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. Author manuscript; available in PMC: 2014 Jan 1.
Published in final edited form as: Infancy. 2012 Feb 29;18(2):233–255. doi: 10.1111/j.1532-7078.2012.00118.x

Physiological Regulation at 9 Months of Age in Infants Prenatally Exposed to Cigarettes

Pamela Schuetze 1,2, Rina D Eiden 2, Craig R Colder 3, Teresa R Gray 4, Marilyn A Huestis 4
PMCID: PMC3640595  NIHMSID: NIHMS355087  PMID: 23646002

Abstract

The primary purpose of this study was to examine the association between prenatal cigarette exposure and physiological regulation at 9 months of age. Specifically, we explored the possibility that any association between prenatal cigarette exposure and infant physiological regulation was moderated by postnatal environmental tobacco smoke (ETS) exposure or infant gender. We evaluated whether male infants with prenatal cigarette exposure or infants who were also exposed to ETS after birth had the highest levels of physiological dysregulation. Respiratory sinus arrhythmia (RSA) was obtained from 206 (142 exposed and 64 nonexposed) infants during a baseline period and during procedures designed to elicit both positive and negative affect. There was a significant suppression of RSA during the negative affect task for nonexposed infants but not for exposed infants. Postnatal ETS exposure did not moderate this association; however, gender did moderate this association such that boys with prenatal cigarette exposure had a significant increase in RSA rather than the suppression seen among both nonexposed boys and girls. These results provide additional support for the idea that boys are particularly vulnerable to the effects of prenatal cigarette exposure.

Keywords: Prenatal cigarette exposure, Physiological Regulation, Respiratory Sinus Arrhythmia, Gender, Environmental Tobacco Smoke Exposure

Prenatal exposure to cigarettes has been linked to a range of nonoptimal developmental outcomes including an increased risk of behavioral and physiological dysregulation during infancy and early childhood (Fried & Makin, 1987; Law et al., 2003; Jacobson, Fein, Jacobson, Schwartz, & Dowler, 1984; Nugent, Lester, Greene, Weiczorek-Deering, & O'Mahony, 1996; Picone, Allen, Olsen & Ferris, 1982; Saxton, 1978; Schuetze & Zeskind, 2001; Streissguth, Barr & Martin, 1983). The regulatory system is conceptualized as consisting of both physiological and behavioral processes. Although most studies examining regulatory processes in cigarette-exposed infants have focused on behavioral regulation, few studies have found evidence of physiological dysregulation among cigarette-exposed infants during infancy. During early infancy, studies have found higher heart rates during quiet and active sleep, lower long-term heart rate variability, lower baseline respiratory sinus arrhythmia (RSA) during rest and higher basal cortisol levels and a lower cortisol response to a stressor among cigarette-exposed infants (Franco, Chabanski, Szliwowski, Dramaix, & Kahn, 2000; Ramsay, Bendersky & Lewis, 1996; Schuetze & Zeskind, 2001; Schuetze & Eiden, 2006; Zeskind & Gingras, 2006). Fewer studies, however, have found the association between prenatal cigarette exposure and physiological regulation beyond the first few months of life.

One particularly useful measure of autonomic regulation is RSA. RSA is a measure of the high-frequency portion of heart rate variability that occurs within the frequency range at which respiration occurs (approximately .24 to 1.04 Hz for infants; Porges et al., 1996) and, although multiply-determined, is believed to index activity of the parasympathetic nervous system in autonomic control of heart rate via the vagus nerve. Two commonly used indices of autonomic regulation (Porges, 1996) include RSA at rest (baseline RSA) and changes in RSA during environmental demands (RSA regulation; Bornstein & Suess, 2000; Calkins, 1997). Baseline RSA is a measure of the infant's ability to maintain physiological homeostasis during periods of minimal external stimulation. During exogenous challenges to homeostasis, activity of the parasympathetic nervous system is often reduced, allowing HR to increase which, in effect, releases the parasympathetic brake on HR (Porges, Doussard-Roosevelt, Portales, & Greenspan, 1996). RSA regulation during periods of environmental challenge is believed to reflect the infant's ability to appropriately engage or disengage with the environment (Bornstein & Suess, 2000; Porges, 1996) such that RSA is suppressed during stressful situations. Thus, the measurement of change in RSA from baseline to challenging situations may be an important concurrent and predictive index of autonomic regulation in infants. The first goal of the present study is to examine the association between prenatal cigarette exposure and RSA at rest and during environmental challenge. We hypothesized that, compared to nonexposed infants, cigarette-exposed infants would have lower resting RSA and a reduced RSA suppression during environmental challenge.

