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PEDIATRICS Vol. 113 No. 3 March 2004, pp. 623-624

Effects of Maternal Smoking During Pregnancy on Newborn Neurobehavior: Neonatal Nicotine Withdrawal Syndrome

Óscar García-Algar, MD^a
Carme Puig, MD^a
Oriol Vall, MD^a
Roberta Pacifici, PhD^b
Simona Pichini, PhD^b
a Pediatrics Unit
Hospital del Mar
Pg Marítim 25-29
08003 Barcelona, Spain
^b Istituto Superiore di Sanità
V.Le Regina Elena 299
00161 Rome, Italy

To the Editor.—

We read with great interest the paper of Law et al¹ wherein the effects of maternal smoking on newborn neurobehavior was investigated. The authors compared 29 and 27 newborns unexposed and exposed to maternal smoking, respectively. A mean of 6.7 cigarettes per day was declared by smoking mothers during pregnancy. Mean maternal salivary cotinine, obtained only in 16 cases (3 of which showed a zero value), was 32.9 ng/mL. Newborn neurobehavioral function was measured by the NICU Network Neurobehavioral Scale within 48 hours after birth.¹ The authors disclosed neurotoxic effects of prenatal tobacco exposure, suggesting a likely neonatal withdrawal syndrome. In the studies by our team,^2,3 we already postulated the existence of a neonatal nicotine withdrawal among newborns exposed to cigarette smoke. The Finnegan clinical score⁴ was used in 50 newborns from smoking mothers to evaluate the withdrawal syndrome together with the measure of newborn urinary cotinine as a biomarker of acute exposure to tobacco smoke⁵ and neonatal hair nicotine detection to verify a chronic exposure to cigarette constituents during the entire fetal life.

No definitive positive result for defining a withdrawal syndrome by means of the Finnegan test (2 consecutive scores >8) was registered. However, scores between 0 and 8, especially by irritability and tremor over the first 24 hours of life, were recorded in 17 newborns. All these newborns, from mothers who smoke >20 cigarettes per day, presented quite high concentrations of both urinary cotinine and hair nicotine (median concentration: 450.2 ng of cotinine/mL and 4.6 ng of nicotine/mg, respectively). Furthermore, increasing Finnegan values were related to increasing concentration of urinary cotinine and hair nicotine, and these newborns showed birth weight statistically lower than that of newborns from both nonsmoking and smoking mothers from the same hospital recruited for a different study.⁶

Our data agree with the findings of Law et al,¹ although there are some points we would like to make about this article.

In the study of Law et al,¹ smoking during pregnancy was assessed by questionnaire and maternal salivary cotinine, which only accounted for smoking in the last 2 or 3 days before delivery and not in early pregnancy (a relevant period with regard to a correct neonatal neurodevelopment) nor informed on levels of smoke constituents in the newborn.

Smoking mothers who denied cigarette use during pregnancy and/or showed a salivary cotinine value of zero should have been eliminated by the smoking group or the saliva bioassay reported as useless. Indeed, a "dilution" effect in the group of newborns exposed to maternal smoking could have occurred, making observations on neurobehavior significant but not conclusive of any withdrawal syndrome. Indeed, different from all the other reports on this matter, newborns from smoking mothers did not show birth weight lower than those from nonsmoking mothers.

We advocate assessing fetal exposition to self-reported maternal smoking by the measurement biomarkers of both acute and chronic exposure to tobacco smoke on neonatal biological matrices minus other drugs of abuse including caffeine. With this information available, we recommend that the authors characterize a group of highly exposed newborns in which the NICU Network Neurobehavioral Scale could be administered more than once within the 48 hours after birth. Withdrawal symptoms and signs begin at 12 hours of life and last no more than 48 hours, with irritability and tremor being the prominent findings. We believe that results should be even more conclusive than those obtained, and the authors could succeed in demonstrating what we could only hypothesize: the existence of neonatal nicotine withdrawal syndrome.

