help button home button
AJRCCM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hafström, O.
Right arrow Articles by Sundell, H. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hafström, O.
Right arrow Articles by Sundell, H. W.
American Journal of Respiratory and Critical Care Medicine Vol 166. pp. 92-97, (2002)
© 2002 American Thoracic Society

Original Article

Altered Breathing Pattern after Prenatal Nicotine Exposure in the Young Lamb

Ola Hafström, Joseph Milerad and Håkan W. Sundell

Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee

Correspondence and requests for reprints should be addressed to Håkan W. Sundell, M.D., Professor of Pediatrics, Vanderbilt University School of Medicine, U-1212, MCN, Nashville, Tennessee 37232-2585. E-mail: hakan.sundell{at}mcmail.vanderbilt.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Maternal smoking during pregnancy is a risk factor for sudden fetal and infant death as well as obstructive airway disease in childhood. Fetal nicotine exposure affects organ development. The aim of the present study was to investigate effects of fetal nicotine exposure on lung function in young lambs. Nine unanesthetized, awake, prenatally nicotine-exposed lambs (N) (approximate maternal dose: 0.5 mg/kg) and 12 nonexposed control lambs (C) were studied repeatedly for 5 weeks after birth using a pneumotachograph and a computerized method for breath-by-breath determinations. N and C lambs had similar minute ventilation but a markedly different breathing pattern. At both 5 and 21 days, average age, N lambs had significantly lower tidal volumes and higher respiratory rates than C lambs. Inspiratory drive (P0.1) and effective impedance were significantly higher in N lambs compared with C lambs only at 5 days. Prenatal nicotine exposure appears to have long-term effects on the postnatal breathing pattern, suggesting altered lung function, e.g., increased airway resistance, decreased lung compliance, or both. The increased inspiratory drive is most likely secondary to increased impedance of the respiratory system. These changes are most marked close to birth but persist during the initial postnatal period.

Key Words: respiration • respiratory mechanics • nicotine • prenatal exposure delayed effects • tobacco


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Exposure to tobacco smoke before birth continues to be a leading cause of perinatal mortality and morbidity. Infants of smoking mothers have lower birth weight (1), increased risk of late fetal and early neonatal death (2), and higher prevalence of pulmonary morbidity in infancy and childhood (3–5).

Studies based on the "fetal origins" hypothesis have shown that low birth weight is associated with increased pulmonary and cardiovascular morbidity and mortality in adult life (6, 7). Whether the small size at birth reported in these studies was caused by maternal under-nutrition or other known causes of impaired fetal growth such as maternal smoking is still unclear, but it is important to note that adverse events during fetal life seem to have a long-term impact on organ function. A number of studies have demonstrated that tobacco exposure during fetal life rather than inhalation of tobacco fumes after birth may be the cause of respiratory problems in infants of smoking mothers. For instance, infants of smoking mothers appear to have compromised respiratory function already shortly after birth (8), and these effects tend to persist during infancy and childhood (9, 10). In addition to these effects on lung function, autonomic regulation appears to be impaired with regard to increase in systolic blood pressure later during childhood (11). These findings of compromised regulation of vital physiologic functions are in agreement with epidemiologic data suggesting a link between fetal tobacco exposure and the sudden infant death syndrome (SIDS) (12, 13).

Whereas there is little disagreement regarding the adverse effects of prenatal tobacco smoke exposure, it is less clear whether these effects are produced by exposure to nicotine or other substances present in tobacco smoke. The issue is of clinical significance, because nicotine replacement for pregnant women is often regarded as a safe alternative in smoking cessation programs. The aim of the present study was to evaluate whether nicotine exposure at a dosage comparable to mild to moderate cigarette smoking during the fetal period produces long-term effects on breathing pattern in a resting state similar to those described following maternal smoking. The studies were performed in a broader context of experiments designed to study effects of prenatal nicotine exposure on the control of breathing.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
Nine term lambs of mixed breed were exposed to nicotine prenatally (N), and 12 unexposed lambs acted as control animals (C). Apart from registration of resting respiratory variables, the lambs were subjected to acute hypoxia and hyperoxia. The resting ventilation data reported here were collected before any other experiment was performed on the same day. Fifty-four measurements were performed in the N lambs and 104 in the C lambs. The research protocol was approved by the Vanderbilt University Animal Care Committee.

Prenatal Nicotine Exposure
Osmotic pumps (Alzet, Model 2ML4 Durect Corp., Cupertino, CA) were implanted subcutaneously in the ewe on approximately the 98th day of the 147-day gestation. The pumps delivered nicotine bitartrate continuously at 40 mg/day or approximately 0.5 mg/kg/day. The pumps were replaced after 28 days and removed after delivery of the lamb. Plasma concentrations of nicotine and cotinine were determined at 120 ± 15 days of gestation (14). The control lambs were unexposed. Sham control capsule implantation in the ewes was not deemed necessary, because an indirect effect from the capsules on the fetus seemed unlikely.

