Prenatal cocaine use and maternal depression: Effects on infant neurobehavior

Neurotoxicology and Teratology 29 (2007) 331 – 340 www.elsevier.com/locate/neutera

Prenatal cocaine use and maternal depression: Effects on infant neurobehavior Amy L. Salisbury a,b,⁎, Barry M. Lester a,b , Ronald Seifer a,c , Linda LaGasse a,b , Charles R. Bauer d , Seetha Shankaran e , Henrietta Bada f , Linda Wright g , Jing Liu a,b , Ken Poole h a Brown Medical School, Providence, RI, United States Women and Infants Hospital, Providence, RI, United States c Bradley Hospital, Providence, RI, United States d University of Miami School of Medicine, Miami, FL, United States e Wayne State University School of Medicine, Detroit Michigan, United States f University of Kentucky, Lexington, KY, United States g National Institutes of Health, Department of Health and Human Services, Bethesda, MD, United States h Research Triangle Institute, Statistics Research Division, Research Triangle Park, NC, United States b

Received 3 November 2005; received in revised form 9 November 2006; accepted 1 December 2006 Available online 14 December 2006

Abstract Objective: The present study examined the impact of both perinatal maternal depression and cocaine use on infant neurobehavior at 1 month of age in a large, multi-site study. Methods: Infant neurobehavior was examined in 1053 infants at 1 month of age using the NICU Network Neurobehavioral Scale (NNNS). Mothers were interviewed using The Addiction Severity Index to determine present and past psychiatric history. Four groups were derived from the total sample: 385 prenatally cocaine-exposed infants, 76 whose mothers reported current postpartum depression (DEP/COC) and 309 without current postpartum depression (nonDEP/COC); 668 infants were not exposed to cocaine, 104 whose mothers reported current postpartum depression (DEP/nonCOC), 564 without current postpartum depression (nonDEP/nonCOC). A 2 × 2 Analysis of Covariance was used with covariates (birthweight, maternal age, SES, nicotine, alcohol, and research site) to examine infant neurobehavior in these four conditions. Secondary analyses were conducted to examine the effects of amount and timing of prenatal cocaine exposure. Results: DEP group by COC exposure status interactions were significant; there was only a DEP effect in the nonCOC infants. Infants in the nonCOC/DEP group had poorer self-regulation and more stress signs, excitability, and arousal than infants in the other groups. Conclusions: Postpartum maternal depression has negative effects on infant neurobehavior at 1 month of age. Prenatal cocaine exposure may serve to suppress or buffer the effects of postpartum depression on infant neurobehavior. Maternal mood could explain some of the inconsistencies found in the prenatal cocaine exposure literature. © 2006 Elsevier Inc. All rights reserved. Keywords: Cocaine; Depression; Infant; Neurobehavior; Postpartum

1. Introduction A 2003 National Survey on Drug Use and Health (NSDUH) estimated the rate of illicit drug use among pregnant women at 4.3%; over 130,000 infants were exposed to illicit drugs in utero ⁎ Corresponding author. Brown University Center for the Study of Children at Risk, Women and Infants' Hospital, 101 Dudley Street, Providence, RI 029052499, United States. Tel.: +1 401 276 7840 (Office); fax: +1 401 453 7639. E-mail address: [email protected] (A.L. Salisbury). 0892-0362/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ntt.2006.12.001

each year [1]. Substance abuse remains a major public health problem that affects millions of children and places enormous financial and social burdens on society. The NSDUH reported that adults who used illicit drugs were more than twice as likely to have a serious mental illness as nonusing adults; 26.9% of illicit drug users reported having a serious mental illness in the past year. Major depressive disorder (MDD) is the predominant mental illness reported by women, with a lifetime occurrence of 17% [28]. The first onset of MDD is most likely to occur during the childbearing years [16,28]. Postpartum

332

A.L. Salisbury et al. / Neurotoxicology and Teratology 29 (2007) 331–340

depression occurs at a rate of 7.4% to 25%, with the highest rates occurring in lower socioeconomic samples [10,33,56,69]. Thus the probability that a woman who used cocaine during her pregnancy will experience a depressive episode in the postpartum period is at least 1 in 6 (based on an average 15% prevalence) [28,60]. Yet, little is known about the association between maternal depression and prenatal substance abuse and the effects on infant outcomes. Prenatal cocaine exposure is often associated with a subtle but statistically significant decrease in infant birthweight, gestational age and head circumference [6,12,25,59,66,71]. There is emerging evidence supporting a neurobehavioral profile of the cocaineexposed infant, namely, that prenatally cocaine-exposed infants tend to have difficulty with arousal and state regulation, including increased or impaired behavioral and physiological reactivity to stress [11,48,49,51,54,65]. In a previous report, we found results consistent with these prior studies. One-month old cocaine-exposed infants had lower arousal, poorer quality of movement and selfregulation, as well as increased motor tone and lower auditory brain response measures after controlling for other drug use and maternal care giving variables [44,45]. Data conflicting with these findings have also been reported with no differences found in young infants prenatally exposed to cocaine [55,70]. The collective data on prenatal cocaine exposure effects on infant neurobehavior has been inconclusive and warrants further research. Maternal depression in the first 30 days postpartum is an integral component of the care giving environment of the infant and may have a significant impact on infant development, particularly in an already vulnerable environment [39]. Consistent evidence documents an association between postpartum depression and less positive mother–infant interactions during play and care-taking routines. In addition, women who are depressed immediately postpartum are more likely to have been depressed during the pregnancy, presenting another potential exposure to the fetus [15,27]. Infants born to mothers with depression during pregnancy were reported to be more aroused, reactive, harder to console, had poorer self-regulation and sleep and less mature neuromotor development. [3,32,72]. Despite the growing evidence that depression is highly prevalent in women using cocaine and that both cocaine exposure and maternal depression is associated with adverse infant outcomes, the impact of postpartum depression on infant neurobehavioral development in cocaine-exposed samples has not been previously reported. Therefore, the purpose of this study was to examine the effects of postpartum depression on infant neurobehavior outcomes in infants prenatally exposed to cocaine compared to non-exposed infants. The infants were originally recruited for the Maternal Lifestyles Study (MLS) [39]. The MLS was developed in the early 1990s as an interagency collaborative effort involving the National Institute of Child Health and Human Development (NICHD); the National Institute on Drug Abuse (NIDA); the Administration on Children, Youth and Families; and the Center for Substance Abuse Treatment and is the largest prospective longitudinal study of acute neonatal events and long-term health and developmental outcomes associated with cocaine use during pregnancy. We hypothesized that the infants whose mothers were experiencing depression in the early postpartum would perform less opti-

