Journal of Perinatology (2017) 00, 1–5

© 2017 Nature America, Inc., part of Springer Nature. All rights reserved 0743-8346/17
www.nature.com/jp

ORIGINAL ARTICLE
Effect of maternal smoking on stress physiology in healthy
neonates
C Haslinger1, H Bamert1, M Rauh2, T Burkhardt1 and L Schäffer3

OBJECTIVE: To assess the impact of maternal smoking during pregnancy (MSDP) on the neonatal hypothalamic–pituitary–
adrenal axis.
STUDY DESIGN: In a prospective observational study, salivary cortisol and cortisone levels were measured at the fourth day of life
during resting conditions and in response to a pain-induced stress event in healthy neonates whose mothers smoked cigarettes
during each stage of pregnancy and compared with controls.
RESULTS: Neonates in the control group (n = 70) exhibited a physiologic stress response with a significant increase in cortisol (1.3 to
2.1 ng ml − 1; Po 0.05) and cortisone (11.8 to 17.8 ng ml − 1; P o 0.05) from baseline levels, whereas in neonates from mothers who
smoked (n = 33), cortisol (0.9 to 0.8 ng ml − 1; P = 0.77) and cortisone (11.5 to 13.0; P = 0.19) stress response was not significantly
different from baseline levels. A two-way analysis of variance confirmed these findings in both groups.
CONCLUSIONS: Healthy neonates whose mothers smoked during pregnancy show a blunted stress response on the fourth day of
life. Thus, MSDP leads to a dysregulation of the HPA axis with continued effects in neonatal life. This might explain long-term
consequences of MSDP such as overweight, diabetes mellitus and modification of blood pressure control mechanisms in adult life.
Journal of Perinatology advance online publication, 9 November 2017; doi:10.1038/jp.2017.172

INTRODUCTION
Cigarette smoking in pregnancy is the most important modifiable
risk factor for adverse pregnancy outcome.1 Approximately 11% of
women reported smoking cigarettes in the 3 months before
pregnancy as well as at the time of giving birth.2,3 Maternal
smoking during pregnancy (MSDP) is associated with stillbirth and
neonatal death,4 preterm premature rupture of membranes,5 low
birth weight,6 placental abruption,7 preterm delivery8 and sudden
infant death syndrome.9,10
Long-term consequences have also been shown, such as
childhood overweight,11 diabetes mellitus12 and ‘re-programming’
of infant blood pressure control mechanisms.13 Several studies
have reported an association between intrauterine adverse
environments and adaptions of the fetus with impact on adult
diseases (‘fetal programming’)14–16 with the hypothalamic–pitui-
tary–adrenal (HPA) axis playing a major role in this hypothesis.17,18
Nicotine has been shown to be a potent stimulator of the HPA axis
with effects on the secretion of adrenocorticotropic hormone and
cortisol19 and chronic modifications of the HPA axis in smokers.20
Information about the alteration of the neonatal HPA axis owing
to MSDP is still scarce. As the neonatal HPA axis has been
suggested to play a crucial role in long-term consequences, the
objective of this study was to further explore the effect of MSDP
on the neonatal HPA axis in healthy term neonates. We
hypothesized that MSDP leads to a persistent ‘re-programming’
of HPA axis activity in neonatal life.
MATERIALS AND METHODS
This is a prospective observational trial at the University Hospital of Zurich,
Switzerland. The study has ethical approval according to the ethics review
board of Zurich (SPUK GGU reference number 15/2003). Written maternal
consent was obtained from all participants.
Inclusion/exclusion criteria
Included were all healthy neonates from mothers who smoked a minimum
of five cigarettes per day during each stage of pregnancy and with a
normal neonatal weight between the 10th and 90th percentiles (nicotine
group). Exclusion criteria were preterm birth before 34 weeks of gestation,
collection of insufficient amounts of saliva, presence of malformation,
admission to neonatal intensive care unit or necessity for invasive
procedures, other maternal substance abuse (drugs, alcohol) during
pregnancy and maternal HIV or hepatitis C infection. Furthermore,
neonates with antenatal betamethasone treatment for lung maturation
were also excluded. The control group consisted of healthy neonates from
non-smoking mothers with otherwise identical inclusion and exclusion
criteria. In the nicotine group, 45 neonates were initially recruited. In
twelve neonates insufficient amounts of saliva were collected, resulting in
a study population of 33 neonates. The control group consisted of 70
neonates.
Trial principle
Stress reactivity was tested in neonates using a standardized procedure
with an automated heel lance (heel–prick test) as a pain-induced stress
event. This test is a routinely applied screening test in which blood is
sampled and analyzed for metabolic disorders (Guthrie Test). This
procedure induces activation of the HPA axis with a significant increase
of cortisol levels in the neonate21 and with salivary cortisol levels that
correlate well with serum cortisol levels.22 The test was performed 72 to
96 h postpartum to exclude birth-related fluctuation of cortisol levels.23
Although the neonate develops a circadian cortisol rhythm only after
several weeks of life,24 the tests were performed between 8 AM and 12 AM
in order to exclude potential circadian fluctuations. Furthermore, the
neonates were not fed for a minimum of one hour before the test to
eliminate a possible bias due to contamination with breast milk. Moreover,