Instrumentation
The lambs were instrumented with placement of a tracheal window and arterial and venous catheters at 2 ± 1 days of age (15–17). When not studied, tracheal patency was reestablished with a piece of endotracheal tube (Portex, Keene, NH). At least 48 hours postoperative recovery was allowed before the first study.

Study Protocol and Equipment
Studies were performed using a previously described method (15–17). Briefly, the lambs were breathing spontaneously through a cuffed endotracheal tube. Inspiratory airflow was measured by a penumotachograph positioned before an inspiratory pneumatic occlusion valve. Airway occlusion pressure (P0.1), inspiratory time (TI), total breath time, inspiratory flow, and end-tidal CO2 (EtCO2) were measured on a breath-by-breath basis. The analog signals were digitized, stored, and used for calculation of tidal volume (VT), respiratory rate (RR), minute ventilation (V·I), and mean inspiratory flow (VT/TI). Effective impedance (P0.1/[VT/TI]) was calculated to detect changes in respiratory mechanics. Arterial mean blood pressure (BP) and heart rate (HR) were recorded continuously. Arterial PO2, PCO2, and packed cell volume (PCV) were measured once.

When the unsedated lambs were found to rest quietly during wakefulness for several minutes, ventilation, HR, and BP were recorded for 2 to 5 minutes.

Data Analysis and Statistical Methods
To evaluate maturational changes, regression analysis was performed on results from all studies in each lamb. The mean rate of change (i.e., regression coefficient) for the two groups was compared using Mann–Whitney U test. Statistica (Statsoft; Tulsa, OK) and the statistical package of Quattro Pro version 7 (Corel; Farmingdale, NY) were used for statistical analyses. Results from selected studies in the N and C groups were compared using two-sample t test at two time intervals: (1) the first study performed at an age of 3–8 days (4.7 ± 1.6); and (2) the first study performed at an age of 16–24 days (20.9 ± 1.4). Significant differences were accepted for p < 0.05. Data are presented as mean ± SD.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Birth Weight and Postnatal Growth
Lambs exposed to nicotine during fetal life had similar birth weight as control lambs, 4.3 ± 1.1 kg (N) and 5.0 ± 1.1 kg (C) (NS, t test), and they gained weight at a similar rate. Weight at 5 days average age was 5.8 ± 1.4 kg (N) and 6.1 ± 1.4 kg (C) (NS) and at 21 days, 10.0 ± 2.2 kg (N) and 9.5 ± 2.5 kg (C) (NS).

Nicotine Concentrations
Mean plasma concentrations of nicotine and cotinine in the ewes were 7 ± 1 and 18 ± 5 ng/ml, respectively.

Respiratory Variables
N and C lambs had similar resting V·I at both 5 and 21 days of age (Table 1). V·I decreased to a similar value with increasing age in the two groups (regression analysis, Mann–Whitney U test) (Table 2).


View this table:
[in this window]
[in a new window]
  		TABLE 1. Cardiorespiratory variables, blood gases, and pcv for control lambs and prenatally nicotine-exposed lambs at 5 and 21 days postnatal age

 

View this table:
[in this window]
[in a new window]
  		TABLE 2. Regression coefficients for cardiorespiratory variables for control lambs and prenatally nicotine-exposed lambs

 
VT.
Although V·I was similar in the two groups, VT was significantly lower in N lambs than in C lambs at both 5 and 21 days of age, 7.8 ± 1.1 versus 10.6 ± 2.1 ml/kg (p = 0.002) (t test) and 6.7 ± 1.2 versus 8.3 ± 1.5 ml/kg (p = 0.04), respectively (Figure 1 upper panel). VT decreased more with increasing postnatal age in C lambs than in N lambs (Figure 1 lower panel and Table 2).



View larger version (18K):
[in this window]
[in a new window]
  		Figure 1. Upper panel: Tidal volume (VT) in 12 control lambs and nine prenatally nicotine-exposed lambs measured at an average postnatal age of 5 and 21 days (mean ± SD). *p < 0.05 and ** p < 0.01 for difference between groups. Lower panel: Individual VT results from repeated measurements in these lambs (104 control studies and 54 studies in nicotine-exposed lambs) illustrating that VT decreased more with increasing postnatal age in C lambs than in N lambs.

 
RR.
N lambs had higher RR than C lambs at both 5 and 21 days of age, 61 ± 14 versus 40 ± 7 min-1 (p < 0.001) and 41 ± 7 versus 34 ± 5 min-1 (p = 0.02), respectively (Figure 2 upper panel). RR decreased more with increasing postnatal age in N lambs than in C lambs (Figure 2 lower panel and Table 2).



