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. Author manuscript; available in PMC: 2020 May 11.
Published in final edited form as: Dev Psychobiol. 2019 Jul 24;62(1):116–122. doi: 10.1002/dev.21896

Maternal Hair Cortisol Levels as a Novel Predictor of Neonatal Abstinence Syndrome Severity: A Pilot Feasibility Study

Elisha M Wachman 1,2, Richard G Hunter 3, Hira Shrestha 1, Hannah E Lapp 3, Jerrold Meyer 4, Crystal D Alvarez 5, Edward Tronick 3,6
PMCID: PMC7212239  NIHMSID: NIHMS1584819  PMID: 31342518

Abstract

Neonatal Abstinence Syndrome (NAS) after in-utero opioid exposure remains a poorly understood condition with multiple factors contributing to severity. Exposure to maternal stress may be one contributing factor. Hair cortisol measurement represents a novel technique for assessing prenatal stress. In this pilot study, the association between maternal hair cortisol levels and NAS severity was examined in 70 postpartum women with opioid use disorder within 72 hours of delivery. Infants were monitored for NAS and treated according to institutional protocol. Forty-four (63%) of the infants were pharmacologically treated for NAS, with a mean length of hospital stay (LOS) for all infants of 14.2 (SD 9.0) days. The mean cortisol level in the mothers was 131.8 pg/mg (SD 124.7). In bivariate analysis, higher maternal hair cortisol levels were associated with shorter infant LOS (R=−0.26, p=0.03) and fewer infant opioid treatment days (R=−0.28, p=0.02). Results were no longer statistically significant in regression models after adjusting for maternal opioid and smoking. In conclusion, we demonstrated the feasibility of hair cortisol assaying within the first few days after delivery in mothers with opioid use disorder as a novel marker for NAS. The findings suggest that maternal stress may impact the severity of infant opioid withdrawal.

Keywords: Hair cortisol, Neonatal Abstinence Syndrome, NAS, Opioids, Neonatal Opioid Withdrawal, Stress

INTRODUCTION:

Infants exposed in-utero to opioids are at risk of Neonatal Abstinence Syndrome (NAS), otherwise known as Neonatal Opioid Withdrawal Syndrome (NOWS), an opioid withdrawal syndrome characterized by alterations in the central nervous, gastrointestinal, and respiratory systems after the cessation of the chronic in-utero exposure (Wachman, 2018). NAS has increased 5-fold in the United States between 2000 and 2012, affecting 5 per 1000 live birth in 2012, with higher rates up to 20 per 1000 reported over the past 5 years (Milliren, 2018; Patrick, 2015). NAS is often associated with prolonged hospitalizations and extensive medication treatment, given in approximately 50–80% of cases, with an average length of hospital stay (LOS) for pharmacologically treated infants of 23.0 days (Patrick, 2015).

NAS is a highly variable disorder, with current inability to accurately predict which infants will receive pharmacologic treatment and which will have the most severe phenotype treated with a multi-drug regimen. Some factors known to be associated with differences in NAS severity include maternal opioid medication, co-exposure to illicit drugs, nicotine, and psychiatric medications, infant sex, breastfeeding, rooming-in, parental presence, as well as genetic and epigenetic factors (Charles, 2017; Jones, 2010; MacMillan, 2018; Seligman, 2008; Wachman, 2013; Wachman 2014; Wachman 2018).

Exposure to prenatal maternal stress may also alter infant response to opioid withdrawal and may contribute to severity of NAS. Maternal stress is defined as life experiences that exceed the functional capacity of the physiologic and behavioral regulatory coping systems (Davis, 2011). Pregnant women with opioid use disorder (OUD) have very high rates of lifetime trauma, with 70–80% reporting histories of either physical abuse, sexual abuse, or exposure to trauma and violence (Martin, 2003; McHugo, 2005; Najavitis 1997). Co-occurring psychiatric disorders among pregnant women with OUD are highly prevalent (25–73%), with women often having more than one co-morbid psychiatric diagnosis including depression, anxiety, and posttraumatic stress syndrome (Arnaudo, 2017; Fitzsimons, 2007). Beyond mental and behavioral health issues, this population also suffers from extreme housing and food insecurity with over 60% reporting homelessness and food insecurity, and 80% who have public insurance as one indicator of poverty (Patrick, 2015; Rose-Jacobs, 2018).

