Nicotine patch use in pregnant smokers: Nicotine and cotinine levels and fetal effects

doi:10.1016/S0002-9378(99)70521-1

American Journal of Obstetrics and Gynecology

Volume 181, Issue 3, September 1999, Pages 736-743

https://doi.org/10.1016/S0002-9378(99)70521-1 Get rights and content

Abstract

Objective: The aims of this study were (1) to determine whether nicotine patch therapy for pregnant women smokers acutely compromises fetal well-being and (2) to determine the serum and urine nicotine and cotinine levels in pregnant women while smoking, while abstinent from smoking, and while receiving nicotine patch therapy compared with levels in a historical control group of nonpregnant women smokers who abstained from smoking while receiving comparable doses of nicotine patch therapy. Study Design: Pregnant cigarette smokers (n = 21) aged ≥18 years whose fetuses were beyond 24 weeks’ gestational age were recruited for this 1-sample, repeated-measures study. Serial measurements of the mother and fetus were made at baseline while the mother was smoking, while abstaining from smoking, and while using nicotine patch therapy for 4 days in a special care hospital unit. Nonpregnant women smokers of similar age were used for comparison. Morning and afternoon serum and 24-hour urine levels of nicotine and cotinine were obtained during hospitalization. Indicators of fetal well-being assessed were fetal heart rate and reactivity, systolic/diastolic ratio of blood flow in the umbilical artery, and fetal activity seen on ultrasonography and quantitated as biophysical profiles. Results: No evidence of fetal compromise was seen during the inpatient phase while nicotine patch therapy was administered. Steady state (inpatient day 4) serum levels of nicotine were similar to smoking levels and to those seen in historical control subjects (ie, nonpregnant women of child-bearing age who were abstinent from smoking and who used the same nicotine patch). Morning serum cotinine levels were significantly higher (P = .038) in the nonpregnant subjects than in the pregnant subjects, whereas afternoon levels were not significantly different. Steady state urinary levels of nicotine and cotinine were also not significantly different in pregnant versus nonpregnant patients. On inpatient days 2, 3, and 4, when the women were not smoking and were wearing the nicotine patch, the morning fetal heart rates were significantly reduced relative to baseline when the subjects were smoking. Conclusions: Nicotine patch therapy was not found to be associated with indications of fetal compromise during the in-hospital phase of nicotine patch therapy in pregnant smokers who were abstaining. Although not conclusive because of the small sample sizes, serum nicotine levels (morning and afternoon) appear similar in pregnant and nonpregnant subjects and similar for both groups when smoking (baseline) as compared to the steady state of nicotine patch use. (Am J Obstet Gynecol 1999;181:736-43.)

Section snippets

Subjects

After study approval by the Mayo Institutional Review Board, pregnant cigarette smokers who were in their third trimester of pregnancy were recruited from the Department of Obstetrics at the Mayo Clinic. All potential participants underwent obstetric ultrasonography to confirm the gestational age and to screen for detectable fetal anomalies. Those who met the following inclusion criteria were invited to participate in this study: age ≥18 years; general good health as determined by the study

Results

There were a total of 23 subjects enrolled in the study, but 2 subjects discontinued study participation before the inpatient phase. These 2 subjects have been excluded from all analyses. Demographic and baseline characteristics of the 21 pregnant subjects included in the study are given in Table I.

. Baseline subject characteristics (n = 21)

Characteristic	No.	Mean ± SD	Range
Age (y)	—	26.5 ± 5.7	19-41
Gestational age (wk)	—	27.4 ± 2.7	24-33
Married	11	—	—
No. of prior live births	—	1.0 ± 1.0	0-3
Current cigarettes/d

Comment

In this report on nicotine patch therapy in pregnant smokers, we found no evidence of serious detrimental short-term effects to the fetus as measured by nonstress tests, biophysical profiles, and umbilical artery Doppler studies. We observed, compared with baseline levels during maternal smoking, that mean fetal heart rate decreased on the mornings of days 2, 3, and 4 of the nicotine patch therapy. Although statistically significant, the differences in fetal heart rates were small and may not

Acknowledgements

We thank the following people for their hard work and assistance in completing this project: Jaci Stensland, RN, Judy Trautman, RN, Karen Hurtis, Richard Morris, and Rhonda Baumberger.