mally on a structured examination of infant neurobehavior, and that infants in the maternal depression condition who were prenatally exposed to cocaine would have the poorest performance, particularly in self-regulation, arousal, and reactivity (more handling needed, more excitability) than infants who were not exposed to cocaine prenatally. 2. Methods 2.1. Study design The Maternal Lifestyles Study (MLS) was conducted at four NICHD Neonatal Research Network sites (Brown University, University of Miami, Wayne State University, and the University of Tennessee at Memphis). Mother–infant dyads were screened and recruited immediately after delivery (N = 11,811 consented to participate). A trained nurse or social worker conducted a semi-structured interview with the mother to determine past and current drug use and sociodemographic information. A physical examination of the infant was conducted, and the infant's meconium collected. Before mothers and infants were discharged from the hospital, their charts were abstracted to collect selected medical data. Procedures used to determine exposure status have been described previously [21,43]. Briefly, meconium samples were collected in the nursery and analyzed in a central laboratory. The study definition of “exposure” was maternal admission of cocaine or opiate use during this pregnancy based on the hospital interview or positive gas chromatography/mass spectroscopy (GC/MS) confirmation of cocaine metabolites. “Unexposed” was defined as denial of cocaine or opiate use during this pregnancy and a negative enzyme-multiplied immunoassay technique screen for cocaine and opiate metabolites. Once exposure status was confirmed by GC/MS analyses, the eligible participants were invited to come into the center for followup visit. 2.2. Participants The infant's first follow-up visit took place between 42 and 44 weeks post-menstrual age. An approximate time of one-month post delivery was determined to be a period that would allow for exposure status confirmation and a time when potential birth effects of labor and delivery stress and substance withdrawal are less likely to impact infant neurobehavior. Mothers were eligible to participate in the study if they were at least 18 years old, had no identified psychosis, were not institutionalized for mental retardation or mental illness, had no language barriers, and planned to stay in the catchment area. Their singleton infants were eligible if they were at least 501 g and less than 42 weeks gestational age at birth without chromosomal abnormalities, fatal illnesses or TORCH infection. All eligible exposed infants who attended the one-month visit were matched with an unexposed infant on race, gender, and gestational age [45]. At the one-month visit, 1388 mother–infant dyads (658 in the exposed group and 730 in the comparison group) were enrolled in the MLS longitudinal study. The analyses conducted for the present study were limited to those infants still residing with their biological mothers at the follow-up visit to control for a consistent physiological and care

A.L. Salisbury et al. / Neurotoxicology and Teratology 29 (2007) 331–340 Table 1 Number of participants in the depression groups by cocaine exposure Cocaineexposed

Depressed (DEP) Non-depressed (nonDep) Total in cocaine groups

Non-cocaineexposed

(COC)

(NonCOC)

N (%)

N (%)

76 309 385

(19.3) (80.7)

104 564 668

(15.5) (84.6)

Total in depression groups

180 873 1053

giving environment from prenatal to postnatal life (N = 1260). Only dyads without prenatal opiate exposure were included in these analyses to limit potential substance exposure confounds (N = 1165). 1053 mother–infant dyads met these criteria and accurately completed the semi-structured interview of psychiatric symptoms. The methods used to determine the final sample of 1053 are detailed in the maternal measures Section 2.3.1. 2.3. Measures The one-month visit included neurobehavioral, medical and physical status measures of the infant; social and demographic questionnaires; The Maternal Interview of Substance Use (MISU), and the Addiction Severity Index (ASI). 2.3.1. Maternal measures The MISU was developed for the MLS and is a structured interview that provides information about the frequency and quantity of substance use for each trimester during this pregnancy for cocaine, alcohol, marijuana, and nicotine. The ASI is a structured clinical interview that evaluates treatment outcomes of alcohol and drug problems [35,64]. The respondents are asked about current and lifetime substance use, psychiatric symptoms, diagnoses and hospitalizations. In addition, the interview elicits severity and duration for each psychiatric symptom present in the past 30 days to produce a summary score for psychiatric status [35,64]. The ASI was used to determine participants who “experienced serious depression” in the past 30 days and those that experienced “a lifetime history of depression”. Although this measure is not diagnostic, the ASI as an indicator of depression has been correlated with diagnoses of depression attained via semi-structured interview and has been a strong predictor of functional outcome in opiate and cocaine abusing cohorts [5,64]. In comparison to semi-structured interview diagnoses of depression, the ASI was found to separate depressed from nondepressed addicts with a sensitivity of .83 and a specificity of .55 [64]. The ASI has been used successfully as a screening tool for depression in pregnant and postpartum women [50]. The presence or absence of a reported serious depression in the past 30 days (lasting at least 2 weeks), coupled with the symptom severity scores on the ASI “psychological problems” subscale (0–5) was used to determine study depression groups (Table 1): Depressed group: experienced serious depression in the past 30 days AND psychiatric symptom score of 3 or more.

333

Non-depressed group: denied serious depression in the past 30 days AND psychiatric symptom score less than 3, regardless of psychiatric history. Participants that did not meet these criteria were eliminated from the analyses, as their psychiatric status could not be determined from their ASI data (N = 112). 2.3.2. Infant measures In addition to medical and demographic characteristics of the sample, the NICU Network Neurobehavioral Scale (NNNS) was used to examine infant neurobehavior at 42–44 weeks post-menstrual age. The NNNS was specifically designed for the MLS [41] and used in studies of intrauterine exposure to cocaine, opiates, and nicotine [22,31,37,42,40,54]. The NNNS is composed of three parts: neurological, behavioral, and stress/abstinence. The neurological component includes active and passive tone, primitive reflexes, and items that reflect the integrity of the central nervous system and maturity of the infant. The behavioral component is based on items from the Neonatal Behavioral Assessment Scale (NBAS) modified to be sensitive to putative drug effects [8]. The stress/abstinence component is a checklist of signs observed throughout the examination organized by organ system based primarily on the work of Finnegan that are indicative of stress, hyperstimulation, or nervous system instability [24]. The NNNS follows a relatively invariant sequence of administration that starts with a Table 2 Summary scores of the NICU Network Neurobehavioral Scale (NNNS) Attention