Chronic stress is known to influence the hypothalamic pituitary adrenal (HPA) axis and can alter cortisol levels (Schreier, 2015). Acutely, stress leads to high levels of cortisol, while over time, individuals who are chronically stressed can have a blunting of their cortisol response (Miller, 2007). In addition, it is well established that chronic opioid use can profoundly alter stress-responsive systems, including suppression of the HPA axis (Zhou, 2010; Zhou, 2016).

Hair cortisol is a novel marker for exposure to chronic stress, thought to reflect the past 3 months of cortisol exposure when assessed in a 3-cm hair sample (D’Anna-Hernandez, 2011; Hoffman, 2013; Kalra, 2007; Karlen, 2013; Liu, 2016; Schreier, 2015). Hair cortisol levels have been shown to correlate with early life adversity and stress-related psychiatric conditions, therefore making it a useful biomarker for chronic maternal stress (D’Anna-Hernandez, 2011; Kirschbaum, 2009; Schreier, 2015).

In addition, exposure to maternal stress may influence infant cortisol levels and stress reactivity and may alter infant neurobehavior which is relevant to the acute stress of neonatal opioid withdrawal (Liu, 2016). It has previously been demonstrated that exposure to maternal stress during the pregnancy can alter fetal neurobehavior such as heart rate and motor responses, often with a blunted response to higher levels of maternal stress (DiPietro, 2002; DiPietro, 2003).

This pilot study aimed to evaluate the association between maternal hair cortisol levels as a biomarker of chronic stress with the severity of NAS in opioid-exposed mother-infant dyads for the first time. We hypothesize that higher maternal hair cortisol levels will be associated with worse NAS inpatient outcomes.

METHODS:

Mother-infant dyads were enrolled between January 2016 and April 2017, anytime between the second trimester of pregnancy and before discharge of their infant from the hospitalization after birth. Eligibility criteria were that the mother was on prescribed methadone or buprenorphine for the treatment of OUD in pregnancy receiving prenatal care at Boston Medical Center (BMC), singleton pregnancy, English speaking, absence of known major congenital or genetic condition, and gestational age at birth of 35 weeks or greater. Women with severe psychiatric comorbidities or social concerns per provider evaluation, incarcerated women, and infants not in maternal custody at the time of approach for consent were excluded. Mothers provided written informed consent on behalf of themselves and their infants. This study was approved by the Boston University Medical Campus Institutional Review Board.

All women were recruited from BMC, a tertiary care urban academic medical center with a specialized prenatal program called Project RESPECT for women with OUD. BMC practices a rooming-in model of care for these mother-infant dyads where infants remain with their mothers on the postpartum unit until maternal discharge. The infant is transferred to the inpatient pediatric unit for continued monitoring and NAS treatment where the mother can continue to room-in.

All infants were monitored in the hospital for a minimum of 5–7 days for signs of NAS that might require pharmacologic treatment. During the study period, the original Finnegan scale was used to assess infants every 4 hours (Finnegan, 1992). The criteria for initiating and escalating medication were 2 scores ≥8 or 1 score ≥12. Neonatal morphine solution was used as the first-line medication from January 2016 – June 2016, and methadone from July 2016 – April 2017. Opioids were weaned by 10% of the maximum dose daily down to 20% of the maximum dose, and then infants were monitored for 24–48 hours off medication prior to discharge home. Second line adjunctive medication treatment, for infants who reached maximum doses of morphine or methadone with persistent Finnegan scores ≥8, consisted of phenobarbital or clonidine depending on prenatal exposures. Clonidine was weaned as an inpatient after weaning off the opioid, while phenobarbital was weaned as an outpatient. Mothers were encouraged to breastfeed if they were enrolled in an addiction recovery program, had attended prenatal care visits, and no illicit / un-prescribed drug use close to the time of delivery assessed by urine toxicology testing.