Continued maternal cigarette smoking during the postpartum period may also moderate the association between prenatal cigarette exposure and infant autonomic regulation. Although the effects of postnatal environmental tobacco smoke (ETS) exposure on sudden infant death syndrome and respiratory illnesses are well known (e.g., Cornelius & Day, 2000; Jinot & Bayard, 1996), other developmental outcomes have not been well studied. After birth, infants are exposed to cigarette side-stream smoke that contains high concentrations of toxins that readily enters the infant's bloodstream (Gillies, Kristmundsdottir, Wilcox, & Pearson, 1986). Furthermore, Slotkin, Pinkerton, Auman, Qiao & Seidler (2002) found that postnatal ETS exposure was associated with up-regulation in the number of nicotine receptors, which are associated with neurobehavioral functioning in the brain using a primate model of prenatal and ETS exposure. Consequently, postnatal exposure to ETS may have significant physiological influences on the infant. Studies that have examined both prenatal cigarette exposure and postnatal exposure to ETS have found that postnatal exposure to ETS is associated with externalizing behavior problems and conduct disorder even after accounting for the effects of the prenatal cigarette exposure (Maughan et al., 2001; Williams et al., 1998). Consequently, we hypothesized that the association between prenatal cigarette exposure and physiological regulation would be stronger in the presence of heavier maternal postpartum cigarette smoking.

Evidence is also accumulating that suggests gender may moderate the association between prenatal cigarette exposure and developmental outcome. Studies have consistently found that boys are more vulnerable to a range of developmental problems (Gualitieri & Hicks, 1985). Gender differences seem particularly pronounced among at-risk infants (e.g., Hay, 1997; Weinberg, Tronick, Cohn, & Olsen, 1999). There is some consensus in the literature that the male fetus may be more susceptible to teratogenic influences affecting the central nervous system than the female fetus (Flannery & Leiderman, 1994; Hans, 1994; Weinberg, Zimmerberg, & Sonderegger, 1992). Although there is a paucity of studies with humans examining whether sex moderates the association between prenatal cigarette exposure and developmental outcomes, animal work has consistently found sex effects in animals prenatally exposed to nicotine (Ernst, Moolchan & Robinson, 2001). In addition, several studies with humans have found evidence of an interaction effect between prenatal cigarette exposure and sex on developmental outcomes. During infancy, higher levels of prenatal cigarette exposure have been associated with decreased gross motor movement, levels of approach, reactivity and attention (Willoughby, Greenberg, Blair, Stifter and The Family Life Investigative Group, 2007), higher peak cortisol reactivity (Schuetze, Lopez, Granger & Eiden, 2008) and an increased risk for low sociability and negative emotionality (Wakschlag & Hans, 2002) in male, but not female, infants. During childhood, prenatal cigarette exposure is associated with more symptoms of conduct disorder for boys (Wakschlag & Hans, 2002; Weissman, Warner, Wickramaratne, & Kandel, 1999). Consequently, another goal of the present study was to determine if gender moderated the association between prenatal cigarette exposure and physiological regulation. We hypothesized that the association between prenatal cigarette exposure and regulation would be stronger for boys.

The primary purpose of this study was to examine the association between prenatal cigarette exposure and physiological regulation at 9 months of age. Because previous studies have found differences in resting RSA between cigarette-exposed and nonexposed infants during early infancy (Schuetze & Eiden, 2006; Schuetze, Eiden, Colder, Gray & Huestis, 2011), we hypothesized that cigarette exposed infants would have lower resting RSA compared to nonexposed infants. We also hypothesized that infants who had been prenatally exposed to cigarettes would have a reduced RSA suppression during environmental challenge, particularly during conditions eliciting negative affect. The second goal of this study was to test the possibility that infant sex and maternal postpartum cigarette smoking would moderate the association between prenatal cigarette exposure and physiological regulation. Specifically, based on previous literature regarding greater biological vulnerability among males, we hypothesized that the association between prenatal cigarette exposure and regulation would be stronger for boys compared to girls and would be stronger in the presence of heavier maternal postpartum cigarette smoking.

Method

Sample Selection

Women who presented for care at the prenatal clinic of a large urban hospital were asked to complete a screening form during their first prenatal appointment. Women who were eligible were invited to participate in an ongoing longitudinal study of maternal health and child development. Initial exclusionary criteria included: more than 20 weeks gestation, maternal age under 18 years, and multiple fetuses. Additional eligibility criteria were: no illicit drug use (other than cannabis), no heavy alcohol use (more than 1 drink/day on average or 4 drinks on one occasion) after pregnancy recognition, and no heavy marijuana use (more than 1 joint/day on average) after pregnancy recognition. Women who agreed to participate were scheduled for four appointments: one at the end of each trimester of pregnancy and one at 2 months postpartum (at age corrected for prematurity). A second postpartum assessment was scheduled for 9 months postpartum (at age corrected for prematurity). At the end of each month of recruitment, the closest matching non-smoker (based upon age and education) was invited to participate. Smokers were over-sampled so that one non-smoker was recruited for every two smokers (taking the average of age and education of both). Participants included a total of 258 mothers and their infants. Of these dyads, 181 were infants prenatally exposed to cigarettes through maternal smoking, and 77 were infants not exposed to cigarettes.

Mothers ranged in age from 18 to 39 (M = 24.6, SD = 4.92). Maternal race was 52% African-American, 30% Caucasian, 18% Hispanic, and 8% other or mixed race with several mothers reporting more than one race. Fifty-eight percent of the women were married or living with their partner, while the remainder of the sample reported being in a relationship, but not living with their partner. 29% of the women had less than a high-school education, 30% completed high-school, 30% completed some college courses, 8% had a vocational degree or technical training degree and 4% had a bachelor's degree.

