with risk of stillbirth. If women who quit smoking reduce their risk of stillbirth, the hypothesis of a causal association would be supported. DESIGN: Prospective cohort study. SETTING: Nationwide study in Sweden. POPULATION: All primiparous women who delivered their first and second consecutive single births between 1983 and 2001, giving a total number of 526,691 women. METHOD: A population-based Swedish study with data from the Medical Birth Registry, the Immigration Registry and the Education Registry. Logistic regression analyses were used to estimate odds ratios, using 95% confidence intervals. MAIN OUTCOME MEASURE: Stillbirth in the second pregnancy. RESULTS: Compared with nonsmokers in both pregnancies, women who smoked during the first pregnancy but not during the second do not have an increased risk of stillbirth (OR 1.02; 95% CI 0.79-1.30), while corresponding risk among women who smoked during both pregnancies was 1.35 (95% CI 1.15-1.58). CONCLUSION: The result supports that maternal smoking during pregnancy is causally associated with stillbirth risk. Smoking is a preventable cause of stillbirth, and smoking interventions is an important issue in antenatal care.

Weese-Mayer DE, Ackerman MJ, Marazita ML, Berry-Kravis EM.
Sudden Infant Death Syndrome: Review of implicated genetic factors.
Am J Med Genet A. 2007 Apr 15; 143(8):771-88.

Genetic studies in Sudden Infant Death Syndrome (SIDS) have been motivated by clinical, epidemiological, and/or neuropathological observations in SIDS victims, with subsequent pursuit of candidate genes in five categories: (1) genes for ion channel proteins based on electrocardiographic evidence of prolonged QT intervals in SIDS victims, (2) gene for serotonin transporter based on decreased serotonergic receptor binding in brainstems of SIDS victims, (3) genes pertinent to the early embryology of the autonomic nervous system (ANS) (and with a link to the 5-HT system) based on reports of ANS dysregulation in SIDS victims, (4) genes for nicotine metabolizing enzymes based on evidence of cigarette smoking as a modifiable risk factor for SIDS, and (5) genes regulating inflammation, energy production, hypoglycemia, and thermal regulation based on reports of postnatal infection, low birth weight, and/or overheating in SIDS victims. Evidence for each of these classes of candidate genes is reviewed in detail. As this review indicates, a number of genetically controlled pathways appear to be involved in at least some cases of SIDS. Given the diversity of results to date, genetic studies support the clinical impression that SIDS is heterogeneous with more than one entity and with more than one possible genetic etiology. Future studies should consider expanded phenotypic features that might help clarify the heterogeneity and improve the predictive value of the identified genetic factors. Such features should be evaluated to the extent possible in both SIDS victims and their family members. With 2,162 infants dying from SIDS in 2003 in the U.S. alone, and improved but still imperfect parent and caretaker compliance with known modifiable risk factors for SIDS, it behooves clinicians, researchers, and parents to combine efforts to reach a common goal. The message of the "Back to Sleep" campaign needs to be re-introduced/re-engineered to reach families and caretakers of all ethnic groups. Clinicians and researchers need to gently inform new SIDS parents about the opportunity to contribute tissue to the NICHD-funded University of Maryland Brain and Tissue Bank. By expanding the network of clinicians, scientists, and families working together, and by combined efforts in a collaborative multi-center study of candidate genes and/or genomics, the discovery of the genetic profile of the infant at risk for SIDS can ultimately be determined.

Markowitz S.
Effectiveness of cigarette regulations in reducing cases of Sudden Infant Death Syndrome.
Journal of Health Economics. Article in Press, Corrected Proof. Available online 8 April 2007.

Sudden Infant Death Syndrome (SIDS) is a leading cause of mortality among infants and is responsible for thousands of infant deaths every year. Prenatal smoking and postnatal environmental smoke have been identified as strong risk factors for SIDS. Given the link between smoking and SIDS, this paper examines the direct effects of cigarette prices, taxes and clean indoor air laws in explaining changes in the incidence of SIDS over time in the United States. State-level counts of SIDS cases are generated from death certificates for 1973-2003. After controlling for some observed and unobserved confounding factors, the results show that higher cigarette prices and taxes are associated with reductions in SIDS cases. Stronger restrictions on smoking in workplaces, restaurants and child care centers are also effective in reducing SIDS deaths.

Horsley T, Clifford T, Barrowman N, Bennett S, Yazdi F, Sampson M, Moher D, Dingwall O, Schachter H, Cote A.
Benefits and harms associated with the practice of bed sharing: A systematic review.
Arch Pediatr Adolesc Med. 2007 Mar; 161(3):237-45.

Objective: To examine evidence of benefits and harms to children associated with bed sharing, factors (eg, smoking) altering bed sharing risk, and effective strategies for reducing harms associated with bed sharing. Data Sources: MEDLINE, CINAHL, Healthstar, PsycINFO, the Cochrane Library, Turning Research Into Practice, and Allied and Alternative Medicine databases between January 1993 and January 2005. Study Selection: Published, English-language records investigating the practice of bed sharing (defined as a child sharing a sleep surface with another individual) and associated benefits and harms in children 0 to 2 years of age. Data Extraction: Any reported benefits or harms (risk factors) associated with the practice of bed sharing. Data Synthesis: Forty observational studies met our inclusion criteria. Evidence consistently suggests that there may be an association between bed sharing and sudden infant death syndrome (SIDS) among smokers (however defined), but the evidence is not as consistent among nonsmokers. This does not mean that no association between bed sharing and SIDS exists among nonsmokers, but that existing data do not convincingly establish such an association. Data also suggest that bed sharing may be more strongly associated with SIDS in younger infants. A positive association between bed sharing and breastfeeding was identified. Current data could not establish causality. It is possible that women who are most likely to practice prolonged breastfeeding also prefer to bed share. Conclusion: Well-designed, hypothesis-driven prospective cohort studies are warranted to improve our understanding of the mechanisms underlying the relationship between bed sharing, its benefits, and its harms.