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Nicotine replacement therapy is available in multiple formats to pregnant women, including patches, inhalators, chewing gum and lozenges [10]. Patches provide long-acting nicotine exposure, whereas chewing gum and lozenges act more quickly with a shorter duration of action [16]. There is no evidence that a specific type of NRT is superior in pregnancy [10].
Nicotine replacement therapy (NRT) and e-cigarettes are recommended to pregnant women who wish to stop smoking. Albeit eliminating other harmful components of cigarettes, those alternatives still expose the developing fetus to nicotine. The lungs may be particularly vulnerable to damage by nicotine as there is widespread nicotinic-acetylcholine receptor expression in the lungs. There is, however, a paucity of information about the effect of NRT and e-cigarette use in pregnancy on infant respiratory outcomes.
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A literature search was undertaken to examine the use and safety of nicotine-replacement strategies in pregnancy, with a focus on infant respiratory outcomes. This included experimental studies investigating the effect of isolated “gestational” nicotine on the developing lung.
Respiratory outcomes in animal studies and infants.
Animal studies investigating the effect of gestational nicotine exposure on fetal lung development demonstrated abnormal lung growth; including abnormal airway branching and alveolar development. Consequently, offspring display altered pulmonary mechanics, including both increased respiratory rate and airway resistance. These findings mirror respiratory pathology observed in infants born to smoking mothers. Human trials of NRT and e-cigarette use in pregnancy have not identified adverse perinatal outcomes regarding reduced birthweight or prematurity, but have not considered infant and childhood respiratory outcomes.
Nicotine can impair fetal lung development, leading to concerns regarding the safety of NRT and e-cigarettes in pregnancy. Studies have yet to explore the impact of these nicotine-containing products on infant respiratory outcomes.
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When compared with the other forms of NRT, transdermal patches produce lower, longer-lasting, steadier concentrations of nicotine rather than high concentrations for shorter periods. Limited pharmacokinetic studies have reported that NRT results in plasma cotinine and nicotine levels that are no higher than that observed with smoking more than 10 cigarettes per day, which is considered moderate to heavy smoking.37,38 In contrast, nicotine gum and nasal spray can provide nicotine exposure similar to that of smoking when used regularly throughout the day.39
Prenatal nicotine exposure in rhesus monkeys compromises development of brainstem and cardiac monoamine pathways involved in perinatal adaptation and sudden infant death syndrome: Amelioration by Vitamin C
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Pumps were implanted under ketamine anesthesia and were changed every three weeks to maintain a steady-state infusion throughout pregnancy; minipump changes were carried out under the direction of a veterinary surgeon following strict sterile protocols. This regimen produces maternal plasma levels of about 30 ng/ml for nicotine and 120 for cotinine (Slotkin et al., 2005), both well within the range of values typical of maternal smoking in pregnant smokers consuming 10–20 cigarettes per day (Ogburn et al., 1999; Slotkin et al., 2005), importantly, total nicotine delivery and average daily nicotine plasma levels are similar in pregnant smokers and in users of transdermal nicotine patches (Oncken et al., 1997). Concurrently with the nicotine or vehicle infusion, animals received daily oral supplementation with Vitamin C in the form of a chewable vitamin pill; there were four different Vitamin C dose levels (0, 50, 100, and 250 mg per day).