1
Division of Obstetrics, University Hospital of Zürich, Zürich, Switzerland; 2Division of Pediatrics, University Hospital of Erlangen, Erlangen, Germany and 3Division of Obstetrics,
Kantonsspital Baden, Baden, Switzerland. Correspondence: Dr C Haslinger, Division of Obstetrics, University Hospital of Zürich, Frauenklinikstrasse 10, Zürich 8091, Switzerland,
E-mail: christian.haslinger@usz.ch
Received 6 March 2017; revised 18 August 2017; accepted 21 September 2017
 Maternal smoking alters neonatal stress response
C Haslinger et al
2
blood glucose levels were measured and had to be above 2.5 mmol l − 1 to
exclude hypoglycemia-induced increase of cortisol.
Salivary sampling
From each neonate, two saliva samples were collected. Baseline levels
were obtained in an undisturbed environment 10 min before the heel–
prick test. The second saliva sample was collected 20 min after the stress
event. Collection time was based on experiments revealing peak cortisol
responses between 20 and 30 min post manipulation.25 In detail, a cotton
swab was placed in the neonate’s mouth for a collection time of 5 min.
Samples were placed in saliva-collection tubes (Salivette, Sarstedt,
Nümbrecht, Germany), immediately frozen, and stored at − 20 °C until
further analysis. Saliva cortisol and cortisone were determined simulta-
neously by liquid chromatography tandem mass spectrometry, with
atmospheric pressure chemical ionization in the positive ion mode,
according to a modified method first introduced by Rauh et al.,26 using 100
microliters of the samples and calibrators. Our method was previously
described in detail.27
Statistical analysis
All statistical analyses were performed using the statistic program STATA
10 (Stata Corporation College Station, TX, USA). P o0.05 was considered
statistically significant. Baseline characteristics were compared using
Mann-Whitney and Chi-square tests when appropriate. A Mann–Whitney
test was used for comparison of baseline cortisol and cortisone levels.
Because cortisol and cortisone values were not distributed normally as
analyzed by the Shapiro–Francia W’ test, we analyzed the difference
between cortisol and cortisone baseline levels and time point ‘20 min post
heel–prick’ using the Wilcoxon signed rank test. To account for within-
subject variations, a two-way analysis of variance for repeated measure-
ments was conducted. A stepwise multiple regression was applied to test
for putative influencing factors on cortisol alterations such as gestational
age at delivery, neonatal weight, sex and delivery mode. A Spearman rank
correlation was performed to evaluate the influence of the amount of
maternal smoking (number of cigarettes). Finally, cortisol and cortisone
levels in the nicotine group were tested for correlation using the Spearman
rank correlation test to exclude an altered 11β-hydroxysteroid dehydro-
genase type 2-initiated transformation of cortisol to cortisone.
RESULTS
The women in the nicotine group smoked between five and 30
cigarettes daily during each stage of pregnancy. Maternal and
neonatal baseline characteristics are shown in Table 1 and did not
differ significantly between the nicotine and control group.
The median baseline levels for cortisol and cortisone were
comparable for neonates in the nicotine group and those in the
control group (0.9 ng ml − 1 (range 0.04 to 7.0) compared with
1.3 ng ml − 1 (range 0.09 to 15.7) for cortisol, P = 0.11; 11.5 ng ml − 1
(range 4.6 to 26.8) compared with 11.8 ng ml − 1 (range 4.6 to 44.3)
Table 1. Maternal and neonatal baseline characteristics
Control group (n = 70)
Gestational age (days) 276 (240–294)
Birth weight (g) 3315 (2100–4430)