View larger version (19K):
[in this window]
[in a new window]
  		Figure 2. Upper panel: RR in 12 control lambs and nine prenatally nicotine-exposed lambs measured at an average postnatal age of 5 and 21 days (mean ± SD). *p < 0.05 and ***p < 0.001 for difference between groups. Lower panel: Individual RR results from repeated measurements in these lambs (104 control studies and 54 studies in nicotine-exposed lambs) illustrating that RR decreased more with increasing postnatal age in N lambs than in C lambs.

 
EtCO2, PCO2, and PO2.
N lambs had lower EtCO2 than C lambs at 5 days, 4.6 ± 0.6% versus 5.2 ± 0.5% (p = 0.03), but EtCO2 was similar in the two groups at 21 days, 5.2 ± 0.3% versus 5.4 ± 0.3% (NS) (Figure 3 upper panel). EtCO2 increased with increasing postnatal age in N lambs but remained unchanged in C lambs (Figure 3 lower panel and Table 2). Arterial PCO2 and PO2 were similar in the groups at both ages (Table 1).



View larger version (18K):
[in this window]
[in a new window]
  		Figure 3. Upper panel: EtCO2 in 12 control lambs and nine prenatally nicotine-exposed lambs measured at an average postnatal age of 5 and 21 days (mean ± SD). *p < 0.05 for difference between groups. Lower panel: Individual EtCO2 results from repeated measurements in these lambs (104 control studies and 54 studies in nicotine-exposed lambs) illustrating that EtCO2 increased with increasing postnatal age in N lambs but remained unchanged in C lambs.

 
P0.1 and VT /TI.
Inspiratory drive measured as P0.1 was higher in N lambs compared with C lambs at 5 days of age, and there was a trend toward a higher P0.1 in N lambs at 21 days of age (p = 0.07) (Table 1). P0.1 did not change with increasing age in either of the groups (Table 2). There was no significant difference between groups in VT/TI at either age.

Effective impedance.
Effective impedance was higher in N lambs compared with C lambs at 5 days of postnatal age, 0.050 ± 0.021 cm H2O · s/ml versus 0.025 ± 0.010 cm H2O · s/ml (p = 0.002), (Figure 4 upper panel). Although not at the level of statistical significance, there was a trend toward a higher effective impedance in N lambs at 21 days of postnatal age compared with the control lambs, 0.032 ± 0.011 cm H2O · s/ml versus 0.021 ± 0.011 cm H2O · s/ml (p = 0.06) (Figure 4 upper panel). Effective impedance decreased more with increasing age in N lambs compared with C lambs (Figure 4 lower panel and Table 2).



View larger version (21K):
[in this window]
[in a new window]
  		Figure 4. Upper panel: Effective impedance in 12 control lambs and nine prenatally nicotine-exposed lambs measured at an average postnatal age of 5 and 21 days (mean ± SD). +p = 0.06 and **p < 0.01 for difference between groups. Lower panel: Individual effective impedance results from repeated measurements in these lambs (104 control studies and 54 studies in nicotine-exposed lambs) illustrating that effective impedance decreased more with increasing age in N lambs compared with C lambs.

 
Cardiovascular variables and PCV.
N lambs had a trend toward slightly higher HR compared with C lambs at 5 days of age (p = 0.06), and HR was similar at 21 days of age (Table 1). BP was similar in the two groups at both ages (Table 1). HR decreased and BP increased similarly with increasing postnatal age in the two groups (Table 2). PCV was similar in both groups at both ages (Table 1).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Altered Breathing Pattern
We found that young lambs exposed to a low dose of nicotine during the last third of fetal life had minute ventilation at rest similar to nonexposed control lambs but had a breathing pattern suggestive of altered pulmonary mechanics. Nicotine-exposed lambs had smaller tidal volumes, higher respiratory rate, and elevated effective impedance (18, 19)—a combination suggestive of increased inspiratory effort as also evidenced by higher airway occlusion pressures. Such alterations in respiratory mechanics, if present in the absence of lung disease, may be caused by impaired lung development leading to smaller and/or stiffer lungs, i.e., decrease in lung compliance and/or increase in airway resistance. Although the present study lacks data on lung morphology and specific pulmonary function tests, the present results suggest that nicotine exposure may have specific adverse effects similar to maternal smoking on fetal lung development (8–10).

Whereas earlier studies have attributed airway morbidity and impaired expiratory flow in childhood to the irritant effects of environmental smoke exposure, it is now generally believed that the origins of respiratory illness during childhood arise in fetal life as a consequence of maternal tobacco use (3–5).