Procedure

Informed written consent was obtained from interested, eligible mothers. Infant assessments were conducted at 2 (M = 2.51, SD = .41) and 9 months (M = 9.01, SD = 2.95) of infant age. Data from the prenatal interviews and from the maternal interview and physiological assessment conducted at the 9-month visit were included in these analyses. Only dyads with complete data at the 9-month visit were included in these analyses. Of the 258 infants recruited into the study, 22 did not show up for the 9-month assessment after repeated reschedules (8 cigarette-exposed), 6 were unable to be located (2 cigarette-exposed), and 6 (4 cigarette-exposed) were dropped (severe medical problems) or withdrew from the study. An additional 18 infants did not have complete physiological data due to equipment failure (n = 5), research assistant error or excessive movement artifact in the EKG data (n = 5), infant irritability (n = 6; 5 cigarette-exposed) or caregiver interference during the assessment procedure (n = 2). Thus, the final sample was 206 (142 cigarette-exposed, 64 nonexposed) dyads. There were no significant differences between families with complete versus missing data at 9 months on demographic or substance use variables.

The study protocol was approved by the appropriate institutional review board. Participants were informed that data confidentiality was protected by a Federal Certificate of Confidentiality issued by the National Institute on Drug Abuse. Participants received a $20.00 check, a $20.00 infant toy, and $40.00 gift certificate at the 9-month visit for their participation.

Infant Growth and Risk Status

Three growth measures were taken by obstetrical nurses in the delivery room: birth weight (g), birth length (cm), and head circumference (cm). Medical chart review after delivery was used to complete the Obstetrical Complications Scale (OCS; Littman & Parmelee, 1978), a scale designed to assess perinatal risk factors. Higher numbers indicate a more optimal score.

Maternal Substance Use

Maternal pregnancy smoking status was determined through a combination of self-report, meconium and maternal saliva results (see Schuetze, Eiden, Colder, Gray & Huestis, 2011 for details on these methods). At each prenatal interview and at the postnatal interviews, the Timeline Follow-Back Interview (TLFB, Sobell & Sobell, 1995) was used to gather daily tobacco, alcohol, and cannabis use for the previous three months. The TLFB was also used at each postpartum visit (2 and 9 months of infant age) to assess postnatal substance use.

Maternal saliva was collected at each prenatal interview to provide objective evidence of recent exposure. The saliva specimens were analyzed by a commercial laboratory for cotinine, a metabolite of nicotine that indicates exposure to nicotine (Jarvis et al., 2003). Maternal prenatal saliva was used to determine maternal smoking status and was not used for identification of prenatal ETS exposure.

After birth, meconium specimens were collected from soiled diapers twice daily until the appearance of milk stool, transferred to storage containers, and frozen until transport to the National Institute on Drug Abuse for analysis. Meconium specimens were assayed with a validated LC-MS/MS method (Gray, Shakleya, & Huestis, 2009) for the presence of nicotine, cotinine, or trans-3-hydroxycotinine as evidence of prenatal nicotine exposure.

Postnatal Substance Use

Postnatal ETS was assessed for infants during their 9-month visit using infant saliva samples and maternal report of postnatal smoking. Infant saliva samples assessed cotinine levels. Salivary cotinine concentrations are highly correlated to those in the blood (Jarvis et al., 2003) and, thus, are an accurate, yet noninvasive, way of measuring ETS exposure. Saliva samples were collected by placing eye spears (BD Opthalmology “Visispears” (product #581089), marketed by Salimetrics as “Sorbettes” (product #5029)) in the mouth of infants. These samples were placed in a storage vial and immediately placed in −80°C freezer and sent to the Center for Interdisciplinary Salivary Bioscience at Johns Hopkins University for assay. The advantage of saliva testing is that it quantifies exposure to cigarette smoke from all possible sources including other household smokers. However, since saliva samples were not available from all infants. Thus, maternal report of the mean number of cigarettes smoked between birth and the 9-month laboratory visit (obtained from the TLFB) also provided a measure of infant postnatal ETS exposure. The TLFB was also used to assess maternal postnatal alcohol and marijuana use.

Infant Physiological Assessment

Assessment of Infant Reactivity and Regulation

Physiological reactivity and regulation were recorded during a 3-minute baseline period (watching a video), a 2-minute positive affect paradigm, a second 3-minute baseline interval (watching a video) and a negative affect episode (2 minutes) by examiners blind to infant group status. Infants were tested while seated in a high chair. Recording of the physiological data began once the infant was observed to be in a stable, quiet, alert state which was induced by having the infant watch a 3-minute segment of a neutral videotape “Baby Einstein” (see Calkins, 1997). The positive affect paradigm consisted of a puppet show that measured positive affect in response to social stimulation using a standardized presentation (Goldsmith & Rothbart, 1999). A scripted dialogue was used which took approximately 90 seconds to present followed by 30 seconds during which the child was allowed to play with the puppets. The negative affect paradigm consisted of a gentle arm restraint episode that is a widely used, well-validated measure of anger/frustration used to assess infant regulation and reactivity (Goldsmith & Rothbart, 1999; Stifter & Braungart, 1995). In this episode, the child was presented and encouraged to play with an attractive toy for 30 seconds. The experimenter stood behind the child, placed her hands on the child's forearms, moved them to the child's sides, holding them there for 30 seconds, while maintaining a neutral expression (first negative affect trial). After the first trial, the infant was allowed to play with the toy for 30 seconds followed by a second arm restraint (negative affect trial 2). The infant was again allowed to play with the toy after the 30 seconds of arm restraint. The session was stopped at the caregiver's request or if the child reached a maximum distress code, defined as the child reaching the highest intensity of negative affect of a full cry. This occurred for six infants (1 nonexposed and 5 cigarette-exposed) who were not included in subsequent data analyses.