Weight percentile 53.2 (12.7–91.6)
Male/female 29/41
Head circumference 34.5 (30.5–36.5)
5-min Apgar score 9 (8–10)
10-min Apgar score 9 (7–10)
Cesarean delivery (%) 32.9%
Maternal age (years) 30.5 (18–39)
Parity 2 (1–4)
Maternal pregestational BMI 22.4 (16–43.9)
Maternal BMI at delivery 28.8 (22.4–47.4)
Number of cigarettes per day 0 9 (5–30)
Abbreviation: BMI, body mass index. Data are median (range) unless otherwise specified. Baseline characteristics were compared using Mann–Whitney or χ2-
tests as appropriate.
Journal of Perinatology (2017), 1 – 5
for cortisone, P = 0.55). Individual baseline and stimulated cortisol
and cortisone levels are presented in Figure 1.
Salivary cortisol and cortisone levels 20 min after the pain-
induced stress event were significantly increased in the neonates
in the control group; this was expected as a physiological
response to stress (2.1 ng ml − 1 (range 0.03 to 24.8) for cortisol,
P = 0.04; and 17.8 ng ml − 1 (range 2.8 to 76.0) for cortisone,
Po 0.01). In contrast, neonates in the nicotine group displayed a
noticeably blunted stress response: cortisol and cortisone levels
20 min after the stress event did not differ significantly from
baseline levels (0.77 ng ml − 1 (range 0.1 to 16.4) for cortisol,
P = 0.77; and 13.0 ng ml − 1 (range 3.3 to 45.1) for cortisone,
P = 0.19). A two-way analysis of variance again revealed that there
was no significant alteration of cortisol after the stress stimulus in
the nicotine group (P = 0.36), whereas it was significant in the
control group (P = 0.02). A one-sample t-test power calculation
validated the absent cortisol response in neonates in the nicotine
group with a power of 99% at a significance level of 0.05. For
better visualization of alterations before and after stress stimulus
as well as medians of relative alterations for cortisol and cortisone,
see Figure 2.
A stepwise multiple regression model was applied to analyze a
potential influence of gestational age at delivery, neonatal weight,
sex, and delivery mode, but none of them had a significant
influence on cortisol response levels in the nicotine group
(P = 0.22, P = 0.83, P = 0.55, P = 0.94, respectively). Moreover, a
Spearman rank correlation revealed that the amount of maternal
smoking (number of cigarettes) was not correlated significantly
with the response in the HPA axis (ρ: 0.02, P = 0.90 for cortisol; and
ρ: 0.06, P = 0.76 for cortisone).
Finally, another Spearman rank correlation was performed to
exclude the possibility that the decreased cortisol response in the
nicotine group was mediated by an increased conversion of
cortisol to cortisone. Cortisol and cortisone levels were strongly
correlated in the nicotine group, thus excluding this possibility (ρ:
0.85, P o 0.01).
DISCUSSION
Our results support the hypothesis that MSDP leads to a persistent
re-programming of the fetal HPA axis. Neonatal stress response on
the fourth day of life, measured as an increase in cortisol levels
after a stress stimulus, is significantly blunted in neonates of
mothers who smoked during pregnancy.
Our findings go along with data presented by Stroud et al.28
that provided evidence for attenuated basal and reactive cortisol
levels over the first postnatal month in MSDP-exposed neonates.
However, in their study the two groups of smokers and controls
Nicotine group (n = 33) P-value
280 (259–292) 0.24
3350 (2480–4060) 0.60
42.5 (10.8–89.6) 0.45
18/15 0.21
34.3 (25.0–36.0) 0.57
9 (8–10) 0.71
9 (9–10) 0.72
27.3% 0.57
29 (18–37) 0.21
2 (1–5) 0.47
21.5 (16.1–35.3) 0.24
28.2 (22.5–39.1) 0.27
© 2017 Nature America, Inc., part of Springer Nature.
 Maternal smoking alters neonatal stress response
C Haslinger et al
3