Indicates an infant's ability to attend and respond to auditory and visual stimulation; high scores on this scale show good response and sustained alertness. Handling Indicates the number and type of maneuvers necessary to keep the infant in the appropriate state to administer items; high scores indicate infants who need substantial input from the examiner in order to elicit attention and response to stimuli. Quality A measure of motor control including smoothness, maturity, movement modulation of movement of the arms and legs as well as startles and tremors; high scores indicate good quality of movement. SelfIndicates how the infant copes with the demands of the exam, regulation with higher scores indicating better regulation. Non-optimal The number of non-optimal reflex responses. refl. Stress/ The number of stress/abstinence signs displayed by the infant abstinence across five organ systems. Arousal Indicates the infant's overall level of arousal and associated motor activity during the exam; high scores indicate high arousal, activity, and fussing and crying during the exam. Hypertonia Indicates increased muscle tone in the arms, legs, and trunk; a high score describes an infant whose overall tone is consistently hypertonic. Hypotonia Indicates decreased muscle tone in the arms, legs, and trunk; a high score on this scale describes an infant who was consistently hypotonic. Asymmetrical A count of the number of times a reflex on one side of the body refl. is stronger or weaker than on the other side. Excitability A measure of high levels of motor, state and physiological reactivity; high scores indicate high levels of irritability even with attempts to soothe. Lethargy A measure of low levels of motor, state and physiological reactivity; high scores indicate extreme under-arousal despite the necessary handling during the exam.

334

A.L. Salisbury et al. / Neurotoxicology and Teratology 29 (2007) 331–340

(Depression: depressed/non-depressed) factorial ANOVA was conducted with each NNNS summary score variable. 2). An ANCOVA with the 2 × 2 design with covariates selected because they met the following statistical criteria: the variable was correlated with the independent variables (cocaine exposure or depression group) or with the NNNS subscales ( p b .05) and not correlated with other covariates (Pearson r b 0.70) [30,36,38,63]. The covariates that were used in the adjusted analysis included Index of Social Position Score from the Hollingshead scale of socioeconomic status (SES), birthweight, maternal age, research site, nicotine, marijuana, and alcohol use throughout the pregnancy. 3.) An ANCOVA design using a three cocaine exposure groups: no exposure, some exposure, and heavy exposure by the 2 depression groups was conducted to determine if depression effects would differ based on amount of cocaine exposure. 4.) An ANCOVA design comparing depression effects based on trimester of exposure, no exposure, first trimester only, and second or third trimester. Post-hoc analyses were conducted on the significant variables using Tukey HSD tests.

pre-examination observation, followed by the neurological and behavioral components. The individual NNNS items are aggregated into summary scales (see Table 2). The summary scores were formed from a conceptual and statistical approach and have psychometric properties with coefficient α ranging from 0.56 to 0.85 [46]. The habituation data were not used, as infants are required to be asleep for this part of the assessment and most infants were awake at the beginning of the examination. The actual sequence of administration and the means used by the examiner to maintain an infant's participation in the examination were recorded. All infants were examined between 42 and 44 weeks post-menstrual age by certified psychometrists at each site who were masked to infant exposure status. The certification process for the NNNS ensures initial reliability with certified trainers. A gold-standard NNNS trainer visited each site for the training and certification process to ensure reliability across sites. 2.4. Ethics The procedures followed for this study were approved by the Internal Review Board of each institution involved. All participants signed an IRB-approved consent form prior to participating in the study. A NIDA Certificate of Confidentiality was obtained by each site that assured confidentiality of information regarding the subjects' drug use. The certificate superseded the mandatory reporting of illegal substance use that was in effect in the Florida and Rhode Island sites. The certificate was explained to the mother during the recruitment and informed consent procedure, including the condition that the certificate did not exclude reporting evidence of child abuse or neglect.

3. Results 3.1. Prevalence of reported depression The number of participants excluded from the analyses due to lack of consistent ASI data was significantly greater in the cocaine-exposed (COC) group (N = 59; 13.29%) than the non cocaine-exposed (nonCOC) groups (N = 53; 7.35%) (χ2/Yates = 10.48, p b .002). The 112 participants excluded from further analyses were not different on demographic characteristics or infant outcome measures than the participants that were included in the remaining analyses. Based on the ASI, there was not a significant difference in the number of women meeting criteria for depression in the past 30 days in the COC group than the nonCOC group (χ2/Yates = 2.71, p = .09) (Table 2). Only 14 of the 172 depressed (DEP) mothers reported taking psychotropic medication in the past 30 days; 3 of them were cocaine users.

2.5. Statistics Analysis of variance (ANOVA) and Chi-square were used to determine group differences on infant and maternal characteristics. The neurobehavioral dependent measures were tested for main effects and interactions using a series of ANOVA with Type III sums of squares: 1). A 2 (Cocaine: exposed/non-exposed) × 2 Table 3 Characteristics of women in the depression groups by cocaine exposure COC

Age Marital status Parity

Race

SES Insurance

18–25 26–49 Married Single First born 2–3 children 4 or more Black White Other % low % Medicaid

NonCOC

Dep

NonDep

Dep

NonDep

N = 76

N = 309

N = 104

N = 564

N

%

N

%

18 58 8 68 6 30 40 62 10 4 22 67

23.68 76.32 10.53 89.47 7.89 39.47 52.63 81.58 13.16 5.26 28.95 88.16

57 252 35 274 31 128 150 253 34 22 86 276

18.45 81.55 11.33 88.67 10.03 41.42 48.54 81.88 11.00 7.12 27.83 89.32

Within group percentages presented. n.s.: p N .05, ⁎p b .05.

n.s. n.s. n.s.

n.s.

n.s. n.s.

N

%

N

%

67 37 18 86 27 44 33 88 12 4 21 89

66.67 29.89 17.31 82.69 25.96 42.31 31.73 84.62 11.54 3.85 29.81 85.58

284 280 154 410 175 269 119 439 84 41 103 434

49.35⁎ 42.62 27.30 72.70 31.08 47.78 21.14 77.84 14.89 7.27 18.26 76.95

n.s. n.s.

n.s.

n.s. n.s.