A five-channel Bioamp (James Long Company, Caroga Lake, NY) recorded respiration and electrocardiograph (ECG) data. Disposable electrodes were triangulated on the infant's chest. A respiration bellows was placed at the bottom of the sternum (zyphoid process) to measure inspiration and expiration.

IBI Analysis software (James Long Company, Caroga Lake, NY) processed the HR data and calculated RSA. HR samples, which were collected every 10 ms, were used to calculate mean HR. A level detector was triggered at the peak of each R-wave. The interval between sequential R-waves was calculated to the nearest millisecond. Data files of R-wave intervals were later manually edited to remove incorrect detection of the R-wave or movement artifacts that occurred in less than 2% of cases. The software computes RSA using respiration and interbeat interval data as suggested by Grossman (1983). The difference between maximum interbeat interval during expiration and the minimum interbeat interval during inspiration was calculated. The difference, measured in seconds, is considered to be a measure of RSA, and is measured twice for each respiration cycle (once for each inspiration and once for each expiration). The time for inspirations and expirations is assigned as the midpoint for each. The time for each arrhythmia sample is assigned as the midpoint between an inspiration time and an expiration time. The software synchronizes with respiration and is, thus, relatively insensitive to arrhythmia due to tonic shifts in heart rate, thermoregulation, and baroreceptor.

Average RSA was calculated for the first 3-minute baseline period, for the positive affect task, the second 3-minute baseline period and for each of the two negative affect tasks. Three RSA change scores, from the first baseline to the positive affect task and from the second baseline to each of the two negative affect tasks, were calculated to assess autonomic regulation. These were termed RSA responses during positive affect (RSA-PA) and RSA responses during negative affect (RSA-NA1 and RSA-NA2). Negative scores indicate a decrease in RSA and are reflective of more optimal parasympathetic regulation.

Analytic Strategy

First, sample characteristics were obtained by examining associations between group status and demographics; infant growth outcomes; maternal ETS exposure during pregnancy, infant postnatal ETS exposure, and maternal prenatal and postnatal use of alcohol, cigarettes, and marijuana using analyses of variance (ANOVAs) or multivariate analyses of variance (MANOVAs). MANOVAs were used when multiple theoretically associated constructs were the dependent measures in order to control for high Type I error rate. These were followed by analyses of potential confounds using correlations. Confounds with significant bivariate associations with RSA or maternal cigarette smoking during pregnancy or those of theoretical value (e.g., other prenatal substance use) were used as covariates in all remaining analyses (if they were associated at p < .10).

The first goal of the study was to examine group differences in RSA measures. These hypotheses were examined using MANOVAs. The second goal of the study was to explore the possibility that gender and/or postnatal ETS exposure moderated any existing association between prenatal cigarette exposure and measures of RSA. Separate regression analyses of RSA variables (baseline 1, RSA-PA, baseline 2, RSA-NA1 and RSA-NA2) were performed to test 1) whether gender moderated the effect of prenatal exposure on physiological regulation, and 2) whether the effects of prenatal and postnatal maternal use of cigarettes was additive.

Results

Smoking during Pregnancy

Mothers were included in the smoking group if self-reports were positive or if saliva (62% of women in the smoking group) or meconium samples (72%) were positive for a nicotine biomarker. Similarly, mothers who reported that they did not smoke but had positive saliva samples (1% of women in the smoking group) were included in the smoking group. There were no women who reported no smoking but had infants with positive meconium samples. Of the women in the smoking group, 76% had a positive saliva sample, 72% had an infant with a positive meconium sample, and 99% reported smoking.

Group Differences in Demographics and Other Substance Use

Descriptive statistics for the demographic and substance use variables for mothers of the two groups are presented in Table 1. In this predominantly low-income sample, there were no group differences in maternal education, age, marital status, work status, Temporary Assistance for Needy Families (TANF) or Women, Infants and Children (WIC) use among smokers and nonsmokers. However, mothers who smoked during pregnancy consumed significantly more alcohol during the first trimester of pregnancy and smoked significantly more marijuana during the first and second trimesters of pregnancy, although the range was restricted on both these variables due to inclusion/exclusion criteria. Smokers also consumed significantly more alcohol and smoked significantly more cigarettes and marijuana postnatally than nonsmokers.

Table 1.