Mothers had a hair sample collected during the delivery hospitalization within 72 hours of delivery. Approximately 20 strands of hair were cut at the level of the scalp from two or three locations and then measured and cut to 3cm at the distal end and placed in a plastic vial. The samples were stored at room temperature and then shipped in batches to the University of Massachusetts Boston or the University of Massachusetts Amherst for cortisol measurements. Hair cortisol levels were obtained using the established protocol as developed by Meyer et al. (Meyer, 2012; Meyer, 2014). Briefly, hair was washed with isopropanol then dried. It was then ground in a bead mill and suspended in methanol to extract cortisol. Supernatants where then dried in a vacuum evaporator prior to resuspension in assay buffer for ELISA. Cortisol levels were determined using Enzo Cortisol Elisa kits (Enzo Life Sciences Inc., Farmingdale NY). Cortisol levels were reported in pg/mg levels.

Prenatal characteristics were collected on all mothers via chart review including demographics, type of OUD treatment at the time of delivery (methadone vs. buprenorphine), psychiatric comorbidities and medications, illicit drug use in the third trimester (via urine toxicology results), and pregnancy outcomes. For the infants, birth parameters and complications, other diagnoses, and breastfeeding (defined as any breast milk consumed by the infant during the hospitalization) were collected. Outcome measures for NAS included: 1) any infant medication treatment (yes/no), 2) type of NAS pharmacotherapy (morphine or methadone), 3) any adjunctive medication treatment for NAS (yes/no), 4) length of hospital stay (LOS), and 5) total opioid treatment days. Data was hand abstracted from the medical record and entered into an electronic database. Abstracted data was routinely monitored for accuracy and cross-checked with an additional database used for quality improvement purposes at our institution.

Baseline demographics and hair cortisol levels were summarized for the mother-infant dyads using descriptive statistics. Cortisol levels were log transformed. NAS outcomes were then evaluated for association with maternal hair cortisol levels using independent sample t-tests and chi square test of association. We then looked for associations between maternal demographics and cortisol levels. Potential co-variates associated with NAS outcomes included in the multivariable linear and logistic regression models were chosen based on established prior literature showing associations with these variables and differences in NAS outcomes. Only co-variates that reached an alpha level of 0.05 were used for inclusion in the final multivariable models. SAS version 9.4 was used for all analyses.

RESULTS:

During the study period, there were 133 pregnant women with OUD who were assessed for eligibility. Eighty-seven were eligible, of which seven were missed for consent and 10 declined participation. Of the 63 who were not eligible, reasons included prematurity (n=12), no maintenance opioid medication or naltrexone for the treatment of OUD (n=6), severe social concerns or current incarceration (n=17), delivery at another hospital (n=5), and twin gestation (n=6). The final cohort included 70 women (87.5% of those approached for consent) who participated in the study and had hair collection after birth. The mean cortisol level for the mothers was 131.8 (SD 124.7) pg/mg.

The demographics of the 70 mother-infant dyads are shown in Table 1. Fifty percent of the infants were exposed to methadone and 50% to buprenorphine. Sixty-three percent of the infants were pharmacologically treated for NAS, with 12.9% were treated with two medications, and an average LOS for all infants of 14.2 days (SD 9.0).

Table 1:

Demographics of 70 mother-infant dyads

Demographic Mean (SD) or N(%)
Maternal age (years) 29.6 (4.8)
Infant gestational age (weeks) 38.7 (1.6)
Infant birth weight (grams) 3076 (659)
C-section delivery 32 (45.7%)
Infant sex = male 35 (50.0%)
Maternal opioid agonist treatment
 Methadone
 Buprenorphine
34 (49.3%)
35 (50.7%)
Dose of agonist at delivery (mg per day)
 Methadone
 Buprenorphine
99.4 (40.8)
12.9 (6.2)
Breastfed to any extent 43 (61.4%)
Co-exposures in third trimester
 Nicotine smoking
 Selective serotonin reuptake inhibitors
 Benzodiazepines
 Illicit drugs
52 (78.8%)
11 (16.2%)
15 (21.7%)
32 (46.4%)
White Non-Hispanic 59 (84.3%)
NICU admission 11 (15.7%)
NAS Outcomes
Pharmacologically treated
 Morphine
 Methadone		 44 (62.9%)
27 (61.4%)
17 (38.6%)
Adjunctive pharmacologic agent† 9 (12.9%)
Length of hospital stay (days) 14.2 (9.0)
Opioid treatment days 8.6 (8.2)
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Abbreviations: NAS = neonatal abstinence syndrome; mg = milligrams

†

Phenobarbital or clonidine in addition to morphine or methadone

In bivariate analysis, higher maternal hair cortisol levels (log transformed) were associated with shorter LOS (R = −0.26, p=0.03), and fewer days of infant opioid treatment (R = −0.28, p=0.02).(Table 2, Figure 1) Associations between maternal hair cortisol levels with infant medication treatment and need for adjunctive medications were not statistically significant. Hair cortisol levels in the mother were not associated with demographic factors, including maternal opioid medication (methadone versus buprenorphine) or dose at the time of delivery, breastfeeding, psychiatric conditions, psychiatric medications, nicotine use, or illicit drug use.