Maternal smoking during pregnancy greatly enhances perinatal morbidity/mortality and is the major risk factor for Sudden Infant Death Syndrome (SIDS). Studies in developing rodents indicate that nicotine is a neuroteratogen that targets monoamine pathways involved in the responses to hypoxia that are in turn, hypothesized to contribute to these adverse events. We administered nicotine to pregnant Rhesus monkeys from gestational day 30 through 160 by continuous infusion, achieving maternal plasma levels comparable to those in smokers; we examined neurochemical parameters immediately after Cesarean delivery at the end of the exposure period. Nicotine evoked elevations in brainstem serotonin levels and serotonin turnover, indicating hyperactivity of these pathways. The same treatment evoked a deficit in cardiac norepinephrine levels. Both effects were offset by coadministration of the antioxidant, Vitamin C. Brainstem serotonin hyperinnervation is a hallmark of SIDS, and the hyperactivity seen here can also account for the downregulation of serotonin receptors noted in this disorder. Deficient cardiac sympathetic innervation is also consistent with increased vulnerability to hypoxia during delivery or in the agonal event in SIDS. Our results thus indicate that nicotine exposure in a primate model produces brainstem and autonomic abnormalities of the key monoamine systems that govern the response to hypoxia, indicate an important role of oxidative stress in the adverse effects, and point to potential amelioration strategies that could offset these particular effects of nicotine.
Nicotine restores endothelial dysfunction caused by excess sFlt1 and sEng in an in vitro model of preeclamptic vascular endothelium: a possible therapeutic role of nicotinic acetylcholine receptor (nAChR) agonists for preeclampsia
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In this study we tested the hypothesis that nicotine restores proangiogenic functions to endothelial cells pretreated with soluble fms-like tyrosine kinase 1 and/or soluble endoglin.
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Nicotine significantly facilitated endothelial migration and tube formation. By contrast, soluble fms-like tyrosine kinase 1 and/or soluble endoglin suppressed these endothelial functions. Nicotine restored these soluble fms-like tyrosine kinase 1 and/or soluble endoglin-reduced endothelial functions. Placental growth factor, but not transforming growth factor-β1, production was significantly stimulated by the presence of nicotine. Vascular endothelial growth factor was undetectable.
Our results suggest a possible mechanism for the protective effects of cigarette smoking against preeclampsia, thus proposing a therapeutic potential of nicotine or other nicotinic acetylcholine receptor agonists for preeclampsia.
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The purpose of this study was to determine the contribution of randomization to nicotine replacement therapy (NRT), sociodemographic and psychosocial factors, and pregnancy and medical history to serious perinatal adverse events among pregnant smokers.
We performed a retrospective review of all medical records for participants in the Baby Steps Trial. Data that were abstracted from 157 records were combined with baseline characteristics for logistic regression modeling of serious adverse events and adjusted for covariates.
Serious adverse events occurred in 17% (9/52 pregnancies) and 31% (33/105 pregnancies) of participants in the control and NRT arms, respectively. Black race, adverse pregnancy history, and use of analgesic medication during pregnancy were significant predictors (P = .02, .04, and .01, respectively). Remaining covariates, which included randomization to NRT, were not statistically significant.
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^☆: From the Department of Obstetrics,^a the Nicotine Research Center,^b the Section of Biostatistics,^c and the Department of Laboratory Medicine and Pathology,^d Mayo Clinic and Mayo Foundation.

^☆☆: Supported by a grant from Elán Pharmaceutical Corporation, Athlone, Ireland.

^★: Reprint requests: Paul L. Ogburn, Jr, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905.

^★★: 0002-9378/99 $8.00 + 06/1/100253

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Nicotine patch use in pregnant smokers: Nicotine and cotinine levels and fetal effects☆,☆☆,★,★★

Abstract

Section snippets

Subjects

Results

Comment

Acknowledgements

Am J Obstet Gynecol

Brain Res Bull

Am J Obstet Gynecol

Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

The effects of maternal smoking on fetal and infant mortality

Am J Epidemiol

Smoking and reproduction

Fertil Steril

The health benefits of smoking cessation: a report of the Surgeon General, 1990

Smoking before, during, and after pregnancy

Am J Public Health

Medical-care expenditures attributable to cigarette smoking during pregnancy—United States, 1995

MMWR Morb Mortal Wkly Rep

Nicotine patch therapy for smoking cessation combined with physician advice and nurse follow-up—one-year outcome and percentage nicotine replacement

JAMA

Nicotine replacement therapy during pregnancy

JAMA

Behavioral effects of prenatal exposure to nicotine in guinea pigs

Neurobehav Toxicol Teratol