Group Differences for Maternal Demographics and Substance Use

Non-Smokers
n = 64 		Smokers
n = 142
Variables M SD M SD df F p
Demographic Characteristics
 Age (years) 23.82 4.69 25.0 4.99 204 2.66 .10
 Education (years completed) 12.27 1.46 12.06 1.66 205 .81 .37
Cigarette Use During Pregnancy (cigarettes/day)
 First trimester 0 0 7.20 6.05 205 93.24 .001
 Second trimester 0 0 3.99 4.73 205 46.84 .001
 Third trimester 0 0 3.88 5.53 205 32.41 .001
Alcohol Use During Pregnancy (standard drinks/day)
 First trimester .04 .10 .22 .60 205 5.98 .02
 Second trimester .002 .01 .005 .01 205 2.61 .11
 Third trimester .004 .02 .004 .015 205 .001 .97
Average Marijuana Use During Pregnancy (joints smoked/day)
 First trimester .20 .97 .72 1.66 205 5.7 .02
 Second trimester .01 .04 .14 .48 205 4.79 .03
 Third trimester 0 0 .06 .32 205 2.44 .12
Postnatal Substance Use
 Average # cigarettes smoked/day .10 .64 6.63 5.68 205 86.68 .001
 Average # standard drinks/day 1.14 1.58 3.31 4.15 205 16.87 .001
 Average # joints/day .15 .62 1.27 3.14 205 8.24 .005
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Group differences for infant characteristics are presented in Table 2. Infants who were prenatally exposed to cigarettes had a significantly lower score on the OCS than nonexposed infants indicating a higher number of perinatal complications and had a significantly lower birthweight and smaller head circumference at birth. There were no group differences in gestational age or birth length.

Table 2.

Group Differences for Infant Characteristics

Nonexposed
n = 64 		Exposed
n = 142
Variables M SD M SD df F p
Perinatal Growth/Risk
 Gestational age (weeks) 39.08 1.39 38.9 1.51 205 .68 .41
 Birth Weight (g) 3397.12 573.98 3211.82 486.04 205 5.95 .02
 Birth Length (cm) 50.53 3.84 50.07 2.79 205 .95 .33
 Birth Head Circumference (cm) 34.53 1.89 33.78 1.67 198 7.89 .005
 Obstetrical Complications Scale 91.23 13.27 84.17 15.49 202 10.06 .002
Gender (% male) 46% (n = 29) 52% (n = 74) X2 = .71 .24
Respiratory Sinus Arrhythmia
 Baseline 1 .019 .013 .021 .022 205 .12 .73
 RSA-PA .008 .009 .001 .008 205 .06 .81
 Baseline 2 .018 .013 .019 .021 205 .18 .68
 RSA-NA1 −.001 .010 .003 .020 205 2.06 .15
 RSA-NA2 −.010 .010 .010 .030 205 4.16 .04
Heart Rate (beats per minute)
 Baseline 1 129.05 9.4 128.49 10.86 205 .12 .73
 Puppet Show 130.69 11.72 128.27 12.15 205 1.78 .18
 Baseline 2 131.66 8.93 132.12 11.78 205 .08 .78
 Arm Restraint 1 141.85 11.87 138.78 15.08 205 2.01 .16
 Arm Restraint 2 137.37 12.26 136.69 15.92 205 .09 .77
ETS Exposure (cotinine) 2.64 3.21 7.24 8.13 202 18.52 .001
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Examination of Potential Covariates

We examined the relation of maternal demographic variables (age, education, parity), and fetal growth variables (birthweight, head circumference at birth, birth length and gestational age) to the average number of cigarettes smoked per day during each trimester of pregnancy and to infant RSA measures at 9 months of age. Cigarette smoking during the first trimester was associated with the number of years of maternal education completed, r = −.17, p = .014, and with birthweight, r = −.13, p = .05. Maternal education was also significantly associated with baseline RSA, r = −.15, p < .04, and with RSA-NA2, r = −.15, p < .04. Consequently, maternal education and birthweight were included as covariates in all subsequent analyses of RSA.

We also examined the relation of maternal alcohol and marijuana use during and after pregnancy to the average number of cigarettes smoked per day during each trimester of pregnancy and to infant RSA measures at 9 months of age. Cigarette smoking (average number of cigarettes per day) during the first trimester was significantly associated with alcohol (average number of standard drinks per day), r = .20, p = .001, and marijuana (average number of joints per day), r = .17, p = .005, during the first trimester. Consequently, alcohol and marijuana use during the first trimester were also included as covariates in all subsequent analyses of RSA.

Group Differences in RSA

Because physiological responses may be influenced by the Law of Initial Value (Lacey, 1956; Wilder, 1956), the association between baseline RSA and subsequent RSA values was examined. Baseline RSA was significantly associated with RSA during all of the other conditions (rs ranging from .30 to .93, all ps < .001). Thus, consistent with the Law of Initial Value, measures of RSA were adjusted for baseline levels by including baseline RSA as a covariate in all analyses of RSA change. Analyses were, however, repeated without baseline RSA as a covariate. There were no substantial differences in findings.