Table 2:

Cortisol Associations Log of Maternal Hair cortisol levels and NAS outcomes

NAS Outcome Maternal Cortisol Levels – log transformed in pg/mg
Mean (SD) or Correlation Coefficient		 P-Value
Pharmacologic Treatment
 Yes (N=44)
 No (N=26)
4.33 (1.21)
4.68 (0.69)
0.14
Adjunctive Treatment
 Yes (N=9)
 No (N=61)
3.82 (1.23)
4.65 (1.01)
0.05
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Figure 1:

Figure 1:

Figure 1:

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Higher maternal hair cortisol measurements were associated with shorter infant LOS (R=−0.26, p=0.03)(Fig. 1a) and fewer infant opioid treatment days (R=−0.28, p=0.02) (Fig. 1b).

Figure 1a. Maternal cortisol levels (log transformed) and infant length of hospital stay

Figure 1b. Maternal hair cortisol levels (log transformed) and infant opioid treatment days

In co-variate analysis, maternal methadone (vs buprenorphine) treatment was associated with longer infant LOS [16.4 (SD 10.3) vs 13.0 (SD 8.1) days, p=0.03]; nicotine smoking was associated with more infant opioid treatment days (17.1 (SD 8.5) vs 8.9 (SD 2.1) days, p=0.003); and infant treatment with methadone vs morphine was associated with fewer opioid treatment days [11.3 (SD 3.2) vs 15.9 (SD 3.2) days, p=0.01]. There were no statistically significant associations with dose of maternal opioid medication, breastfeeding, illicit drug exposure, selective serotonin reuptake inhibitors, benzodiazepines, or male sex in this small cohort with NAS outcomes. In linear regression models that adjusted for maternal opioid (methadone versus buprenorphine) and smoking (any amount of nicotine smoking in the third trimester per maternal report), the association between the log transformed maternal hair cortisol levels and LOS (β = −3.15, 95% CI −6.95, 0.66), and opioid treatment days (β = −2.09, 95% CI −5.48, 1.30) was no longer statistically significant.

DISCUSSION:

In this pilot study, hair cortisol levels in postpartum women with OUD collected shortly after delivery were associated with difference in infant NAS outcomes, including the amount of opioid treatment received and hospital LOS, though associations no longer met statistical significance after covariate adjustment. In addition, feasibility of collection of maternal hair samples from opioid-dependent women in the perinatal period was demonstrated.

A strength of this study is that it is the first to our knowledge to measure hair cortisol levels in postpartum women with OUD and to link this biomarker of maternal stress with the severity of infant opioid withdrawal. Hair cortisol levels in our opioid-exposed dyads were significantly higher than the reported mean of 13.1 pg/mg in non-opioid dependent postpartum women (Hoffman, 2013). This is likely related to the high rates of lifetime trauma in mothers with OUD (70–80%), frequent co-occurring psychiatric disorders, and high prevalence of material hardships such as food and housing insecurity in mothers with OUD compared with those without OUD (Arnaudo, 2017; Fitzsimons, 2007; Martin, 2003; McHugo, 2005; Najavitis 1997; Rose-Jacobs, 2018). Given the increasing desire to identify predictors of NAS outcomes, this represents a novel biomarker that warrants further study. Hair cortisol is a non-invasive biomarker that is feasible to obtain, is not time sensitive, reflects cortisol levels over a 3-month period of time, and can be collected at multiple time points for trending purposes (D’Anna-Hernandez, 2011; Kirschbaum, 2009; Liu, 2016). Hair cortisol levels have been shown to correlate with early life adversity and stress-related psychiatric conditions, therefore making it a useful biomarker for chronic maternal stress which is highly prevalent in this patient population (D’Anna-Hernandez, 2011; Karlen, 2013; Kirschbaum, 2009; Liu, 2016).