Few studies of infants of smoking mothers have included measurements of VT and RR, and the reported results are somewhat divergent. Sovik and colleagues showed that RR was increased and VT was decreased during quiet sleep in 1- to 10-day-old infants of smoking mothers, but when these infants were studied again at 10 weeks of life, the breathing pattern was normalized (20). Similar findings of lower VT in infants of smoking compared with nonsmoking mothers at 4 weeks age was reported by Hanrahan and colleagues (21), whereas Poole and colleagues reported similar RR in infants of smoking and nonsmoking mothers at 11 weeks age (22). Major differences in study designs (natural sleep versus chloral hydrate–induced sleep, face mask versus impedance plethysmography) and different doses of prenatal smoke exposure make these comparisons of breathing patterns difficult. However, results of pulmonary function studies on human infants are consistent with our hypothesis that the altered breathing pattern is a consequence of increased airway resistance and/or lower compliance (8, 9, 21), and some of these changes appear to persist in children until school age (10).

Despite similar V·I and arterial PCO2, the 5-day-old nicotine-exposed lambs in the present study had lower EtCO2 compared with control lambs. A respiratory pattern with smaller VT and higher RR, as in the nicotine-exposed lambs, is known to result in higher dead space ventilation, which may explain the lower EtCO2 (23). Experimental data on the effects of nicotine on respiratory physiology are available on rats and monkeys. St.-John and Leiter found that rat pups exposed to nicotine during fetal life had depressed baseline V·I (24), a finding that was not reproduced by other investigators (25–27). Sekhon and colleagues demonstrated decreased expiratory flow rates and increased pulmonary resistance in newborn rhesus monkeys exposed to nicotine in utero (28).

Inspiratory Drive
Airway occlusion pressure is widely used as a noninvasive estimate of central inspiratory activity in intact subjects (see [29] for a review). In the absence of airflow, as during the occlusion maneuver, the respiratory system can be shown mathematically to have an infinite impedance; individual variations in the mechanical properties of the lungs and chest wall can consequently be disregarded, and comparisons of inspiratory activity can be made across a wide range of subjects and experimental conditions. Unlike ventilation and tidal volume, occlusion pressure determinations are, therefore, at least in theory, not affected by the mechanical properties of the respiratory system. They will provide information on respiratory control in situations where ventilation is affected by changes in respiratory mechanics (30), e.g., during early postnatal development. The technique of measuring airway occlusion pressures was originally developed for determination of central inspiratory activity in patients with chronic obstructive pulmonary disease (31, 32). The flow restriction secondary to mechanical properties of the respiratory system had previously led to the erroneous assumption of hypoventilation—and measurements of airway occlusion pressure showed that these patients had increased respiratory drive to compensate for an elevated impedance of the respiratory system. The elevated P0.1 of nicotine-treated lambs in the present study in conjunction with elevated RR and elevated effective impedance most likely represents a typical load compensation response, i.e., an increase in inspiratory effort in response to an increased impedance of the respiratory system, whether due to increased airway resistance, decreased lung compliance, or both.

Lung Development
Morphologic studies have shown that nicotine can interfere with different aspects of lung development. Airway branching is increased in the presence of nicotine in explanted embryonic mouse lungs (33), whereas neonatal rats have disturbed alveolar architecture after exposure to nicotine during pregnancy and lactation (34). On a cellular level, nicotine binds to nicotinic acetylcholine receptors (nAChR), ligand-gated ion channels controlling influx of calcium and sodium into cells. Neuronal nicotinic receptors are present not only in cholinergic nerves innervating bronchial smooth muscle and submucosal glands but also in several nonneuronal cell types, i.e., bronchial epithelial (35) and vascular endothelial cells (36). Acetylcholine acting on nonneuronal nAChR is involved in modulating cell shape and motility (35) and may also moderate cell proliferation and differentiation (37). Nicotine administered to pregnant monkeys caused fetal lung hypoplasia, marked increase in {alpha}7 nAChR subunit expression, increased collagen deposition, and increased numbers of Type II and neuroendocrine cells (38). Altered lung development following prenatal nicotine exposure may, thus, be attributed to stimulation of nAChR resulting in premature onset of cell differentiation at the expense of replication, in analogy with what has been demonstrated in the central nervous system of fetal rats exposed to a continuous nicotine infusion (39).

Control of Breathing
VT and RR are to a large extent regulated by the activity of slowly adapting pulmonary stretch receptors. An increased activity of these lung vagal afferents terminates inspiration at a lower level of lung inflation, which in turn shortens inspiratory time and decreases VT (40, 41). Theoretically, an increase in vagal tone produced by cholinergic stimulation due to nicotine exposure may result in an altered breathing pattern even in the absence of structural pulmonary changes. Chronic stimulation of nicotinic cholinergic receptors with nicotine during fetal life leads to increased {alpha}7 nAChR subunit expression in the airways (38), but it is not known whether fetal nicotine exposure affects vagal pulmonary afferents. However, all three major types of vagal pulmonary afferents, i.e., slowly adapting pulmonary stretch receptors as well as C-fibers and rapidly adapting receptors, have been shown to respond to acute nicotine administration in adult dogs or rats (42–44).