Bajanowski T, Brinkmann B, Mitchell EA, Vennemann MM, Leukel HW, Larsch KP, Beike J; the GeSID Group.
Nicotine and cotinine in infants dying from sudden infant death syndrome.
Int J Legal Med. 2007 Feb 7; [E-pub ahead of print]

The aim of this component of the German Study on Sudden Infant Death was to determine (1) nicotine concentrations in hair (NCH), as a marker of long standing exposure to tobacco, (2) cotinine concentrations in pericardial fluid (CCP) and (3) cotinine concentrations in liquor cerebrospinalis (CCL), the latter measures being markers of recent exposure to tobacco in the last few hours of life. The results obtained were compared with data on parental smoking revealed from interviews. In 100 cases of sudden infant death syndrome, material was taken at autopsy to determine NCH. In 41 cases, NCH and CCP, and in 70 cases, NCH and CCL were determined. Infants of mothers who stated having smoked during pregnancy had higher NCH than infants of non-smoking mothers (p = 0.008). Furthermore, there was a weak but statistically significant relationship between NCH's and the daily cigarette consumption of the mother during pregnancy (n = 64, r = 0.24, p = 0.05). In 43% of infants, nicotine could be detected in their hair, although the mothers had said at the interview that they did not smoke during pregnancy. On the other hand, in 33% of infants whose mother stated they had smoked during pregnancy nicotine was not detectable in the infant's hair. CCP's were strongly correlated with CCL's (r = 0.62, p = 0.0027). For this reason, both parameters were treated as equivalent for the detection of tobacco smoke exposure in the last hours before death. The influence of breast-feeding was evaluated by comparison of the nicotine concentrations in breast fed and non-breast-fed infants from smokers and non-smokers. Fivefold higher nicotine concentrations were determined in non-breast-fed infants of parents who smoked as compared to all other groups. It can be concluded that nicotine intake by passive smoking is much more important than by breast-feeding. We conclude that both interview data and biochemical measures should be sought to understand the true exposure to tobacco smoke.

Thompson JM, Thach BT, Becroft DM, Mitchell EA; New Zealand Cot Death Study Group.
Sudden infant death syndrome: Risk factors for infants found face down differ from other SIDS cases.
J Pediatr. 2006 Nov; 149(5):630-633.

Objective: To test the hypothesis that infants with sudden infant death syndrome (SIDS) found face down (FD) would have SIDS risk factors different from those found in other positions (non-face-down position, NFD). Study Design: We used the New Zealand Cot Death Study data, a 3-year, nationwide (1987 to 1990), case-control study. Odds ratios (univariate and multivariate) for FD (n = 154) and NFD SIDS (n = 239) were estimated separately, and statistical differences between the two groups were assessed. Results: Of 12 risk factors for SIDS, there were 8 with a statistically significant difference between FD and NFD infants. After adjustment for the potential confounders, younger infant age, Maori ethnicity, low birth weight, prone sleep position, use of a sheepskin, and pillow use were all associated with a greater risk of SIDS in the FD than the NFD group. Sleeping during the nighttime, maternal smoking, and bed-sharing were associated with a risk of SIDS only in the NFD group. Pacifier use was associated with a decreased risk for SIDS only in the NFD group, whereas being found with the head covered was associated with a decreased risk for SIDS for the FD group. Conclusions: Infants with SIDS in the FD position appear to be a distinct subgroup of SIDS. These differences in risk factors provide clues to mechanisms of death in both SIDS subtypes.

Matturri L, Ottaviani G, Lavezzi AM.
Maternal smoking and sudden infant death syndrome: Epidemiological study related to pathology.
Virchows Arch. 2006 Nov 8; [E-pub ahead of print]

Various risk factors have been postulated to be related to sudden infant death syndrome (SIDS). Despite its reduction, thanks to the "Back to Sleep" campaign, SIDS is still a major cause of infant mortality in the first year of life. The purpose of this study was to correlate the different risk factors with the autopsy results and thus to determine if one or more of these variables is really specific for SIDS. We collected 128 sudden infant death victims with clinical diagnosis of SIDS and performed a complete autopsy with in-depth histology on serial sections, particularly of the brainstem, in accordance with our necropsy protocol. Histopathologic and immunohistochemical examination of the central autonomic nervous system revealed, in 78 cases of the SIDS group, the following anomalies: hypodevelopment of the arcuate nucleus, somatostatin positive hypoglossus nucleus, tyrosine hydroxylase negativity in the locus coeruleus, gliosis, and hypoplasia of the hypoglossus nucleus. A significant relation was found between maternal smoke and brainstem alterations.

Shah T, Sullivan K, Carter J.
Sudden infant death syndrome and reported maternal smoking during pregnancy.
Am J Public Health. 2006 Oct; 96(10):1757-9.