The idea that maternal stress may impact infant neurobehavior has been demonstrated in prior studies. Prenatal stress can compromise the intrauterine environment and can be transmitted to the infant, with associated elevations in cortisol levels, epigenetic modification, and impaired maternal-infant interaction, all of which can impact infant neurobehavior (Conradt, 2015; Conradt, 2013; Davis, 2011; Lesseur, 2014; Palma-Gudiel, 2015; Paquette, 2015). Maternal stress and elevated cortisol levels can impact the development of the fetal hypothalamic-pituitary-adrenal (HPA)-axis, a main regulator of the stress response. Previous studies in pregnant women have demonstrated higher hair cortisol levels in stressed women, and corresponding effects in infant hair cortisol levels and alterations in neurobehavior (Karla, 2007; Shreier, 2015).

In addition, maternal cortisol is metabolized through the placenta, thus changes in placental cortisol metabolism and modifications in DNA methylation may alter the infant’s stress response (Conradt, 2015; Palma-Gudiel, 2015; Paquette, 2015; Lesseur, 2014). Our previous work has also demonstrated a link between epigenetic variation in the mu opioid receptor gene (OPRM1) and differences in NAS severity (Wachman, 2014; Wachman, 2018). Future studies should focus on examining cortisol response genes and link with NAS severity and maternal stress.

Interestingly, we found that the mothers with lower hair cortisol levels had infants with worse NAS severity. This may be that the women who are chronically the most stressed or with the most extensive OUD history have a blunting of their HPA axis and corresponding cortisol responses over time. It is well known that chronic exposure to both stress and drugs of abuse leads to HPA axis suppression (Miller, 2007; Zhou, 2016). Low basal cortisol levels are known to be associated with higher impulsivity in general, and may be related to opioid use. There may also be other non-measured variables such as maternal addiction severity, psychosocial factors, attachment with the infant and time spent at the infant’s bedside after birth which may explain these differences in NAS outcomes in relation to maternal stress (MacMillan, 2018). These infants may be more dysregulated as they are responding to a dysregulated mother who is impacted by years of chronic stress and trauma, which may impact breastfeeding and ability to console the infant, both which are critical to NAS outcomes (Beeghly, Perry, Tronick, 2018; Jansson, 2017).

This study has several limitations. First, the NAS treatment protocol changed during the course of the study; morphine was used as the first-line pharmacologic treatment during the first half of the study, and methadone during the second half. A recent randomized control trial demonstrated that methadone was associated with improved NAS outcomes compared with morphine, thus this may have impacted LOS and length of treatment (Davis, 2018). In addition, inter-rater reliability with Finnegan scoring was not conducted, though all nurses did complete Finnegan training. Given this was a pilot study, we were limited by small sample size, lack of infant samples to correlate with the maternal samples, and no control group. Also, we did not measure maternal stress with questionnaires such as established trauma inventories, depression and anxiety screens, perceived stress scales, assessment of current stressors and coping mechanisms, and we did not formally assess infant neurobehavior. Another limitation is that we did not systematically collect additional variables that can impact cortisol levels such as maternal hair care and hair washing habits, and maternal BMI. Lastly, we did not include infant hair cortisol measurements as the optimal technique for collection within the immediate perinatal period is still being developed.

In conclusion, we demonstrated the feasibility of a non-invasive novel biomarker for NAS, which may reflect exposure to prenatal maternal stress and the altered stress tolerance of the infant to the process of opioid withdrawal. Future studies should look at larger sample sizes, include quantifiable data on maternal stress, examine epigenetic factors, and examine the association of infant cortisol levels and NAS severity and infant neurobehavioral outcomes.

ACKNOWLEDGEMENTS:

We would like to acknowledge the Hunter lab at University of Massachusetts Boston, and the Meyer lab at the University of Massachusetts Amherst for hair cortisol processing. This project was funded by the Boston Medical Center Department of Pediatrics and the University of Massachusetts Boston. Dr. Wachman is supported by NICHD (R01HD096798-01). The project was supported in part by grants from the National Science Foundation (0819839, ET, PI) and NICHD (R01 HD050459-01, ET, PI).

DATA SHARING: The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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