Separate ANCOVAs were performed on the RSA variables: first baseline RSA, RSA-PA, second baseline RSA, RSA-NA1 and RSA-NA2 with smoking during pregnancy status as the independent variable (see Table 2). The analyses on the two baseline RSA measures, RSA-PA, and RSA-NA1 did not indicate any significant effects. However, the analysis on RSA-NA2 indicated that infants of mothers who were smokers during pregnancy increased their RSA during the second negative affect trial while infants whose mothers were not smokers showed the expected decrease in RSA.

Moderational Analyses

We then conducted multiple regression analyses to examine if the association between prenatal cigarette exposure and RSA was moderated by infant gender or maternal postnatal cigarette smoking. Both measures of prenatal and postnatal cigarette exposure were dichotomous variables. As described above, variables that were associated (p<.10) with either prenatal cigarette exposure or RSA variables were included as covariates. In addition, the first baseline RSA variable was included as a covariate in the analysis of RSA regulation during the positive affect task and the second baseline RSA variable was included as a covariate in the analyses of RSA regulation during the negative affect task. The covariates were entered in the first step, followed by prenatal cigarette exposure and gender in the second step and the interaction term in the third step.

The analysis examining gender as a potential moderator indicated that the interaction terms for the first baseline RSA, standardized beta = −.48, p = .07, change in RSA during the positive affect task, standardized beta = −.14, p = .89, second baseline RSA, standardized beta = −1.59, p = .11, and for RSA-NA1, standardized beta = −.77 p = .44, were not significant. However, there was a significant interaction term for RSA-NA2 indicating that gender moderated the effect of prenatal cigarette exposure on RSA regulation during environmental challenge (see Table 3). Cigarette-exposed boys had an increase in RSA during the second trial of the negative affect task rather than the RSA suppression shown by exposed girls and nonexposed boys and girls (see Figure 1).

Table 3.

Hierarchical Linear Regression Models for RSA Reactivity during the Second Trial of the Negative Affect Task: Moderational Analyses for Gender

Predictor Variables Unstandardized Coefficients Beta S.E. Standardized Beta R2 Adjusted R2 F
Step 1: Prenatal Marijuana Exposure .001 .001 −.023 .06 .027 .77
 Prenatal Alcohol Exposure −.002 .005 −.037
 Birthweight −.001 .001 .055
 Head Circumference at Birth −.001 .002 −.05
 Maternal Education −.001 .001 −.051
 Baseline RSA −.494 .181 −.234**
Step 2: Exposed vs. Nonexposed .011 .005 .198* .09 .057 .14
 Gender −.008 .004 −.152+
Step 3: Interaction Term for Prenatal Exposure and Gender −.009 .009 −.284** .13 .060 3.42**
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+

p < .10

*

p < 0.05

**

p < 0.01

Figure 1.

Figure 1

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Sex by Smoking Group Interaction Effect for RSA-NA2.

The analysis examining postnatal ETS exposure (infant cotinine and maternal report of infant ETS exposure were analyzed in separate analyses) as a potential moderator indicated that there was no significant interaction term for any of the RSA variables for either analysis. These findings indicate that postnatal maternal smoking and postnatal ETS exposure did not moderate the association between prenatal cigarette exposure and baseline RSA or physiological regulation during environmental challenge.

Discussion

A growing body of research has found that cigarette exposed infants have more problems with behavioral regulation. Several studies have indicated that this dysregulation extends to autonomic measures of regulation such as higher HR and lower long-term HRV (Franco, Chabanski, Szliwowski, Dramaix, & Kahn, 2000; Schuetze & Zeskind, 2001; Schuetze & Eiden, 2006; Zeskind & Gingras, 2006) during early infancy. Because less is known about autonomic regulation in this population beyond early infancy, one goal of this study was to examine the relation between PCE and measures of autonomic regulation at 9 months of age.

As predicted by the Polyvagal Theory (Porges, 1996), nonexposed infants showed RSA suppression during a task designed to elicit negative affect. This is indicative of adaptive autonomic nervous system regulation for affect-eliciting tasks and is consistent with earlier reports of decreased RSA during arm restraint and other tasks designed to elicit frustration among non-risk samples of infants (Stifter & Fox, 1990; Stifter & Jain, 1996). Thus, consistent with the Polyvagal Theory, these infants released the vagal brake which reduces parasympathetic control during situations of frustration. Consistent with our hypothesis, exposed infants did not display RSA suppression during the negative affect task. Similar patterns of autonomic responses have been noted in other substance-exposed infants. For example, cocaine-exposed infants show increases in heart rate when presented with novel social stimulation compared to the more adaptive decrease in heart rate of control group infants (Coles, Bard, Platzman & Lynch, 1999) and fail to show RSA suppression during a task designed to elicit negative affect (Schuetze, Eiden & Coles, 2007).