An effect of fetal nicotine exposure on central control of breathing should also be considered. A recent study by Nachmanoff and colleagues has shown upregulated nicotine receptor binding in three brainstem nuclei related to cardiorespiratory control in human infants who were exposed to maternal smoking in utero (45). However, it is not known whether this abnormality is associated with an altered breathing pattern.

Breathing Patterns and Control of Breathing
The breathing strategies used by the lambs in the present study, i.e., a rapid, shallow respiration characterized by high RR, low VT, elevated P0.1, and low EtCO2 may offer a mechanical advantage of maintaining blood gas homeostasis with lower energy expenditure, however, at a cost of a decreased ventilatory stability. Augmented breaths that optimize surfactant properties of the lung and open poorly ventilated areas are absent during rapid shallow breathing. This may lead to a lower oxygenation, particularly during rapid eye movement, when a concomitant loss of muscle tone decreases chest wall stability and accentuates the less efficient gas exchange. In addition, if the inspiratory drive is increased already during the resting state, the ability to overcome challenges such as sudden increases in inspiratory resistance or increases in CO2 may be proportionally decreased (46). Hence, the overall risk of developing hypoxemic episodes in response to trivial respiratory challenges is likely to increase, because the ability to increase alveolar ventilation through tidal volume increases is diminished (47).

Nicotine Dose
Nicotine easily passes the placenta, and fetal concentrations of nicotine have been found to be equal to or higher than maternal concentrations (48, 49). The mean maternal nicotine concentrations in the present study were approximately half of those observed in pregnant habitual smokers smoking around 20 cigarettes per day, 7 ng/ml versus 10–14 ng/ml, whereas the mean cotinine concentrations were considerably lower, 18 ng/ml versus 127 ng/ml (50). A nicotine effect on eroplacental circulation and fetal growth was not expected in this study, because no such effects were observed in previous experiments performed on rodents receiving a continuous infusion of nicotine at a slightly higher dose (51).

Cardiovascular Effects
The nicotine-exposed lambs in this study had a trend toward higher HR than but similar BP to the control lambs at 5 days of age. In contrast, infants and children of smoking mothers have higher BP compared with children of nonsmoking mothers (11, 52). Furthermore, this blood pressure elevation correlates with the number of cigarettes smoked per day during the pregnancy (52). Individuals with low birth weight have elevated BP and HR (53, 54). It is, therefore, believed that impaired fetal circulation in infants of smoking mothers due to placental ischemia rather than primary effects of nicotine at a low dose may decrease the size and elasticity of the vascular bed, with increased blood pressure as a possible consequence. The lambs in this study were exposed to low nicotine concentrations and did not show signs of general growth retardation; hence, cardiovascular effects in terms of persistent blood pressure elevation would not be expected.

Conclusions
Prenatal exposure to a low dose of nicotine appears to have long-term effects on the breathing pattern, suggesting an alteration of lung function, although other mechanisms such as altered vagal modulation of respiratory timing are also plausible. The changes are most marked close to birth but persist during the initial postnatal period. Our data indicate that nicotine may act as a developmental pulmonary teratogen and that nicotine substitution may not be a safe alternative to smoking during pregnancy.


   Acknowledgments
 
The authors thank Dr. M. Hariharan, The University of Michigan, for performing nicotine and cotinine determinations, Patricia A. Minton, R.N., Rao Gaddipati, M.S., and Stanley D. Poole, M.S., for their skilled technical assistance, and Donna Staed for typing the manuscript.

Drs. Milerad and Hafström were in part supported by Swedish Medical Research Council grant no. k98-27x-11265-04a.


   FOOTNOTES
 
These results were presented in part at the annual meeting of the American Pediatric Society and Society for Pediatric Research 1996. This research was supported by grants from the National Institute of Health (HD 28916 and HL 14214).