REFERENCES

1. Law KL, Stroud LR, LaGasse LL, Niaura R, Liu J, Lester BM. Smoking during pregnancy and newborn neurobehavior. Pediatrics.2003; 111 :1318 –1323[Abstract/Free Full Text]
2. García-Algar Ó, Puig C, Méndez C, Vall O, Pacifici R, Pichini S. Neonatal nicotine withdrawal sindrome. J Epidemiol Community Health.2001; 55 :687 –688[Free Full Text]
3. García-Algar Ó, Puig C, Méndez C, Vall O, Zuccaro P, Pacifici R, Pichini S. Neonatal nicotine withdrawal syndrome: in utero environmental tobacco smoke. Proceedings of Indoor Air 2002: 9th International Conference on Indoor Air Quality and Climate; June 30–July 5, 2002; Monterey, CA
4. Finnegan LP. Neonatal abstinence syndrome. In: Nelson M, ed. Current Therapy in Neonatal-Perinatal Medicine–2. Toronto, ON, Canada: BC Decker; 1990:315–320
5. Pichini S, Basagaña X, Pacifici R, et al. Cord serum cotinine as a biomarker of fetal exposure to cigarette smoke at the end of pregnancy. Environ Health Perspect.2000; 108 :1079 –1083[Web of Science][Medline]

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Barry M. Lester, PhD
Karen L. Law, BA
Laura R. Stroud, PhD
Linda L. LaGasse, PhD
Jing Liu, PhD
Raymond Niaura, PhD
Brown Medical School
Providence, RI 02905-2499

In Reply.—

We appreciate the comments of García-Algar et al regarding our article relating cigarette smoking during pregnancy to newborn neurobehavior.¹ It is clear that this is an important topic and one that deserves more attention. In a previous letter to the editor, García-Algar et al² reported relations between neonatal abstinence (Finnegan) scores and biomarkers of nicotine in a subset of infants whose mothers smoked >20 cigarettes per day, suggesting the possibility of a neonatal nicotine withdrawal syndrome. Although we agree that there may be such a syndrome, we were careful to point out in our article that neither our findings nor other findings in the literature confirm nicotine withdrawal in infants. This is because what could appear to be withdrawal effects may also be due to acute toxicity or even to more-permanent damage to the central nervous system. We performed only 1 examination of the infant at 48 hours. With the half-life of cotinine in body fluids at 15 to 19 hours, nicotine withdrawal would not be expected to peak until 2 to 3 days. Therefore, we did not follow the infants long enough to determine withdrawal. In addition, withdrawal requires the study of patterns, not single scores. Infants in withdrawal might present at delivery as normal, become worse over time, and then recover. This also presumes that there are also not acute toxic or central nervous system effects that have the same symptoms as withdrawal. We feel confident that we did find neurotoxic effects, but we cannot confirm nicotine withdrawal syndrome. It is also noteworthy that we found effects with mothers smoking "only" an average of 6.7 cigarettes per day, perhaps because of the sensitivity of our neurobehavioral examination.

We agree that maternal salivary cotinine only accounts for smoking in the last 2 or 3 days. However, this measure was correlated (r = .624; P < .01) with self-report of maternal smoking, and it is likely that mothers who were smoking just before delivery were smoking throughout pregnancy.

We did analyze the data after dropping the subjects with "0" cotinine and/or "liars" about smoking. We found the same differences on NICU Network Neurobehavioral Scale (NNNS) scores (with and without covariates) with these subjects eliminated. On the other hand, mothers who quit early in pregnancy would be expected to have 0 cotinine, so it is not reasonable to eliminate them from the smoking group. This is why both self-report and bioassays are important. It is unlikely that a mother would lie to say that she did smoke during pregnancy if she did not. Mothers who denied use and had positive cotinine values are exactly the mothers we were trying to identify with the bioassay. Again, this testifies to the importance of using both self-report and bioassay measures.

Finally, as a result of our selection criteria (term, appropriate-weight-for-gestational-age infants), there were no statistically significant differences in birth weight. However, infants in the smoking group were still 110 g lighter than infants in the nonsmoking group. Although the groups did not differ (probably because of sample size), birth weight was still correlated with NNNS scores and included as a covariate. The effects of smoking on the NNNS that we observed were still significant, even with birth weight covaried, indicating that these indeed are robust effects.

We thank García-Algar et al for bringing these issues to our attention. We look forward to the design of successful "experiments" that can untangle the complex effects of maternal smoking during pregnancy and determine whether there is a nicotine withdrawal syndrome.

REFERENCES

1. Law KL, Stroud LR, LaGasse LL, Niaura R, Liu J, Lester BM. Smoking during pregnancy and newborn neurobehavior. Pediatrics.2003; 111 :1318 –1323
2. García-Algar Ó, Puig C, Méndez C, Vall O, Pacifici R, Pichini S. Neonatal nicotine withdrawal syndrome. J Epidemiol Community Health.2001; 55 :687 –688

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PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics

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This Article Extract Full Text (PDF) Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services E-mail this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Request Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by García-Algar, O. Articles by Niaura, R. Search for Related Content PubMed PubMed Citation Articles by García-Algar, O. Articles by Niaura, R. Social Bookmarking                         What's this?