Interestingly, this group difference in RSA change during challenge was not significant during the first trial of the arm restraint task. Changes in RSA from baseline to RSA during the first trial were negligible for both exposed and nonexposed infants. However, during the second trial, nonexposed infants showed the optimal suppression of RSA while exposed infants increased their RSA. It is possible that the initial environmental challenge was not stressful enough in either exposed or nonexposed infants to require autonomic regulation. However, when environmental challenge was repeated, nonexposed infants responded by reducing parasympathetic control suggesting an autonomic response to stress. One possible explanation for these findings is that infants who did not show RSA suppression during the second arm restraint trial were not distressed enough to require autonomic regulation. A related possible explanation is that failure to show the expected physiological responsiveness to stress may reflect underarousal associated with prenatal cigarette exposure. Prenatal exposure to cigarettes may be associated with increased allostatic load (risk associated with repeated physiological adaptations in response to chronic prenatal and postnatal stress). Optimally, under conditions of environmental challenge, physiological regulatory systems will respond to meet the metabolic needs of the infants. However, repeated challenges over time take a toll on the body which McEwen and colleagues (McEwen, 1998; Schulkin, McEwen & Gold, 1994) have conceptualized as allostatic load. This increased allostatic load may be due to the combination of high prenatal stress, due to fetal hypoxia and ischemia, and continued postnatal stress from cumulative environmental and maternal risks. Prenatal exposure to substances, including cigarettes, can also be conceptualized as a prenatal stressor. To date, most studies have examined allostatic load using the hypothalamic-pituitary-adrencortical (HPA) system, which is a major indicator of physiological states in response to negative affect, and have described both over and under activation (McEwen, 1998; Badanes et al., 2011). Recently, studies have indicated that indices of parasympathetic nervous system functioning such as RSA can also index allostatic load (El-Sheikh & Hinnant, 2011). Reduced responsiveness of these systems have been argued to be a marker of more severe stress exposure, may reflect the effects of allostatic load, and has significant implications for poor self-regulation and risk for behavioral problems (Badanes et al., 2011; Blair, Granger & Razza, 2005; Gunnar & Vasquez, 2001). Future studies should obtain physiological measures of sympathetic reactivity, such as skin conductance, to further explore this issue. This is particularly important since parasympathetic and sympathetic nervous system components of the autonomic nervous system function independently and a handful of studies have found an association between prenatal cigarette exposure and physiological indicators of sympathetic functioning. Thus, a complete understanding of the association between prenatal cigarette exposure and autonomic functioning should include measures of both parasympathetic and sympathetic nervous system.

The failure to suppress RSA in response to environmental challenge is also consistent with previous findings that infants with regulatory disorders did not regulate (suppress) RSA from baseline to a task (DeGangi et al., 1991). We submit that this pattern of dysregulation is a long-term effect associated with prenatal cigarette exposure that is not limited to early infancy. Since other studies have indicated that there is a possible association between vagal regulation and both concurrent and future behavioral regulation during frustration (Calkins, 1997), and social tasks (Doussard-Roosevelt et al., 1997; Suess & Bornstein, 2000), the findings of the current study suggest that cigarette-exposed infants may be at risk for less adaptive behavioral regulation during environmental challenge.

We note that there were no significant group differences in the change of RSA from baseline to the positive affect task. One explanation for this is that elicitation of positive affect may not require active coping and, consequently, RSA suppression is not needed. In fact, some studies have found increases in RSA during positive affect tasks (Bazhenova, Plonskaia, & Porges, 2001) while others have found that behavioral indicators of positive affect did not reliably correspond with changes in RSA (Weinberg & Tronick, 1996). Alternatively, our positive affect task may have elicited a range of emotional responses that may correspond with differential physiological responding. In particular, this type of task may elicit attention rather than positive affect and previous studies have found that focused attention corresponds with increases in RSA rather than RSA suppression (DiPietro, Porges & Uhly, 1992).

Unlike other studies that found group differences in baseline measures of RSA and other measures of HRV during early infancy among substance-exposed infants (Regalado, Schechtman, Khoo, & Bean, 2001; Schuetze & Eiden, 2006; Schuetze, Eiden, & Coles, 2007), we did not find an association between prenatal cigarette exposure and baseline RSA at 9 months of age. This is particularly interesting given the finding of an association between prenatal cigarette exposure and decreased baseline RSA at 2 months of age in this same sample (Schuetze, Eiden, Colder, Gray & Huestis, in press). One possible explanation for this discrepancy may be that the findings of these previous studies were with infants ranging from birth to 7 months of age, while the infants in the present study were 9 months of age. RSA increases over the first year of life (Harper et al., 1978; Reynolds & Richards, 2007). Thus, the findings of a lower baseline RSA at earlier months among exposed infants may reflect a delay in maturation of the autonomic nervous system. There is not a lot of evidence regarding stability in RSA in the first year of life, especially among high-risk infant populations, although one study indicates that stability may be low (Stifter & Jain, 1996). Future studies should explore the possibility that stability in RSA, or conversely lack of stability in RSA, during the first year of life is a useful marker of behavioral regulation.