Received in original form July 17, 2001; accepted in final form January 8, 2002


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. English PB, Eskenazi B. Reinterpreting the effects of maternal smoking on infant birthweight and perinatal mortality: a multivariate approach to birth weight standardization. Int J Epidemiol 1992;21:1097–1105.[Abstract/Free Full Text]
  2. Cnattingius S, Haglund B, Meirik O. Cigarette smoking as risk factor for late fetal and early neonatal death. BMJ 1988;297:258–261.[Medline]
  3. Taylor B, Wadsworth J. Maternal smoking during pregnancy and lower respiratory tract illness in early life. Arch Dis Child 1987;62:786–791.[Abstract]
  4. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med 1995;332:133–138.[Abstract/Free Full Text]
  5. Lux AL, Henderson AJ, Pocock SJ. Wheeze associated with prenatal tobacco smoke exposure: a prospective, longitudinal study. ALSPAC Study Team. Arch Dis Child 2000;83:307–412.[Abstract/Free Full Text]
  6. Barker DJ, Godfrey KM, Fall C, Osmond C, Winter PD, Shaheen SO. Relation of birth weight and childhood respiratory infection to adult lung function and death from chronic obstructive airways disease. BMJ 1991;303:671–675.[Medline]
  7. Barker DJ, Osmond C, Simmonds SJ, Wield GA. The relation of small head circumference and thinness at birth to death from cardiovascular disease in adult life. BMJ 1993;306:422–426.[Medline]
  8. Lodrup Carlsen KC, Jaakkola JJ, Nafstad P, Carlsen KH. In utero exposure to cigarette smoking influences lung function at birth. Eur Respir J 1997;10:1774–1779.[Abstract]
  9. Tager IB, Ngo L, Hanrahan JP. Maternal smoking during pregnancy. Effects on lung function during the first 18 months of life. Am J Respir Crit Care Med 1995;152:977–983.[Abstract]
  10. Cunningham J, Dockery DW, Speizer FE. Maternal smoking during pregnancy as a predictor of lung function in children. Am J Epidemiol 1994;139:1139–1152.[Abstract/Free Full Text]
  11. Morley R, Leeson Payne C, Lister G, Lucas A. Maternal smoking and blood pressure in 7.5 to 8 year old offspring. Arch Dis Child 1995; 72:120–124.[Abstract]
  12. Mitchell EA, Milerad J. Smoking and sudden infant death syndrome. WHO/TFI Reports. http://tobacco.who.int/en/health/background-papers-ets.html 1999.
  13. Blair PS, Fleming PJ, Bensley D, Smith I, Bacon C, Taylor E, Berry J, Golding J, Tripp J. Smoking and the sudden infant death syndrome: results from 1993 5 case-control study for confidential inquiry into stillbirths and deaths in infancy. BMJ 1996;313:195–198.[Abstract/Free Full Text]
  14. Hariharan M, VanNoord T, Greden JF. A high-performance liquid-chromatographic method for routine simultaneous determination of nicotine and cotinine in plasma. Clin Chem 1988;34:724–729.[Abstract/Free Full Text]
  15. Milerad J, Larsson H, Lin J, Sundell HW. Nicotine attenuates the ventilatory response to hypoxia in the developing lamb. Pediatr Res 1995;37:652–660.[Medline]
  16. Milerad J, Larsson H, Lin J, Lindstrom DP, Sundell HW. Breath-by-breath determinations of airway occlusion pressure in the developing lamb. Eur J Appl Physiol 1996;74:44–51.[CrossRef]
  17. Hafström O, Milerad J, Asokan N, Poole SD, Sundell HW. Nicotine delays arousal during hypoxemia in lambs. Pediatr Res 2000;47:646–652.[Medline]
  18. Lynne-Davies P, Couture J, Pengelly LD, Milic-Emili J. Immediate ventilatory response to added inspiratory elastic loads in cats. J Appl Physiol 1971;30:512–516.[Free Full Text]
  19. Wyszogrodski I, Thach BT, Milic-Emili J. Maturation of respiratory control in unanesthetized newborn rabbits. J Appl Physiol 1978;44:304–310.[Abstract/Free Full Text]
  20. Sovik S, Lossius K, Eriksen M, Grogaard J, Walloe L. Development of oxygen sensitivity in infants of smoking and non-smoking mothers. Early Hum Dev 1999;56:217–232.[CrossRef][Medline]
  21. Hanrahan JP, Tager IB, Segal MR, Tosteson TD, Castile RG, Van Vunakis H, Weiss ST, Speizer FE. The effect of maternal smoking during pregnancy on early infant lung function. Am Rev Respir Dis 1992;145:1129–1135.[Medline]
  22. Poole KA, Hallinan H, Beardsmore CS, Thompson JR. Effect of maternal smoking on ventilatory responses to changes in inspired oxygen levels in infants. Am J Respir Crit Care Med 2000;162:801–807.[Abstract/Free Full Text]
  23. West JB. Ventilation (Chapter 2). In: Respiratory physiology - the essentials, 5th ed. Baltimore, MD: Williams & Wilkins; 1995. p. 11–20.
  24. St.-John WM, Leiter JC. Maternal nicotine depresses eupneic ventilation of neonatal rats. Neurosci Lett 1999;267:206–208.[CrossRef][Medline]
  25. Bamford OS, Schuen JN, Carroll JL. Effect of nicotine exposure on postnatal ventilatory responses to hypoxia and hypercapnia. Respir Physiol 1996;106:1–11.[CrossRef][Medline]
  26. Schuen JN, Bamford OS, Carroll JL. The cardiorespiratory response to anoxia: normal development and the effect of nicotine. Respir Physiol 1997;109:231–239.[CrossRef][Medline]
  27. Fewell JE, Smith FG. Perinatal nicotine exposure impairs ability of newborn rats to autoresuscitate from apnea during hypoxia. J Appl Physiol 1998;85:2066–2074.[Abstract/Free Full Text]
  28. Sekhon HS, Keller JA, Benowitz NL, Spindel ER. Prenatal nicotine exposure alters pulmonary function in newborn rhesus monkeys. Am J Respir Crit Care Med 2001;164:989–994.[Abstract/Free Full Text]
  29. Whitelaw WA, Derenne JP. Airway occlusion pressure. J Appl Physiol 1993;74:1475–1483.[Abstract/Free Full Text]
  30. Scott GC, Burki NK. The relationship of resting ventilation to mouth occlusion pressure. An index of resting respiratory function. Chest 1990; 98:900–906.[Abstract/Free Full Text]