We investigated the effect of maternal smoking during pregnancy on the relative risk of sudden infant death syndrome (SIDS) by linking data from Georgia birth and death certificates from 1997 to 2000. We estimated the effect of misclassifying smokers as non-smokers and the effect of being misclassified on SIDS rates, and we calculated the fraction of cases caused by exposure. Of all SIDS cases, 21% were attributable to maternal smoking; among smokers, 61% of SIDS cases were attributable to maternal smoking. Maternal smoking during pregnancy is associated with a significantly increased risk of SIDS.

Polanska K, Hanke W, Ronchetti R, Van Den Hazel P, Zuurbier M, Koppe JG, Bartonova A.
Environmental tobacco smoke exposure and children's health.
Acta Paediatr Suppl. 2006 Oct; 95(453):86-92.

Almost half of the child population is involuntarily exposed to environmental tobacco smoke (ETS). The ETS exposure gives rise to an excessive risk of several diseases in infancy and childhood, including sudden infant death syndrome, upper and lower respiratory infections, asthma and middle ear diseases. It is also linked to cancer, and behavioural problems and neurocognitive deficits in children. Conclusions: Protecting children from ETS exposure is a complex and important issue. The best improvement in children's health is to be gained when parents stop smoking or, when that is not possible, they stop smoking in their children's environment. Paediatricians, because of their authority, and their frequent and regular contact with parents, play a leading role in protecting children from ETS exposure. An ideal approach to help parents to stop smoking seems to be initial minimal-contact advice provided by their paediatrician with feedback and supplemental printed materials, leading to greater intensity and duration of follow-up home visits.

Stick S
The effects of in-utero tobacco-toxin exposure on the respiratory system in children.
Curr Opin Allergy Clin Immunol. 2006 Oct; 6(5):312-6

Purpose of review: Promotion of cigarettes to children and women has resulted in unacceptably high rates of smoking during pregnancy in most developed countries and the potential to greatly increase smoking by mothers in developing countries. The risks of smoking during pregnancy to mothers and unborn children are well known and include growth retardation, respiratory diseases and sudden infant death syndrome. Determining the effects of exposure on the fetus depends upon accurate assessment of maternal smoking, both active and involuntary, and this can be done using self-reports and a variety of biomarkers in the mother and/or newborn. Recent Findings: The evidence is clear that most of the excess respiratory morbidity in children born to smoking mothers is due to in-utero exposure and that deficits in lung function measured soon after birth persist in children and adults. Recent studies have also indicated that some children are genetically predisposed to adverse outcomes in response to in-utero exposure. summary: Although many women attempt to quit during pregnancy and effective interventions are available, ultimately the respiratory health of future generations will depend upon effective public health and tobacco control measures designed to prevent smoking uptake by youth and in particular girls and young women.

Cnattingius S, Akre O, Lambe M, Ockene J, Granath F.
Will an adverse pregnancy outcome influence the risk of continued smoking in the next pregnancy?
Am J Obstet Gynecol. 2006 Sep 29; [E-pub ahead of print]

Objective: The purpose of this study was to study the effect of pregnancy outcomes on risks of continued smoking in subsequent pregnancy. Study Design: Cohort study of first and second single births among 98,778 Swedish women who were daily smokers in first pregnancy. Results: In all, 70.2% of women continued to smoke in second pregnancy. Compared with women with a previous normal pregnancy outcome, risk of smoking in second pregnancy was increased among women with a previous small-for-gestational-age birth (adjusted odds ratio [OR], 95% CI 1.28 [95% CI 1.19-1.37]), and reduced among women who had experienced a stillbirth (OR 0.76 [95% CI 0.63-0.93]) or an infant death because of congenital malformations (OR 0.67 [95% CI 0.49-0.92]. A previous preterm birth, Sudden Infant Death Syndrome, and other causes of infant death did not influence risk. Conclusion: A previous adverse pregnancy outcome has only a modest influence on smoking habits in the successive pregnancy.

Markowitz S.
The Effectiveness of Cigarette Regulations in Reducing Cases of Sudden Infant Death Syndrome
NBER Working Paper No. 12527, September 2006

Sudden Infant Death Syndrome is a leading cause of mortality among infants and is responsible for thousands of infant deaths every year. Prenatal smoking and postnatal environmental smoke have been identified as strong risk factors for SIDS. Given the link between smoking and SIDS, this paper examines the direct effects of cigarette prices, taxes and clean indoor air laws in explaining changes in the incidence of SIDS over time in the United States. State-level counts of SIDS cases are generated from death certificates for 1973 to 2003. After controlling for some observed and unobserved confounding factors, the results show that higher cigarette prices and taxes are associated with reductions in SIDS cases. Stronger restrictions on smoking in restaurants and child care centers are also effective in reducing SIDS deaths.

Rand CM, Weese-Mayer DE, Maher BS, Zhou L, Marazita ML, Berry-Kravis EM.
Nicotine metabolizing genes GSTT1 and CYP1A1 in sudden infant death syndrome.
Am J Med Genet A. 2006 Jul 1;140(13):1447-52.