A.L. Salisbury et al. / Neurotoxicology and Teratology 29 (2007) 331–340

3.2. Maternal variables 3.2.1. Demographics The cocaine groups were originally matched on demographic variables. Therefore, we analyzed demographic variables using Chi-square for DEP differences within the COC groups. Table 3 presents the maternal characteristics of the DEP and non-depressed (nonDEP) groups in both the COC and nonCOC groups. Only one significant difference was found for DEP within COC groups: more women in the nonCOC/DEP group were less than 27 years of age (χ2 = 8.24, df = 2, p b .02) than women in the nonCOC/nonDEP group. 3.2.2. Maternal drug use during pregnancy The amount of cocaine use throughout pregnancy and in the first month postpartum for the DEP and nonDEP cocaine groups is shown in Fig. 1. Both groups decreased their cocaine use throughout the pregnancy and into the first month postpartum (F = 59.27, p b .0001). Although the DEP group reported consistently more cocaine use than the nonDEP, the difference was only marginally significant (F = 3.15, p b .07). Significantly more prenatal cocaine users reported using cocaine in the first 30 days postpartum if they were in the DEP group (26.3%) than those in the nonDEP group (14.3%), χ2 = 6.35, p b .02. Table 4 shows the mean amount of other reported drug use throughout the pregnancy. The COC and nonCOC groups differed in their use of other drugs. Women who used cocaine during the pregnancy also drank more alcohol (F(1, 1039) = 50.56, p b .0001), smoked more marijuana (F(1, 1039)= 8.22, p b .01), and smoked more cigarettes (F(1, 1039) = 103.83, p b .0001) during the pregnancy than those who did not use cocaine. There was a significant depression effect for nicotine use during pregnancy; women in the DEP group smoked more cigarettes throughout the pregnancy than the nonDEP (F(1, 1039) = 11.67, p b .001).

335

Table 4 Other substance use for women in the depression groups by cocaine exposure COC DEP

NonCOC NonDEP

DEP

NonDEP

(N = 74)

(N = 285)

(N = 98)

(N = 546)

M ± SE

M ± SE

M ± SE

M ± SE

Alcohol 0.65 ± .09 0.59 ± .05 0.22 ± .08 0.07 ± .03 ⁎⁎⁎COC (std. drinks/day) Marijuana 0.09 ± .04 0.17 ± .02 0.07 ± .03 0.03 ± .01 ⁎⁎COC ( joints/day) Nicotine 12.03 ± .96 9.17 ± .49 4.72 ± .83 2.57 ± .35 ⁎⁎⁎COC, ⁎⁎⁎DEP (cigs/day) ⁎⁎p b .01, ⁎⁎⁎p b .001. COC, cocaine main effect; DEP, depression main effect.

3.2.3. Maternal mental health treatment in the first 30 days postpartum There was a significant COC effect for the mean number of days women reported receiving outpatient mental health treatment in the first 30 days postpartum (Mean (SE)): 4.46 (0.33) COC/ nonDEP; 4.75 (0.67) COC/DEP; 0.05 (0.03) nonCOC/nonDEP; 0.07 (0.57) nonCOC/DEP, (F(1, 1043)= 88.85, p b .0001). More women in the COC groups were in mental health treatment versus nonCOC groups; 26.5% of women in the COC group received outpatient treatment in the postpartum period compared to only 2.3% of women in the nonCOC group. There was not a significant difference in psychological symptom severity score derived from the ASI between COC (mean (SE) = 0.834 (0.07)) and nonCOC (mean (SE) = 0.692 (.05)) groups, F(1,1049) = 2.68, n.s. 3.3. Infant variables 3.3.1. Demographics Table 5 presents the characteristics of the neonates at birth in the depressed (DEP) and non-depressed (nonDEP) groups by cocaine exposure. There were no significant cocaine effects on infant characteristics at birth. There was a significant interaction effect for the variables of birthweight (F(1,1043)= 6.93, p b .01), Table 5 Neonate characteristics in the depression groups by cocaine exposure COC

Fig. 1. Amount of cocaine exposure during pregnancy reported for the DEP and nonDEP groups. Maternal report of the mean number of days using cocaine per week. PP = first 30 days postpartum.

GAa Birthweight (kg) Length (cm) Head circ. (cm) Apgar 1 (median) Apgar 1 (median) Male (%)

NonCOC

DEP

NonDEP

DEP

NonDEP

(N = 76)

(N = 306)

(N = 104)

(N = 560)

Mean ± SE

Mean ± SE

Mean ± SE

Mean ± SE

36.46 ± 0.46 36.12 ± 0.23 35.61 ± 0.40 36.46 ± 0.17 2.66 ± 0.10 2.56 ± 0.05 2.47 ± 0.08 2.73 ± 0.04 ⁎⁎Int 46.91 ± 0.58 46.44 ± 0.29 45.70 ± 0.50 47.27 ± 0.21 ⁎Int 32.41 ± 0.35 31.96 ± 0.18 31.64 ± 0.31 32.34 ± 0.13 ⁎Int 7.70 ± 0.22 7.58 ± 0.11 7.36 ± 0.19 7.45 ± 0.10 8.75 ± 0.12 41.27

8.61 ± 0.06 49.46

⁎p b .05, ⁎⁎p b .001; abest obstetrical estimate. Int, interaction effect.

8.55 ± 0.10 52.87

8.53 ± 0.04 44.86

336

A.L. Salisbury et al. / Neurotoxicology and Teratology 29 (2007) 331–340

Fig. 2. NNNS scores for the DEP and nonDEP group in each COC use group. a. Self-regulation. b. Stress. c. Arousal. d. Excitability. ⁎p b .05, ⁎⁎p b .01; significant differences on post-hoc Tukey HSD tests.

length (F(1,1045) = 6.13, p b .02), and head circumference (F(1,1045) = 5.40, p b .03). The nonCOC/DEP infants had significantly lower birthweights (F(1,1045) = 6.50, p b .01) and were shorter in length than the nonCOC/nonDEP infants (F(1,1045) = 6.31, p b .01). There were no significant DEP differences. 3.3.2. Neurobehavioral scores on the NNNS There were no significant differences on any of the NNNS measures within the DEP groups for those taking psychotropic medications or receiving psychiatric treatment in the past 30 days. Therefore, psychotropic medication use prescribed by a physician and psychiatric treatment were not used in the following analyses. Infants of women with a lifetime history of depression and not currently depressed did not differ from the infants born to women that were never depressed. Therefore, women with a lifetime history of depression with the absence of a current depression were included in the nonDEP group. Analyses were conducted in two steps. First, ANCOVA analyses were run using the factors of DEP (yes/no) and COC (yes/ no) groups. All NNNS variables that were significant for a main