  31. Robinson RW, White DP, Zwillich CW. Relationship of respiratory drives to dyspnea and exercise performance in chronic obstructive pulmonary disease. Am Rev Respir Dis 1987;136:1084–1090.[Medline]
  32. Scano G, Duranti R, Spinelli A, Gorini M, Lo Conte C, Gigliottie F. Control of breathing in normal subjects and in patients with chronic airflow obstruction. Bull Eur Physiopathol Respir 1987;23:209–216.[Medline]
  33. Wuenschell CW, Zhao J, Tefft JD, Warburton D. Nicotine stimulates branching and expression of SP-A and SP-C mRNAs in embryonic mouse lung culture. Am J Physiol Lung Cell Mol Physiol 1998;274:L165–L170.[Abstract/Free Full Text]
  34. Maritz GS, Woolward KM, du Toit G. Maternal nicotine exposure during pregnancy and development of emphysema-like damage in the offspring. S Afr Med J 1993;83:195–198.[Medline]
  35. Maus AD, Pereira EF, Karachunski PI, Horton RM, Navaneetham D, Macklin K, Cortes WS, Albuquerque EX. Human and rodent bronchial epithelial cells express functional nicotinic acetylcholine receptors. Mol Pharmacol 1998;54:779–788.[Abstract/Free Full Text]
  36. Macklin KD, Maus AD, Pereira EF, Albuquerque EX, Conti-Fine BM. Human vascular endothelial cells express functional nicotinic acetylcholine receptors. J Pharmacol Exp Ther 1998;287:435–439.[Abstract/Free Full Text]
  37. Klapproth H, Reinheimer T, Metzen J, Munch M, Bittinger F, Kirkpatrick CJ, Kirkpatrick CJ, Höhle KD, Schemann M, Racké K, Wessler I. Non-neuronal acetylcholine, a signalling molecule synthezised by surface cells of rat and man. Naunyn-Schmiedeberg'sArch Pharmacol 1997;355:515–523.
  38. Sekhon HS, Jia Y, Raab R, Kuryatov A, Pankow JF, Whitsett JA, Lindsrom J, Spindel ER. Prenatal nicotine increases pulmonary alpha7 nicotinic receptor expression and alters fetal lung development in monkeys. J Clin Invest 1999;103:637–647.[Medline]
  39. Slotkin TA. Prenatal exposure to nicotine: what can we learn from animal models? In: Zagon IS, Slotkin TA, editors. Maternal substance abuse and the developing nervous system. San Diego: Academic Press, Inc.; 1992. p. 97–124.
  40. Clark FJ, von Euler C. On the regulation of depth and rate of breathing. J Physiol 1972;222:267–295.[Abstract/Free Full Text]
  41. Trenchard D. Role of pulmonary stretch receptors during breathing in rabbits, cats and dogs. Respir Physiol 1977;29:231–246.[CrossRef][Medline]
  42. Taylor RF, Lee L-Y, Jewell LA, Frazier DT. Effect of nicotine aerosol on slowly adapting receptors in the airways of the dog. J Neurosci Res 1986;15:583–593.[CrossRef][Medline]
  43. Lee L-Y, Morton RF, Kou YR. Acute effects of cigarette smoke on breathing in rats: vagal and nonvagal mechanisms. J Appl Physiol 1990;68:955–961.[Abstract/Free Full Text]
  44. Kou YR, Morton RF, Lee LY. Stimulatory effect of circulated nicotine on rapidly adapting receptors in canine lungs. Chin J Physiol 1992; 35:169–180.[Medline]
  45. Nachmanoff DB, Panirahy A, Filiano JJ, Mandell F, Sleeper LA, Waldes-Dapena M, Krous HF, White WF, Kinney HC. Brainstem 3H-nicotine receptor binding in the sudden infant death syndrome. J Neuropathol Exp Neurol 1998;57:1018–1025.[Medline]
  46. Parks YA, Paton JY, Beardsmore CS, MacFadyen UM, Thompson J, Goodenough PC, Simpson H. Respiratory control in infants at increased risk for sudden infant death syndrome. Arch Dis Child 1989; 64:791–797.[Abstract]
  47. Matthews T, Dunne K. End-tidal carbon dioxide levels and the sudden infant death syndrome. Ir Med J 1986;79:212–214.[Medline]
  48. Suzuki K, Horiguchi T, Comas-Urrutia AC, Mueller-Heubach E, Morishima HO, Adamsons K. Placental transfer and distribution of nicotine in the pregnant rhesus monkey. Am J Obstet Gynecol 1974;119: 253–262.[Medline]
  49. Luck W, Nau H, Hansen R, Steldinger R. Extent of nicotine and cotinine transfer to the human fetus, placenta and amniotic fluid of smoking mothers. Dev Pharmacol Ther 1985;8:384–395.[Medline]
  50. Oncken CA, Hardardottir H, Hatsukami DK, Lupo VR, Rodis JF, Smeltzer JS. Effects of transdermal nicotine or smoking on nicotine concentrations and maternal-fetal hemodynamics. Obstet Gynecol 1997; 90:569–574.[Abstract]
  51. Navarro HA, Seidler FJ, Schwartz RD, Baker FE, Dobbins SS, Slotkin TA. Prenatal exposure to nicotine impairs nervous system development at a dose which does not affect viability or growth. Brain Res Bull 1989;23:187–192.[CrossRef][Medline]
  52. Beratis NG, Panagoulias D, Varvarigou A. Increased blood pressure in neonates and infants whose mothers smoked during pregnancy. J Pediatr 1996;128:806–812.[CrossRef][Medline]
  53. Phillips DI, Barker DJ. Association between low birthweight and high resting pulse in adult life. Is the sympathetic nervous system involved in programming the insulin resistance syndrome? Diabet Med 1997; 14:673–677.[CrossRef][Medline]
  54. Cheung YB, Low L, Osmond C, Barker D, Karlberg J. Fetal growth and early postnatal growth are related to blood pressure in adults. Hypertension 2000;36:795–800.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Am. J. Respir. Crit. Care Med.Home page
J. D. Pendlebury, R. J. A. Wilson, S. Bano, K. J. Lumb, J. M. Schneider, and S. U. Hasan
Respiratory Control in Neonatal Rats Exposed to Prenatal Cigarette Smoke
Am. J. Respir. Crit. Care Med., June 1, 2008; 177(11): 1255 - 1261.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurophysiol.Home page
Z. G. Huang, K. J. S. Griffioen, X. Wang, O. Dergacheva, H. Kamendi, C. Gorini, and D. Mendelowitz
Nicotinic Receptor Activation Occludes Purinergic Control of Central Cardiorespiratory Network Responses to Hypoxia/Hypercapnia
J Neurophysiol, October 1, 2007; 98(4): 2429 - 2438.
[Abstract] [Full Text] [PDF]