Exposure to tobacco, both to the developing fetus as well as in the postnatal period, has been identified as a key risk factor in the etiology of sudden infant death syndrome (SIDS). Polymorphisms in both the GSTT1 and CYP1A1 genes have been reported to impact the metabolic detoxification process for cigarette smoke and have been associated with low birth weight. Thus, expression of polymorphisms in these genes may account for the varying susceptibility to the adverse health consequences of tobacco exposure, including SIDS. We hypothesized that functional polymorphisms in GSTT1 (gene deletion) and CYP1A1 (m1, m2, and m3) might be associated with SIDS risk. DNA was prepared from 106 SIDS cases and 106 ethnicity- and gender-matched controls using standard methods. Regions of interest were amplified using PCR, subjected to enzyme digestion, and analyzed on agarose gel. No association was observed between the GSTT1 gene deletion or the CYP1A1 m1, m2, and m3 polymorphisms with SIDS risk when considered independently or in combination. These results indicate that the GSTT1 gene deletion and polymorphisms of CYP1A1 are not responsible for increased SIDS risk in our dataset. However, because SIDS cases with confirmed history of nicotine exposure were limited (7/106 cases), a relationship that might be apparent in a cohort with a large subset of SIDS cases with known history of nicotine exposure cannot be ruled out. A prospective study of SIDS cases with nicotine exposure history is necessary to resolve the relationship between nicotine metabolizing genes and SIDS. (c) 2006 Wiley-Liss, Inc.

Lavezzi AM, Ottaviani G, Mauri M, Matturri L.
Alterations of biological features of the cerebellum in sudden perinatal and infant death.
Curr Mol Med. 2006 Jun; 6(4):429-35.

This article intends to show how the cerebellum, a structure ordinarily not considered in mediating breathing or cardiovascular control, may play a critical role in compensatory responses particularly to hypoxic insults occurring pre and/or postnatally and thus may be involved in the sudden unexplained perinatal and infant death. Besides the ontogenesis of the cerebellar cortex in man, we reported alterations of biopathological features (neuronal immaturity, altered apoptotic programs, negative expression of somatostatin and EN2 gene, intense c-fos expression positivity, astrogliosis) in the cortex and in the dentate nucleus of the 63% of sudden deaths, and only in 10% of the controls. The correlation of these results with the mother's smoking habit was highly significant. Therefore, we support the hypothesis, already expressed in previous studies on brainstem, of a close relation between maternal cigarette smoking and a wide range of morpho-physiological defects of the brain, leading to unexplained sudden death in stillbirths, newborns, and Sudden Infant Death Syndrome (SIDS) victims.

Mitchell EA, Milerad J.
Smoking and the sudden infant death syndrome.
Rev Environ Health. 2006 Apr-Jun; 21(2):81-103

The aims of this review are (a) to critically examine the epidemiologic evidence for a possible association between smoking and the sudden infant death syndrome (SIDS), (b) to review the pathology and postulated physiological mechanism(s) by which smoking might be causally related to SIDS, and (c) to provide recommendations for SIDS prevention in relation to tobacco smoking. Over 60 studies have examined the relation between maternal smoking during pregnancy and risk of SIDS. With regard to prone-sleep-position intervention programs, the pooled relative risk associated with maternal smoking was RR = 2.86 (95% CI = 2.77, 2.95) before and RR = 3.93 (95% CI = 3.78, 4.08) after. Epidemiologically, to distinguish the effect of active maternal smoking during pregnancy from involuntary tobacco smoking by the infants of smoking mothers is difficult. Clear evidence for environmental tobacco smoke exposure can be obtained by examining the risk of SIDS from paternal smoking when the mother is a non-smoker. Seven such studies have been carried out. The pooled unadjusted RR was 1.49 (95% CI = 1.25, 1.77). Consideration of the pathological and physiological effects of tobacco suggests that the predominant effect from maternal smoking comes from the in utero exposure of the fetus to tobacco smoke. Assuming a causal association between smoking and SIDS, about one-third of SIDS deaths might have been prevented if all fetuses had not been exposed to maternal smoking in utero.

Parker M, Sharif I.
Inner-city adults' knowledge about the effects of cigarette smoking on child health.
Clin Pediatr (Phila). 2006 May; 45(4):335-9.

Summary: We sought to determine what adults in an inner-city setting know about the specific effects of adult cigarette smoking on child health. A cross-sectional survey was conducted at an inner-city community health center in the Bronx, New York; 684 subjects participated. Overall, 21% were current smokers, 19% had quit, and 60% had never smoked. While the majority of subjects knew about the effects of smoking on adult health, they were unaware of the extent to which smoking was harmful to child health. Notably, 72% did not know that cigarette smoking increased the risk for ear infections in children, 68% did not know that smoking increased the risk of colds in children, and 61% did not know that smoking increased the risk of sudden infant death syndrome. The findings suggest a need for public health education about the effects of adult smoking on child health.

Alm B, Lagercrantz H, Wennergren G.
Stop SIDS--sleeping solitary supine, sucking soother, stopping smoking substitutes.
Acta Paediatr. 2006 Mar; 95(3):260-2.

The recognition of prone sleeping and maternal smoking as modifiable risk factors for sudden infant death syndrome (SIDS), has drastically decreased SIDS incidence. However, during the last years other factors have become necessary to consider to further reduce the risk of SIDS. Side sleeping implies a greater risk than supine sleeping but is still common. Bed sharing may increase the risk of SIDS, while use of a pacifier seems to be protective. Replacement of maternal smoking with nicotine substitutes is not harmless. Conclusion: To further reduce the risk of SIDS, exclusive supine sleeping should be encouraged and side sleeping discouraged. When the breast-feeding is established, a pacifier can very well be used at bedtime. Bed sharing can increase the risk of SIDS if the infant is below 2-3 months of age, especially if the mother is a smoker. Any nicotine use should be avoided during pregnancy and breast-feeding.

Adgent MA.
Environmental tobacco smoke and sudden infant death syndrome: A review.
Birth Defects Res B Dev Reprod Toxicol. 2006 Feb; 77(1):69-85.