or interaction effect were further analyzed for the trimester of cocaine exposure and the amount of cocaine use reported. In the initial analyses there were significant main effects for depression after covariate adjustment for Self-Regulation (F(1, 996)= 4.08, p b .05), Excitability (F(1, 991) = 4.79, p b .03), and Hypotonia (F(1,986) = 4.05, p b .05) with infants in the DEP groups having lower self-regulation, higher excitability, and more hypotonia than infants in the nonDEP groups. There were no significant cocaine main effects after covariate adjustment. There were three significant interaction effects after covariate adjustment: Self-Regulation (F(1, 996) = 7.45, p b .012), Stress (F(1, 991)= 4.01, p b .05), and Arousal (F(1, 980) = 5.93, p b .02). The pattern of results was the same regardless of the trimester of cocaine use; only the nonCOC groups had a significant DEP effect. Therefore, analyses examining the amount of cocaine exposure included infants who were exposed to cocaine in any trimester. Secondary post-hoc analyses were conducted on the NNNS variables using 3 cocaine groups: none, some (b 1.5 days/week) and heavy (≥ 1.5 days/week) cocaine use. Women who denied cocaine use but whose infants showed positive cocaine

A.L. Salisbury et al. / Neurotoxicology and Teratology 29 (2007) 331–340

toxicology from meconium samples were eliminated from the secondary analyses. Fig. 2a–d presents the significant adjusted mean scores on the NNNS for the DEP groups in each of the three cocaine exposure groups. The pattern of results remained the same; only those infants without any prenatal cocaine exposure showed significant DEP differences on the NNNS. The nonCOC/DEP infants compared to nonCOC/nonDEP infants had significantly lower selfregulation (Fig. 2a), more stress signs (Fig. 2b), more arousal (Fig. 2c), and more excitability (Fig. 2d). Due to the large discrepancy in mental health treatment received between COC and nonCOC women, the NNNS analyses were repeated with only those women not receiving mental health treatment. Three interaction effects remained significant: self-regulation, stress, and arousal. 4. Discussion This study examined the effects of early postpartum maternal depression on infant neurobehavior at 1 month post-menstrual age in infants prenatally exposed to cocaine compared to nonexposed infants using the NICU Network Neurobehavioral Scale (NNNS). Using the ASI as a screening tool for depression, we were able to determine neurobehavioral differences of small to medium effect sizes (0.2 to 0.5), demonstrating adequate power for the intended analyses [14]. The prevalence of a serious depression as measured by the ASI in the immediate postpartum period in this sample was substantial in both the cocaine (COC) and non-cocaine (nonCOC) groups (19.3% and 15.5%, respectively). These rates of depression are within the range typically reported in samples with low socioeconomic status and in substance abusing samples and indicate a critical need to measure maternal mood symptoms in cocaine using samples [13,60]. We originally hypothesized that the infants whose mothers were experiencing depression in the early postpartum would perform less optimally on a structured examination of infant neurobehavior, and that infants in the maternal depression condition who were prenatally exposed to cocaine would have the poorest performance. Our hypothesis was only partially correct. We found that infants whose mothers were experiencing a postpartum depression (DEP) were having more difficulty with self-regulation and excitability and they were more hypotonic than infants of non-depressed women (nonDEP). However, we also found significant interaction effects that did not support our hypothesis that prenatal cocaine exposure would result in an exacerbation of the DEP effects. DEP effects were found on 4 of the 12 NNNS variables only for those infants who were not prenatally exposed to cocaine: infants in the DEP group had poorer self-regulation and more stress signs, excitability, and arousal than infants in the nonDEP group. Of note is that the DEP/COC group (double exposure) did not differ on any of the neurobehavioral measures from the nonDEP/nonCOC (control) group. The pattern of results was the same regardless of the amount or trimester of cocaine exposure. Infants in the nonCOC/DEP group also had the lowest birthweights, shortest birth-lengths, and smallest head circum-

337

ferences than the other three groups. Women in the nonCOC/ DEP group were also the youngest mothers. The significant neurobehavioral results persisted after controlling for the effects of maternal age, birthweight, polydrug use, SES and research site. Regression analyses were conducted to further test the relationship between maternal psychiatric symptom severity measured on the ASI and infant neurobehavior after controlling for the effect of infant birthweight. The results remained the same, namely that maternal symptom level was related to infant NNNS scores (self-regulation, stress, arousal excitation, and hypotonia) only for those in the nonCOC group. The results indicate that for infants not prenatally exposed to cocaine, maternal depression is associated with greater difficulty with state regulation and reactivity during the examination. These data are in agreement with prior studies that reported that infants of depressed mothers were more irritable, had more sleep problems, were more tense, and reacted more under the stress of testing conditions than infants of nondepressed women [23,29,52,53,68]. We were unable to determine if the infants were exposed to maternal depression in utero as the psychiatric problems section of the ASI interview did not ask specifically about depression during the pregnancy. A significant depression in the first 30 days after delivery is likely to indicate that the depression started prior to or during the pregnancy as antenatal depression is one of the most predictive factors for postpartum depression [4,15,27,33,57,58]. Therefore, we cannot be sure if the depression effects found in this study are due solely to postnatal maternal depression or if prenatal depression exposure contributes to the effects. Behavioral findings in prenatally cocaine-exposed infants have not always been consistent. Some studies did not find cocaine effects on newborns and young infants, while others reported difficulty in arousal regulation, including greater excitability, poor state regulation, more rapid changes in arousal with stimulation, increased arousal from sleep, and increased physiological lability [7,9,17,26,34,47,62]. Maternal depression was not reported in these papers. Based on our findings, inconsistencies in results may be related to other factors that were not measured or reported, such as maternal mood and depression. Only two studies looking at infant outcomes have reported maternal mood variables in cocaine using samples. Singer et al. (2002) found that maternal psychological distress predicted smaller neonatal head circumference after controlling for the effects of prenatal cocaine use, other drug use and confounding variables [67]. In 1993, Woods and colleagues reported higher maternal depressive scores in cocaine—using women and used the depression scores as a covariate when looking at the effects of prenatal cocaine exposure on infant behavior [70]. This study did not find any differences between cocaine exposed and unexposed infants. The results of this study are consistent with ours in that controlling for maternal depression led to the absence of cocaine main effects. Our results suggest that early postpartum maternal depressive symptoms have a significant effect on infant neurobehavior and that prenatal cocaine exposure might buffer or alter these