Home page
 CMAJHome page
C. E. Hunt and F. R. Hauck
Sudden infant death syndrome.
Can. Med. Assoc. J., June 20, 2006; 174(13): 1861 - 1869.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
N. Simakajornboon, V. Vlasic, H. Li, and H. Sawnani
Effect of prenatal nicotine exposure on biphasic hypoxic ventilatory response and protein kinase C expression in caudal brain stem of developing rats
J Appl Physiol, June 1, 2004; 96(6): 2213 - 2219.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
E. R. Spindel
Neuronal nicotinic acetylcholine receptors: not just in brain
Am J Physiol Lung Cell Mol Physiol, December 1, 2003; 285(6): L1201 - L1202.
[Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
M. J. Tobin
Sleep-Disordered Breathing, Control of Breathing, Respiratory Muscles, and Pulmonary Function Testing in AJRCCM 2002
Am. J. Respir. Crit. Care Med., February 1, 2003; 167(3): 306 - 318.
[Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
M. J. Tobin
Pediatrics, Surfactant, and Cystic Fibrosis in AJRCCM 2002
Am. J. Respir. Crit. Care Med., February 1, 2003; 167(3): 333 - 344.
[Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
G. S. Mitchell and S. M. Johnson
Plasticity in Respiratory Motor Control: Invited Review: Neuroplasticity in respiratory motor control
J Appl Physiol, January 1, 2003; 94(1): 358 - 374.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
J. L. Carroll
Plasticity in Respiratory Motor Control: Invited Review: Developmental plasticity in respiratory control
J Appl Physiol, January 1, 2003; 94(1): 375 - 389.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
O. Hafstrom, J. Milerad, and H. W. Sundell
Prenatal Nicotine Exposure Blunts the Cardiorespiratory Response to Hypoxia in Lambs
Am. J. Respir. Crit. Care Med., December 15, 2002; 166(12): 1544 - 1549.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hafström, O.
Right arrow Articles by Sundell, H. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hafström, O.
Right arrow Articles by Sundell, H. W.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2002 American Thoracic Society