Environmental tobacco smoke (ETS), containing the developmental neurotoxicant, nicotine, is a prevalent component of indoor air pollution. Despite a strong association with active maternal smoking and sudden infant death syndrome (SIDS), information on the risk of SIDS due to prenatal and postnatal ETS exposure is relatively inconsistent. This literature review begins with a discussion and critique of existing epidemiologic data pertaining to ETS and SIDS. It then explores the biologic plausibility of this association, with comparison of the known association between active maternal smoking and SIDS, by examining metabolic and placental transfer issues associated with nicotine, and the biologic responses and mechanisms that may follow exposure to nicotine. Evidence indicates that prenatal and postnatal exposures to nicotine do occur from ETS exposure, but that the level of exposure is often substantially less than levels induced by active maternal smoking. Nicotine also has the capacity to concentrate in the fetus, regardless of exposure source. Experimental animal studies show that various doses of nicotine are capable of affecting a neonate's response to hypoxic conditions, a process thought to be related to SIDS outcomes. Mechanisms contributing to deficient hypoxia response include the ability of nicotine to act as a cholinergic stimulant through nicotinic acetylcholine receptor (nAChR) binding. The need for future research to investigate nicotine exposure and effects from non-maternal tobacco smoke sources in mid to late gestation is emphasized, along with a need to discourage smoking around both pregnant women and infants.

Huang ZG, Griffioen KJ, Wang X, Dergacheva O, Kamendi H, Gorini C, Bouairi E, Mendelowitz D.
Differential control of central cardiorespiratory interactions by hypercapnia and the effect of prenatal nicotine.
J Neurosci. 2006 Jan 4; 26(1):21-9.

Hypercapnia evokes a strong cardiorespiratory response including gasping and a pronounced bradycardia; however, the mechanism responsible for these survival responses initiated in the brainstem is unknown. To examine the effects of hypercapnia on the central cardiorespiratory network, we used an in vitro medullary slice that allows simultaneous examination of rhythmic respiratory-related activity and inhibitory synaptic neurotransmission to cardioinhibitory vagal neurons (CVNs). Hypercapnia differentially modulated inhibitory neurotransmission to CVNs; whereas hypercapnia selectively depressed spontaneous glycinergic IPSCs in CVNs without altering respiratory-related increases in glycinergic neurotransmission, it decreased both spontaneous and inspiratory-associated GABAergic IPSCs. Because maternal smoking is the highest risk factor for sudden infant death syndrome (SIDS) and prenatal nicotine exposure is proposed to be the link between maternal smoking and SIDS, we examined the cardiorespiratory responses to hypercapnia in animals exposed to nicotine in the prenatal and perinatal period. In animals exposed to prenatal nicotine, hypercapnia evoked an exaggerated depression of GABAergic IPSCs in CVNs with no significant change in glycinergic neurotransmission. Hypercapnia altered inhibitory neurotransmission to CVNs at both presynaptic and postsynaptic sites. Although the results obtained in this study in vitro cannot be extrapolated with certainty to in vivo responses, the results of this study provide a likely neurochemical mechanism for hypercapnia-evoked bradycardia and the dysregulation of this response with exposure to prenatal nicotine, creating a higher risk for SIDS.

Lahr MB, Rosenberg KD, Lapidus JA.
Bedsharing and maternal smoking in a population-based survey of new mothers.
Pediatrics. 2005 Oct; 116(4):e530-42.