338

A.L. Salisbury et al. / Neurotoxicology and Teratology 29 (2007) 331–340

effects. One possible explanation for the difference in results in infants exposed to cocaine before birth is the effect of cocaine on developing monoamine systems. Evidence from rodent, rabbit and primate studies suggests that prenatal exposure to cocaine is associated with decreased dopaminergic activity and a resulting decrease in serotonin receptor density (5-HT1a) in the dorsal raphe nucleus [2,18]. The action of serotonin in the raphe nucleus exerts an inhibitory effect on the ascending serotonin system into the cortex; therefore a depletion of raphe serotonin results in an increase in serotonin input to the cortex [19,20,61]. It is possible that a cocaine induced abundance of serotonin in the cortex would contribute to a “buffer” of serotonin and other monoamines for infants that are exposed to maternal depression. Other potential mechanisms may be involved in an interaction effect of depression and cocaine, including other neurotransmitter systems, neuroendocrine alterations, and Hypothalamic–Pituitary–Adrenal Axis (HPA) responses. Glucocorticoids, the main end product of the HPA system, mediate monoaminergic activity particularly in the limbic areas of the brain and may be a primary site for further investigation of potential interactions of prenatal cocaine and depression exposure on offspring development. Other variables we considered include the exclusion of more women in the COC group than the nonCOC group due to inadequate data on the ASI, more days in mental health treatment for women in the COC group in the first 30 days postpartum, and other demographic and neonatal growth variables. More days of treatment for the women in the COC/ DEP group than the nonCOC/DEP group could influence newborn behavior if treatment was associated with greater symptom reduction and improvement in mother–infant interactions. However, there was not a significant difference in COC versus nonCOC for meeting depression criteria in the first 30 days postpartum. The interaction results remained significant when reanalyzing the data without participants in outpatient treatment. There was also no significant difference for number of days using cocaine in the postpartum period between those women receiving outpatient mental health treatment and those who were not. There was limited power in the DEP groups to look at associations with other variables that might also contribute to the results obtained, including maternal anxiety, home environment, time between pregnancies, and general health conditions of the infant at time of testing. In conclusion, these data provide evidence of an interaction between maternal depression and prenatal cocaine exposure on infant neurobehavioral outcomes. Cocaine-exposed infants did not differ from unexposed infants on neurobehavioral scores in depressed groups. Depression effects were only found in infants not exposed to cocaine during gestation. These results suggest a possible buffering effect of cocaine on the effects of maternal depression on infants. Despite the limitations discussed, these findings suggest that past research findings as well as future research on the effects of prenatal substance exposure would benefit from consideration and measurement of maternal mood.

References [1] Results from the 2002 National Survey on Drug Use and Health: National Findings in (DHHS Publication No. SMA 03-3836, NHSDA Series H-22), Office of Applied Studies, Substance Abuse and Mental Health Services Administration, Rockville, MD, 2003. [2] H.M. Akbari, H.K. Kramer, P.M. Whitaker-Azmitia, L.P. Spear, E.C. Azmitia, Prenatal cocaine exposure disrupts the development of the serotonergic system, Brain Res. 572 (1992) 57–63. [3] K.L. Armstrong, H. O'Donnell, R. McCallum, M. Dadds, Childhood sleep problems: association with prenatal factors and maternal distress/ depression, J. Paediatr. Child Health 34 (1998) 263–266. [4] A.K. Atkinson, A.U. Rickel, Postpartum depression in primiparous parents, J. Abnorm. Psychol. 93 (1984) 115–119. [5] H.W. Batson, L.S. Brown Jr., A.R. Zaballero, A. Chu, A.I. Alterman, Conflicting measurements of depression in a substance abuse population, J. Subst. Abuse 5 (1993) 93–100. [6] C.R. Bauer, S. Shankaran, H.S. Bada, B. Lester, L.L. Wright, H. KrauseSteinrauf, V.L. Smeriglio, L.P. Finnegan, P.L. Maza, J. Verter, The Maternal Lifestyle Study: drug exposure during pregnancy and short-term maternal outcomes, Am. J. Obstet. Gynecol. 186 (2002) 487–495. [7] M. Bendersky, M. Lewis, Arousal modulation in cocaine-exposed infants, Dev. Psychobiol. 34 (1998) 555–564. [8] T.B. Brazelton, Neonatal Behavioral Assessment Scale, Lippincott, Philadelphia, PA, 1984. [9] J. Brown, A. Bakeman, C.D. Coles, W.A. Sexson, A.S. Demi, Maternal drug use during pregnancy: are preterms and full-terms affected differently? Dev. Psychol. 34 (1998) 540–554. [10] S.B. Campbell, J.F. Cohn, Prevalence and correlates of postpartum depression in first-time mothers, J. Abnorm. Psychol. 100 (1991) 594–599. [11] I.J. Chasnoff, W.J. Burns, S.H. Schnoll, K.A. Burns, Cocaine use in pregnancy, N. Engl. J. Med. 313 (1985) 666–669. [12] I.J. Chasnoff, K.A. Burns, W.J. Burns, Cocaine use in pregnancy: perinatal morbidity and mortality, Neurotoxicol. Teratol. 9 (1987) 291–293. [13] L.H. Chaudron, H.J. Kitzman, K.L. Peifer, S. Morrow, L.M. Perez, M.C. Newman, Prevalence of maternal depressive symptoms in low-income Hispanic women, J. Clin. Psychiatry 66 (2005) 418–423. [14] J. Cohen, Statistical Power Analysis for the Behavioral Sciences, Second ed., Lawrence Erlbaum Associates, Hillsdale, New Jersey, 1988, p. 567. [15] D. Da Costa, J. Larouche, M. Dritsa, W. Brender, Psychosocial correlates of prepartum and postpartum depressed mood, J. Affect. Disord. 59 (2000) 31–40. [16] H.D. Desai, M.W. Jann, Major depression in women: a review of the literature, J. Am. Pharm. Assoc. 40 (2000) 525–537. [17] J.A. DiPietro, P.E. Suess, J.S. Wheeler, P.H. Smouse, D.B. Newlin, Reactivity and regulation in cocaine-exposed neonates, Infant Behav. Dev. 18 (1995) 407–414. [18] D.L. Dow-Edwards, Cocaine effects on fetal development: a comparison of clinical and animal research findings, Neurotoxicol. Teratol. 13 (1991) 347–352. [19] D.L. Dow-Edwards, Modification of acoustic startle reactivity by cocaine administration during the postnatal period: comparison with a specific serotonin reuptake inhibitor, Neurotoxicol. Teratol. 18 (1996) 289–296. [20] D.L. Dow-Edwards, Preweaning cocaine administration alters the adult response to quipazine: comparison with fluoxetine, Neurotoxicol. Teratol. 20 (1998) 133–142. [21] M.A. ElSohly, D.F. Stanford, T.P. Murphy, B.M. Lester, L.L. Wright, V.L. Smeriglio, J. Verter, C.R. Bauer, S. Shankaran, H.S. Bada, H.C. Walls, Immunoassay and GC–MS procedures for the analysis of drugs of abuse in meconium, J. Anal. Toxicol. 23 (1999) 436–445. [22] A. Ferguson, M.G. Coyle, L. LaGasse, E. Liu, B. Lester, Neurobehavioral effects of treatment for opiate withdrawal, Pediatr. Res. 49 (2001) 18A. [23] T. Field, Maternal depression effects on infants and early interventions, Prev. Med. 27 (1998) 200–203. [24] L.P. Finnegan, R.E. Kron, J.F. Connaughton, J.P. Emich, Assessment and treatment of abstinence in the infant of the drug-dependent mother, Int. J. Clin. Pharmacol. Biopharm. 12 (1975) 19–32.