Figure 1. Salivary absolute levels for cortisol (a, b) and cortisone (c, d), including individual courses of control (n = 70) and nicotine group
(n = 33) neonates before (baseline) and after (after stress stimulus) application of the stress stimulus. The line indicates median levels.

a differed in a statistically significant way on a number of baseline

2.5
characteristics; in fact, the women in the MSDP group had a
Cortisol median relative changes (ng/ml)

* Baseline significantly lower socioeconomic status, smoked marijuana

2 After stress stimulus additionally to tobacco more often, were used to consuming
high amounts of caffeine (4200 mg per day), were suffering from
1.5 additional gestational complications, and showed more evidence
of depressive symptoms. Additional effects of these possible
1 confounders on the re-programming of the fetal HPA axis cannot
be excluded. To account for these putative confounders, in our
0.5
study, additional maternal substance abuse other than tobacco
was an exclusion criteria and it was made sure that maternal and
neonatal baseline characteristics did not reveal any significant
0
Control group Nicotine group difference between groups. Further support for the theory that
b maternal smoking influences the fetal HPA axis has been provided
20 by McDonald et al.29 as they showed that these infants had
* elevated umbilical arterial adrenocorticotropic hormone levels at
Cortisone median relative changes (ng/ml)

18 Baseline

16 After stress stimulus the time of birth.2

14
There are a few more maternal conditions that were shown to
have an influence on the fetal HPA axis, which persists until
12
neonatal life, such as IUGR (intrauterine growth retardation)30 and
10 antenatal corticosteroid therapy.27 For this reason, neonates with
8 a birth weight o 10th percentile as well as neonates with
6 antenatal betamethasone treatment were excluded. It is interest-
4 ing to note that all of these factors—IUGR, antenatal corticosteroid
2
therapy and MSDP—lead to the same endpoint, that is, a fetal re-
programming of the HPA axis. Numerous studies have underlined
0
Control group Nicotine group the influence of environmental factors on fetal development with
long-term effects, potentially leading to diseases in adult life. For
Figure 2. Median relative salivary level alterations for cortisol after MSDP, reported diseases include overweight, diabetes mellitus
stimulus (a) and cortisone after stimulus (b) for control and nicotine and modification of blood pressure control mechanisms.11–13
groups, respectively. *: indicates Po 0.05, Wilcoxon signed rank test A blunted stress response in the neonate points to a persistent
(Cortisol (A) and Cortisone (B) levels compared before (Baseline) and HPA axis dysregulation. Interestingly, infants at the age of
after (after stress stimulus) application of the stress stimulus). 7 months already exhibit an overreaction of cortisol response

© 2017 Nature America, Inc., part of Springer Nature. Journal of Perinatology (2017), 1 – 5
 Maternal smoking alters neonatal stress response
C Haslinger et al
4
after intrauterine smoking exposure.31 These findings strongly
contrast physiologic maturational adaptations of the HPA axis
during the first year of life, where the inverse function has been
observed. Infants tend to decrease their stress response during the
first year of life,32 possibly to protect the vulnerable developing
brain from unfavorable steroid exposure. Thus, this early
maladaptive processing of stress may lead to chronic steroid
exposure, possibly by altered central feedback mechanisms.33
In contrast to IUGR or the need for antenatal lung maturation,
maternal smoking is the only factor that can be modified by the
mother. Information about lifetime adverse effects of maternal
smoking on the unborn—besides known short-term risks—might
help to further motivate women to quit smoking before or in
pregnancy, particularly as pregnancy provides a unique opportu-
nity for a medical intervention for smoking cessation due to
frequent planned consultations.34
In adults, nicotine results in the adrenocorticotropic hormone-
mediated release of cortisol via HPA axis activity,19 an important
mediator of stress response regulation, and chronic exposure to
nicotine was shown to modify this cortisol response to acute stress
events.20 Nicotine easily passes the placental barrier and thus
influences the fetal development in the same way. Furthermore, it
was shown that nicotine has an influence on the expression of
nicotinic and muscarinic acetylcholine receptors in the developing
brain during the first trimester of pregnancy,35 leading to a
decreased activity of the HPA axis. As neuronal development and
modification proceeds in different stages, it is relevant that only
neonates from mothers who smoked during each stage of
pregnancy were included in our study.
Another factor that modifies the developing fetal HPA axis is the
level of maternal cortisol. Under physiological conditions, the
placental enzyme 11β-HSD 2 (11β-hydroxysteroid dehydrogenase
type 2) converts active cortisol to inert cortisone. Nicotine as well
as cadmium, another substance that is found in cigarette smoke,
leads to a decreased expression of 11β-HSD 2 in the placenta and
hence to increased cortisol levels in the fetal compartment.36,37
One of the strengths of our study was to determine the levels of
both cortisol and cortisone and to analyze their correlation in
order to exclude a 11β-HSD 2-mediated inactivation of cortisol.
The study design in general aimed to eliminate putative
confounders; therefore, only healthy neonates with maternal
smoking being the only known risk factor for fetal ‘re-program-
ming’ were included. A possible limitation is that assessment of
maternal smoking activity was based on regular anamnestic
evaluation and not on testing of cotinine levels in maternal saliva.
However, over-reporting of smoking habits in pregnancy is
unlikely.
In conclusion, MSDP leads to increased levels of cortisol in the
fetus owing to several direct and indirect effects of nicotine and
cigarette smoke. As a consequence, the fetal HPA axis might
experience a desensitization with modulation of glucocorticoid
receptors and hence a re-programming. Our data show that the
neonatal HPA axis remains significantly altered on the fourth day
of life after MSDP in terms of a blunted cortisol response to a pain-
mediated stress stimulus.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
Financial Support: there was no financial support of the study.
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