Objective: Sudden infant death syndrome (SIDS) remains the number 1 cause of postneonatal infant death. Prone infant sleep position and maternal smoking have been established as risk factors for SIDS mortality. Some studies have found that bedsharing is associated with SIDS, but, to date, there is only strong evidence for a risk among infants of smoking mothers and some evidence of a risk among young infants of nonsmoking mothers. Despite the lack of convincing scientific evidence, bedsharing with nonsmoking mothers remains controversial. In some states, nonsmoking mothers are currently being told that they should not bedshare with their infants, and mothers of infants who died of SIDS are told that they caused the death of their infant because they bedshared. The objective of this study was to explore the relationship between maternal smoking and bedsharing among Oregon mothers to explore whether smoking mothers, in contrast to nonsmoking mothers, are getting the message that they should not bedshare. Methods: Oregon Pregnancy Risk Assessment Monitoring System surveys a stratified random sample, drawn from birth certificates, of women after a live birth. Hispanic and non-Hispanic black, non-Hispanic Asian/Pacific Islander and non-Hispanic American Indian/Alaskan Native women, and non-Hispanic white women with low birth weight infants are oversampled to ensure sufficient numbers for stratified analysis. The sample then was weighted to reflect Oregon's population. In 1998-1999, 1867 women completed the survey (73.5% weighted response). The median time from birth to completion of the survey was 4 months. Women were asked whether they shared a bed with their infant "always," "almost always," "sometimes," or "never." Frequent bedsharing was defined as "always" or "almost always"; infrequent was defined as "sometimes" or "never." RESULTS: Of all new mothers, 35.2% reported bedsharing frequently (always: 20.5%; almost always: 14.7%) and 64.8% infrequently (sometimes: 41.4%; never: 23.4%). Bedsharing among postpartum smoking mothers was 18.8% always, 12.6% almost always, 45.1% sometimes, and 23.6% never; this was not statistically different from among nonsmoking mothers. Results for prenatal smokers were similar. When stratified by race/ethnicity, there was no association between smoking and bedsharing in any racial or ethnic group. In univariable and multivariable logistic regression, there were no statistical differences in frequent or any bedsharing among either prenatal or postpartum smoking mothers compared with nonsmokers; the adjusted odds ratio for postpartum smokers who frequently bedshared was 0.73 (95% confidence interval [CI]: 0.42-1.25) and for any bedsharing was 1.05 (95% CI: 0.57-1.94). Results for prenatal smoking were similar. This is the first US population-based study to look at the prevalence of bedsharing among smoking and nonsmoking mothers. Bedsharing is common in Oregon, with 35.2% of mothers in Oregon reporting frequently bedsharing and an additional 41.4% sometimes bedsharing. There was no significant association between smoking and bedsharing for either prenatal or postpartum smokers among any racial or ethnic group. Smoking mothers were as likely to bedshare as nonsmoking mothers. The frequency of bedsharing in Oregon was similar to estimates from other sources. Our study has the advantage of being a population-based sample drawn from birth certificates, weighted for nonresponse. Conclusions: Although a number of case series have raised concerns about the safety of mother-infant bedsharing, even among nonsmoking mothers, this has not yet been confirmed by careful, controlled studies. There have been 9 large-scale case-control studies of the relationship between bedsharing and SIDS. Three case-control studies did not stratify by maternal smoking status, but found no increased risk for SIDS. Six case control studies reported results stratified by maternal smoking status: 1 study, while asserting an association, provided an unexplained range of univariable odds ratios without CIs; 3 found no increased risk for older infants of nonsmoking mothers; and 2 found a risk only for infants <8-11 weeks of age. Despite the preponderance of evidence that bedsharing by nonsmoking mothers does not increase the risk for SIDS among older infants, the recent specter of bedsharing as a cause of SIDS, based on uncontrolled case series and medical examiners' anecdotal experience, has led some medical examiners to label a death "suffocation" or "overlay asphyxiation" simply because the infant was bedsharing at the time of death. This "diagnostic drift" may greatly complicate future studies of the relationship between bedsharing and SIDS. Epidemiologic evidence shows that there is little or no increased risk for SIDS among infants of nonsmoking mothers but increased risk among infants of smoking mothers and younger infants of nonsmoking mothers. It seems prudent to discourage bedsharing among all infants <3 months old. Young infants brought to bed to be breastfed should be returned to a crib when finished. It would be worthwhile for other researchers to reanalyze their previous data to evaluate the consistency of the interaction of young infant age and bedsharing. Large controlled studies that include infants who are identified as dying from SIDS, asphyxia, suffocation, and sudden unexplained infant death, analyzed separately and in combination, are needed to resolve this and other issues involving bedsharing, including the problem of diagnostic drift. Recommendations must be based on solid scientific evidence, which, to date, does not support the rejection of all bedsharing between nonsmoking mothers and their infants. Cribs should be available for those who want to use them. Nonsmoking mothers should not be pressured to abstain from bedsharing with their older infants; they should be provided with accurate, up-to-date scientific information. Infants also should not co-sleep with nonparents. In Oregon, if not elsewhere, the message that smoking mothers should not bed share is not being disseminated effectively. Because it is not known whether the risk caused by smoking is associated with prenatal smoking, postpartum smoking, or both, bedsharing among either prenatal or postpartum smokers should be strongly discouraged. Much more public and private effort must be made to inform smoking mothers, in culturally competent ways, of the very significant risks of mixing bedsharing and smoking. Public health practitioners need to find new ways to inform mothers and providers that smoking mothers should not bedshare and that putting an infant of a nonsmoking mother to sleep in an adult bed should be delayed until 3 months of age.

Huang ZG, Wang X, Dergacheva O, Mendelowitz D.
Prenatal nicotine exposure recruits an excitatory pathway to brainstem parasympathetic cardioinhibitory neurons during hypoxia/hypercapnia in the rat: Implications for sudden infant death syndrome.
Pediatr Res. 2005 Sep; 58(3):562-7.

Maternal cigarette smoking and prenatal nicotine exposure increase the risk for sudden infant death syndrome (SIDS) by 2- to 4-fold, yet despite adverse publicity, nearly one of four pregnant women smoke tobacco. Infants who succumb to SIDS typically experience a severe bradycardia that precedes or is accompanied by centrally mediated life-threatening apneas and gasping. Although the causes of the apnea and bradycardia prevalent in SIDS victims are unknown, it has been hypothesized that these fatal events are exaggerated cardiorespiratory responses to hypoxia or hypercapnia. Changes in heart rate are primarily determined by the activity of cardiac vagal neurons (CVNs) in the brainstem. In this study, we tested whether hypoxia/hypercapnia evokes synaptic pathways to CVNs and whether these cardiorespiratory interactions are altered by prenatal exposure to nicotine. Spontaneous rhythmic inspiratory-related activity was recorded from the hypoglossal rootlet of 700- to 800-microm medullary sections. CVNs were identified in this preparation by retrograde fluorescent labeling, and excitatory synaptic inputs to CVNs were isolated and studied using patch-clamp electrophysiologic techniques. Hypoxia/hypercapnia did not elicit an increase in excitatory neurotransmission to CVNs in unexposed animals, but in animals that were exposed to nicotine in the prenatal period, hypoxia/hypercapnia recruited an excitatory neurotransmission to CVNs. This study establishes a likely neurochemical mechanism for the exaggerated decrease in heart rate in response to hypoxia/hypercapnia that occurs in SIDS victims.