A.L. Salisbury et al. / Neurotoxicology and Teratology 29 (2007) 331–340 [25] R. Fulroth, B. Phillips, D.J. Durand, Perinatal outcome of infants exposed to cocaine and/or heroin in utero, Am. J. Dis. Child 143 (1989) 905–910. [26] J.L. Gingras, J. Feibel, B. Dalley, A. Muelenaer, Maternal polydrug use including cocaine and postnatal infant sleep architecture: preliminary observations and implications for respiratory control and behavior, Early Hum. Dev. 43 (1995) 197–204. [27] I.H. Gotlib, V.E. Whiffen, J.H. Mount, K. Milne, N.I. Cordy, Prevalence rates and demographic characteristics associated with depression in pregnancy and the postpartum, J. Consult. Clin. Psychol. 57 (1989) 269–274. [28] D.S. Hasin, M. Hatzenbueler, S. Smith, B.F. Grant, Co-occurring DSM-IV drug abuse in DSM-IV drug dependence: results from the National Epidemiologic Survey on Alcohol and Related Conditions, Drug Alcohol Depend. 80 (2005) 117–123. [29] H. Hiscock, M. Wake, Infant sleep problems and postnatal depression: a community-based study, Pediatrics 107 (2001) 1317–1322. [30] J. Jacobson, S. Jacobson, Methodological issues in human behavioral teratology, in: C. Rovee-Collier, L.P. Lipsitt (Eds.), Advances in Infancy Research, Plenum Publishing, New York, NY, 1990, pp. 111–148. [31] R.E. Johnson, H.E. Jones, D.R. Jasinski, D.S. Svikis, N.A. Haug, L.M. Jansson, W.B. Kissin, G. Alpan, M.E. Lantz, E.J. Cone, D.G. Wilkins, A.S. Golden, G.R. Huggins, B.M. Lester, Buprenorphine treatment of pregnant opioid-dependent women: maternal and neonatal outcomes, Drug Alcohol Depend. 63 (2001) 97–103. [32] N.A. Jones, T. Field, N. Fox, M. Davalos, B. Lundy, S. GHart, Newborns of mothers with depressive symptoms are physiologically less developed, Infant Behav. Dev. 21 (1998) 537–541. [33] A. Josefsson, G. Berg, C. Nordin, G. Sydsjo, Prevalence of depressive symptoms in late pregnancy and postpartum, Acta Obstet. Gynecol. Scand. 80 (2001) 251–255. [34] B.Z. Karmel, J.M. Gardner, Prenatal cocaine exposure effects on arousalmodulated attention during the neonatal period, Dev. Psychobiol. 29 (1996) 463–480. [35] T.R. Kosten, B.J. Rounsaville, H.D. Kleber, Concurrent validity of the addiction severity index, J. Nerv. Ment. Dis. 171 (1983) 606–610. [36] L.L. LaGasse, R. Seifer, B.M. Lester, Interpreting research on prenatal substance exposure in the context of multiple confounding factors, Clin. Perinatol. 26 (1999) 39–54 (vi.). [37] K.L. Law, L.R. Stroud, L.L. LaGasse, R. Niaura, J. Liu, B.M. Lester, Smoking during pregnancy and newborn neurobehavior, Pediatrics 111 (2003) 1318–1323. [38] D.A. Leon, Failed or misleading adjustment for confounding, Lancet 342 (1993) 479–481. [39] B.M. Lester, The Maternal Lifestyles Study, Ann. N.Y. Acad. Sci. 846 (1998) 296–305. [40] B. Lester, E. Tronick, The effects of prenatal cocaine exposure and child outcome: lessons from the past, Inf. Ment. Health J. 15 (1994) 107–120. [41] B.M. Lester, E.Z. Tronick, History and description of the Neonatal Intensive Care Unit Network Neurobehavioral Scale, Pediatrics 113 (2004) 634–640. [42] B. Lester, T. EZ, M.L., Neurodevelopmental consortium, the NICHD Neonatal research network. A neurodevelopmental follow-up battery for substance exposed infants, Pediatr. Res. 35 (1994) 23A. [43] B.M. Lester, M. ElSohly, L.L. Wright, V.L. Smeriglio, J. Verter, C.R. Bauer, S. Shankaran, H.S. Bada, H.H. Walls, M.A. Huestis, L.P. Finnegan, P.L. Maza, The Maternal Lifestyle Study: drug use by meconium toxicology and maternal self-report, Pediatrics 107 (2001) 309–317. [44] B.M. Lester, E.Z. Tronick, L. LaGasse, R. Seifer, C.R. Bauer, S. Shankaran, H.S. Bada, L.L. Wright, V.L. Smeriglio, J. Lu, L.P. Finnegan, P.L. Maza, The maternal lifestyle study: effects of substance exposure during pregnancy on neurodevelopmental outcome in 1-month-old infants, Pediatrics 110 (2002) 1182–1192. [45] B.M. Lester, L. Lagasse, R. Seifer, E.Z. Tronick, C.R. Bauer, S. Shankaran, H.S. Bada, L.L. Wright, V.L. Smeriglio, J. Liu, L.P. Finnegan, P.L. Maza, The Maternal Lifestyle Study (MLS): effects of prenatal cocaine and/or opiate exposure on auditory brain response at one month, J. Pediatr. 142 (2003) 279–285.