Importantly, the present findings provide additional evidence that boys are more vulnerable than girls to the effects of prenatal cigarette exposure as early as infancy. Although prenatal cigarette exposure was associated with reduced RSA suppression during tasks designed to elicit negative affect among both boys and girls, the effects were exacerbated for exposed boys suggesting an enhanced vulnerability. This finding is consistent with the general developmental literature which indicates that boys tend to have less optimal behavioral regulation and more difficulty regulating their emotions than girls (Carter, Mayes, & Pajer, 1990). Furthermore, recent studies have suggested that regulatory behaviors are particularly vulnerable to prenatal substance exposure. For example, low sociability, increased negative emotionality and higher reactivity was found among cigarette-exposed boys, but not girls, during infancy (Wakschlag & Hans, 2002; Willoughby et al., 2007). Others have found that boys, but not girls, were more likely to develop conduct problems and to display antisocial behaviors later in childhood (Fergusson et al., 1998; Weiseman, Warner, Wickramaratne & Kandel, 1999). The present findings contribute to this body of knowledge by indicating that gender differences also exist in autonomic regulation in response to environmental challenge. Moreover, several studies have found that gender differences in behavioral regulation among prenatally exposed children continue beyond infancy (Wakschlag & Hans, 2002; Weissman et al., 1999). However, longitudinal research is needed to examine whether this gender difference for less optimal physiological regulation persists throughout infancy and into the childhood years. In addition, future studies should explore whether disrupted physiological regulation during infancy is one possible pathway to increased externalizing behaviors during childhood.

It is important to note two limitations of this study. First, although care was taken in the present study to identify substance use in this sample, the accurate assessment of substance use is always difficult, particularly among pregnant women. Pregnant women are often hesitant to divulge information regarding the use of substances, including cigarettes, during pregnancy. To address this issue, multiple indices of substance use were used including self-report using the reliable TLFB interview as well as analysis of medical records, prenatal cotinine, and meconium samples. Each of these measures has its limitations. However, when used in combination, they greatly increase the likelihood of accurately identifying prenatal cigarette smoking and other substance use (Ostrea, 1991).

Second, autonomic regulation was assessed in only a single incident of both positive and negative affect. Since these findings may be specific to these environmental challenges, future studies should explore physiological responses in situations involving other stressors before concluding that prenatal cigarette exposure affects autonomic regulation during all environmental challenges involving negative affect. However, the exploration of RSA responsivenss during a social stressor may add to our understanding of pathways from prenatal cigarette exposure to internalizing/externalizing behavior problems during childhood.

In summary, the present findings provide additional support for the negative influence of prenatal cigarette exposure on neurobehavioral functioning beyond the first month of life. The failure to suppress RSA in response to frustration in infants prenatally exposed to cigarettes is suggestive of altered autonomic nervous system regulation. These findings may have implications for later development as deficits in autonomic regulation have been associated with subsequent emotional and behavioral regulatory problems in older infants and children. These findings also provide additional support for the hypothesis that boys are particularly vulnerable to the effects of prenatal exposure to cigarettes. The importance of these findings is underscored by the large developmental literature suggesting that the pattern of physiological dysregulation seen most prominently in exposed boys is linked to a wide range of subsequent developmental problems which may explain, in part, the increased incidence of conduct disorder and externalizing behaviors in exposed boys later in childhood.

Table 4.

Hierarchical Linear Regression Models for RSA Reactivity during the Second Trial of the Negative Affect: Moderational Analyses for ETS Exposure – Maternal Report

Predictor Variables Unstandardized Coefficients Beta S.E. Standardized Beta R2 Adjusted R2 F
Step 1: Prenatal Marijuana Exposure .001 .001 −.007 .06 .027 1.8
 Prenatal Alcohol Exposure −.001 .004 −.022
 Birthweight −.001 .001 .026
 Head Circumference at Birth −.001 .001 .001
 Maternal Education −.001 .001 −.056
 Baseline RSA −.488 .153 −.241**
Step 2: Exposed vs. Nonexposed .01 .005 .197* .09 .044 2.01*
 Postnatal ETS Exposure .001 .001 −.054
Step 3: Interaction Term for Prenatal and Postnatal Exposure .001 .005 .019 .09 .038 1.78+
Open in a new tab
+

p < .10

*

p < 0.05

**

p < 0.01

Table 5.

Hierarchical Linear Regression Models for RSA Reactivity during the Second Trial of the Negative Affect: Moderational Analyses for ETS Exposure – Infant Cotinine

Predictor Variables Unstandardized Coefficients Beta S.E. Standardized Beta R2 Adjusted R2 F
Step 1: Prenatal Marijuana Exposure −.001 .001 −.003 .06 .026 1.74
 Prenatal Alcohol Exposure −.001 .005 −.021
 Birthweight .001 .001 .029
 Head Circumference at Birth .001 .001 .01
 Maternal Education −.001 .001 −.058
 Baseline RSA −.493 .156 −.243*
Step 2: Exposed vs. Nonexposed .009 .004 .173* .09 .041 1.90+
 Postnatal ETS Exposure .001 .001 −.043
Step 3: Interaction Term for Prenatal and Postnatal Exposure .001 .001 −.119 .09 .035 1.69+
Open in a new tab
+

p < .10

*

p < 0.05

**

p < 0.01

Acknowledgements

The authors thank the parents and children who participated in this study and research staff who were responsible for conducting numerous assessments with these families. Special thanks to Drs. Amol Lele for collaboration on data collection at Women and Children's Hospital of Buffalo. This work was supported by the National Institute on Drug Abuse, National Institutes of Health (Intramural Research Program and grant number 1 R01 DA019632-01).

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