Hafstrom O, Milerad J, Sandberg KL, Sundell HW.
Cardiorespiratory effects of nicotine exposure during development.
Respir Physiol Neurobiol. 2005 Jun 18; [Epub ahead of print]

Exposure to tobacco smoke is a major risk factor for the sudden infant death syndrome. Nicotine is thought to be the ingredient in tobacco smoke that is responsible for a multitude of cardiorespiratory effects during development, and pre- rather than postnatal exposure is considered to be most detrimental. Nicotine interacts with endogenous acetylcholine receptors in the brain and lung, and developmental exposure produces structural changes as well as alterations in neuroregulation. Abnormalities have been described in sympathicovagal balance, arousal threshold and latency, breathing pattern at rest and apnea frequency, ventilatory response to hyperoxia or hypoxia, heart rate regulation and ability to autoresuscitate during severe hypoxia. This review discusses studies performed on infants of smoking mothers and nicotine-exposed animals yielding varying and sometimes inconsistent results that may be due to differences in experimental design, species and the dose of exposure. Taken together however, developmental nicotine exposure appears to induce vulnerability during hypoxia and a potential inability to survive severe asphyxia.

Machaalani R, Waters KA, Tinworth KD.
Effects of postnatal nicotine exposure on apoptotic markers in the developing piglet brain.
Neuroscience.2005; 132(2):325-33.

Exposure to cigarette smoke is a risk factor for the sudden infant death syndrome (SIDS), but the ability to distinguish between the neuropathological effects of pre- versus postnatal exposure is limited in the clinical setting. To test whether postnatal nicotine exposure could contribute to the increased neuronal expression of apoptotic markers that we have previously observed in SIDS infants, as well as including study of gender influences, we developed a piglet model to mimic passive smoking in the early postnatal period. Piglets were exposed to nicotine (2 mg/kg/day infused via an implanted osmotic minipump) within 48 h of birth until the age of 13-14 days, when the brain was collected for study. Four piglet groups included: control females (n=7), control males (n=7), nicotine females (n=7), and nicotine males (n=7). Apoptotic markers included immunohistochemistry for activated caspase-3, and for DNA fragmentation or terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) in seven nuclei of the brainstem caudal medulla and two subregions of the hippocampus (CA4 and dentate gyrus). Among control females compared with males, there was less active caspase-3 and less TUNEL in the dorsal motor nucleus of vagus (DMNV), and there was less TUNEL in the nucleus of the spinal trigeminal tract (NSTT). Compared with controls, nicotine-exposed male piglets had increased TUNEL staining in the cuneate nucleus (P=0.05), and increased active caspase-3 in the hypoglossal, gracile and dentate gyrus (P<0.05 for each). Nicotine-exposed females showed no change in TUNEL staining in any of the nuclei studied, but increased active caspase-3 in the hypoglossal, DMNV and NSTT (P<0.05 for each). These results show for the first time that postnatal nicotine exposure can lead to an increase in apoptotic markers in the brain. In piglets, these effects showed regional and gender-specific differences, suggesting that passive, postnatal nicotine exposure may be responsible for some neuropathological changes observed in infants dying from SIDS.

Amarin ZO.
Obstetricians, gynecologists and the anti-smoking campaign: a national survey.
Eur J Obstet Gynecol Reprod Biol. 2005 Apr 1; 119(2):156-60.

Objective: To asses the role Jordanian obstetricians and gynecologists play as tobacco cessation counselors through examining their smoking status, opinions on health risks, factors that influence tobacco use and their perceived barriers to providing effective counseling. Study Design: The setting is a tertiary referral university hospital. A pre-tested postal questionnaire survey was mailed to all 462 licensed obstetricians and gynecologists in Jordan. Descriptive statistics were generated and statistical significance was determined by the chi2-test. Results: Of 392 respondents, 37.9% were smokers. Most associated smoking with low birth weight and sudden infant death syndrome. Fewer associated smoking with infertility, ectopic pregnancy, placenta praevia, abruptio placentae and cancer of the uterine cervix. Friends, stress, parents' attitude, genetic predisposition, income and education were implicated factors for smoking. Current smokers were more likely to permit smoking in their practices. Non-smokers were most inclined to record their patients' tobacco habits. Only 54.3% provided cessation counseling. Lack of time and inadequate training were perceived barriers. Conclusions: A high proportion of obstetricians and gynecologists are smokers. A training program is needed to equip health workers with the skills necessary for the implementation of a successful anti-smoking campaign.

Tong EK, England L, Glantz SA.
Changing conclusions on secondhand smoke in a sudden infant death syndrome review funded by the tobacco industry.
Pediatrics. 2005 Mar; 115(3):e356-66.