339

[46] B.M. Lester, E.Z. Tronick, L. LaGasse, R. Seifer, C.R. Bauer, S. Shankaran, H.S. Bada, L.L. Wright, V.L. Smeriglio, J. Lu, Summary statistics of neonatal intensive care unit network neurobehavioral scale scores from the maternal lifestyle study: a quasinormative sample, Pediatrics 113 (2004) 668–775. [47] L.C. Mayes, M.H. Bornstein, K. Chawarska, C.M. Haynes, A.H. Granger, Impaired regulation of arousal in three-month-old infants exposed prenatally to cocaine and other drugs, Dev. Psychopathol. 8 (1996) 29–42. [48] L.C. Mayes, Developing brain and in utero cocaine exposure: effects on neural ontogeny, Dev. Psychopathol. 11 (1999) 685–714. [49] L.C. Mayes, A behavioral teratogenic model of the impact of prenatal cocaine exposure on arousal regulatory systems, Neurotox. Teratol. 24 (2002) 385–395. [50] A.T. McLellan, H. Kushner, D. Metzger, R. Peters, I. Smith, G. Grissom, H. Pettinati, M. Argeriou, The fifth edition of the Addiction Severity Index, J. Subst. Abuse Treat. 9 (1992) 199–213. [51] C.E. Morrow, E.S. Bandstra, J.C. Anthony, A.Y. Ofir, L. Xue, M.L. Reyes, Influence of prenatal cocaine exposure on full-term infant neurobehavioral functioning, Neurotox. Teratol. 23 (2001) 533–544. [52] L. Murray, The impact of postnatal depression on infant development, J. Child Psychol. Psychiatry 33 (1992) 543–561. [53] L. Murray, A. Fiori-Cowley, R. Hooper, P. Cooper, The impact of postnatal depression and associated adversity on early mother–infant interactions and later infant outcome, Child Dev. 67 (1996) 2512–2526. [54] B. Napiorkowski, B.M. Lester, M.C. Freier, S. Brunner, L. Dietz, A. Nadra, W. Oh, Effects of in utero substance exposure on infant neurobehavior, Pediatrics 98 (1996) 71–75. [55] D.R. Neuspiel, S.C. Hamel, E. Hochberg, J. Greene, D. Campbell, Maternal cocaine use and infant behavior, Neurotox. Teratol. 13 (1991) 229–233. [56] M. O'Hara, D.J. Neunaber, E.M. Zekoski, Prospective study of postpartum depression: prevalence, course, and predictive factors, J. Abnorm. Psychol. 93 (1984) 158–171. [57] M.W. O'Hara, E.M. Zekoski, L.H. Philipps, E.J. Wright, Controlled prospective study of postpartum mood disorders: comparison of childbearing and nonchildbearing women, J. Abnorm. Psychol. 99 (1990) 3–15. [58] M.W. O'Hara, J.A. Schlechte, D.A. Lewis, E.J. Wright, Prospective study of postpartum blues. Biologic and psychosocial factors, Arch. Gen. Psychiatry 48 (1991) 801–806. [59] A.S. Oro, S.D. Dixon, Perinatal cocaine and methamphetamine exposure: maternal and neonatal correlates, J. Pediatr. 111 (1987) 571–578. [60] M. Pajulo, E. Savonlahti, A. Sourander, H. Helenius, J. Piha, Antenatal depression, substance dependency and social support, J. Affect. Disord. 65 (2001) 9–17. [61] N.J. Penington, J.S. Kelly, A.P. Fox, A study of the mechanism of Ca2+ current inhibition produced by serotonin in rat dorsal raphe neurons, J. Neurosci. 11 (1991) 3594–3609. [62] M.G. Regalado, V.L. Schechtman, A.P. Del Angel, X.D. Bean, Sleep disorganization in cocaine-exposed neonates, Infant Behav. Dev. 18 (1995) 319–327. [63] G. Richardson, N. Day, Studies of prenatal cocaine exposure: assessing the influence of extraneous variables, J. Drug Issues 29 (1999) 225–236. [64] B.J. Rounsaville, T.R. Kosten, M.M. Weissman, H.D. Kleber, Prognostic significance of psychopathology in treated opiate addicts. A 2.5-year follow-up study, Arch. Gen. Psychiatry 43 (1986) 739–745. [65] F.A. Scafidi, T.M. Field, A. Wheeden, S. Schanberg, C. Kuhn, R. Symanski, E. Zimmerman, E.S. Bandstra, Cocaine-exposed preterm neonates show behavioral and hormonal differences, Pediatrics 97 (1996) 851–855. [66] L. Singer, R. Arendt, S. Minnes, Neurodevelopmental effects of cocaine, Clin. Perinatol. 20 (1993) 245–262. [67] L.T. Singer, A. Salvator, R. Arendt, S. Minnes, K. Farkas, R. Kliegman, Effects of cocaine/polydrug exposure and maternal psychological distress on infant birth outcomes, Neurotoxicol. Teratol. 24 (2002) 127–135. [68] V.E. Whiffen, I.H. Gotlib, Infants of postpartum depressed mothers: temperament and cognitive status, J. Abnorm. Psychol. 98 (1989) 274–279.

340

A.L. Salisbury et al. / Neurotoxicology and Teratology 29 (2007) 331–340

[69] K.L. Wisner, K.S. Peindl, B.H. Hanusa, Psychiatric episodes in women with young children, J. Affect. Disord. 34 (1995) 1–11. [70] N.S. Woods, F.D. Eyler, M. Behnke, M. Conlon, Cocaine use during pregnancy: maternal depressive symptoms and infant neurobehavior over the first month, Infant Behav. Dev. 16 (1993) 83–98. [71] B. Zuckerman, D.A. Frank, R. Hingson, H. Amaro, S.M. Levenson, H. Kayne, S. Parker, R. Vinci, K. Aboagye, L.E. Fried, et al., Effects of

maternal marijuana and cocaine use on fetal growth, N. Engl. J. Med. 320 (1989) 762–768. [72] B. Zuckerman, H. Bauchner, S. Parker, H. Cabral, Maternal depressive symptoms during pregnancy, and newborn irritability, J. Dev. Behav. Pediatr. 11 (1990) 190–194.