Background: Prenatal and postnatal exposure to tobacco smoke adversely affects maternal and child health. Secondhand smoke (SHS) has been linked causally with sudden infant death syndrome (SIDS) in major health reports. In 1992, the US Environmental Protection Agency (EPA) first noted an association between SHS and SIDS, and both prenatal exposure and postnatal SHS exposure were listed as independent risk factors for SIDS in a 1997 California EPA report (republished in 1999 by the National Cancer Institute) and a 2004 US Surgeon General report. The tobacco industry has used scientific consultants to attack the evidence that SHS causes disease, most often lung cancer. Little is known about the industry's strategies to contest the evidence on maternal and child health. In 2001, a review was published on SIDS that acknowledged funding from the Philip Morris (PM) tobacco company. Tobacco industry documents related to this review were examined to identify the company's influence on the content and conclusions of this review. Methods: Tobacco industry documents include 40 million pages of internal memos and reports made available to the public as a result of litigation settlements against the tobacco industry in the United States. Between November 2003 and January 2004, we searched tobacco industry document Internet sites from the University of California Legacy Tobacco Documents Library and the Tobacco Documents Online website. Key terms included "SIDS" and names of key persons. Two authors conducted independent searches with similar key terms, reviewed the documents, and agreed on relevancy through consensus. Thirty documents were identified as relevant. Two drafts (an early version and a final version) of an industry-funded review article on SIDS were identified, and 2 authors independently compared these drafts with the final publication. Formal comments by PM executives made in response to the first draft were also reviewed. We used Science Citation Index in July 2004 to determine citation patterns for the referenced SIDS reviews. Results: PM executives feared that SHS and maternal and child health issues would create a powerful and emotional impetus for smoke-free areas in the home, public areas, and the workplace. In response to the 1992 US EPA report on SHS, the Science and Technology Department of PM's Switzerland subsidiary, Fabriques de Tabac Reunies, searched for "independent" consultants to publish articles addressing SHS. The first industry-funded article was a literature review focusing on smoking and SIDS, conducted by consultant Peter Lee and co-author Allison Thornton, which stated that the association between parental smoking and SIDS could have been attributable to the failure to control fully for confounders. That first review has only been cited once, in the subsequent industry-funded review. In 1997, PM commissioned a consultant, Frank Sullivan, to write a review, with coauthor Susan Barlow, of all possible risk factors for SIDS. The first draft concluded that prenatal and postnatal smoking exposures are both independent risk factors for SIDS. After receiving comments and meeting with PM scientific executives, Sullivan changed his original conclusions on smoking and SIDS. The final draft was changed to emphasize the effects of prenatal maternal smoking and to conclude that postnatal SHS effects were "less well established." Changes in the draft to support this new conclusion included descriptions of Peter Lee's industry-funded review, a 1999 negative but underpowered study of SIDS risk and urinary cotinine levels, and criticisms of the conclusions of the National Cancer Institute report that SHS was causally associated with SIDS. In April 2001, the Sullivan review was published in the United Kingdom journal Paediatric and Perinatal Epidemiology, with a disclosure statement that acknowledged financial support from PM but did not acknowledge contributions from PM executives in the preparation of the review. By 2004, the Sullivan SIDS review had been cited at least 19 times in the medical literature. Conclusions: PM executives responded to corporate concerns about the possible adverse effects of SHS on maternal and child health by commissioning consultants to write review articles for publication in the medical literature. PM executives successfully encouraged one author to change his original conclusion that SHS is an independent risk factor for SIDS to state that the role of SHS is "less well established." These statements are consistent with PM's corporate position that active smoking causes disease but only public health officials conclude the same for SHS. The author's disclosure of industry funding did not reveal the full extent of PM's involvement in shaping the content of the article. This analysis suggests that accepting tobacco industry funds can disrupt the integrity of the scientific process. The background of this SIDS review is relevant for institutions engaged in the debate about accepting or eschewing funding from the tobacco industry. Those who support acceptance of tobacco industry funds argue that academic authors retain the right to publish their work and maintain final approval of the written product, but this argument fails to recognize that the tobacco industry funds work to ensure that messages favorable to the industry are published and disseminated. Clinicians, parents, and public health officials are most vulnerable to the changed conclusions of the SIDS review. The national SIDS "Back to Sleep" campaign has been very successful in reducing SIDS rates. However, estimates of SIDS risk from SHS (odds ratios range from 1.4 to 5.1) have considerable overlap with estimates of risk from prone sleep positioning (odds ratios range from 1.7 to 12.9). With the Back to Sleep campaign well underway, efforts to address parental smoking behavior in both the prenatal and postnatal periods should be intensified. The tobacco industry's disinformation campaign on SHS and maternal and child health can be counteracted within clinicians' offices.

Anderson ME, Johnson DC, Batal HA.
Sudden Infant Death Syndrome and prenatal maternal smoking: rising attributed risk in the Back to Sleep era.
BMC Med. 2005 Jan 11; 3(1):4.

Background: Parental smoking and prone sleep positioning are recognized causal features of Sudden Infant Death. This study quantifies the relationship between prenatal smoking and infant death over the time period of the Back to Sleep campaign in the United States, which encouraged parents to use a supine sleeping position for infants. Methods: This retrospective cohort study utilized the Colorado Birth Registry. All singleton, normal birth weight infants born from 1989 to 1998 were identified and linked to the Colorado Infant Death registry. Multivariable logistic regression was used to analyze the relationship between outcomes of interest and prenatal maternal cigarette use. Potential confounders analyzed included infant gender, gestational age, and birth year as well as maternal marital status, ethnicity, pregnancy interval, age, education, and alcohol use. Results: We analyzed 488,918 birth records after excluding 5835 records with missing smoking status. Smokers were more likely to be single, non-Hispanic, less educated, and to report alcohol use while pregnant (p < 0.001). The study included 598 SIDS cases of which 172 occurred in smoke-exposed infants. Smoke exposed infants were 1.9 times (95% CI 1.6 to 2.3) more likely to die of SIDS. The attributed risk associating smoking and SIDS increased during the study period from approximately 50% to 80%. During the entire study period 59% (101/172) of SIDS deaths in smoke-exposed infants were attributed to maternal smoking. Conclusions: Due to a decreased overall rate of SIDS likely due to changing infant sleep position, the attributed risk associating maternal smoking and SIDS has increased following the Back to Sleep campaign. Mothers should be informed of the 2-fold increased rate of SIDS associated with maternal cigarette consumption.

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November 2009

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