ARTICLE

Neonatal Head Circumference in Newborns With Neonatal Abstinence SyndromeCraig V. Towers, MD, Branson W. Hyatt, MD, Kevin C. Visconti, MD, Lindsey Chernicky, BS, Katie Chattin, BS, Kimberly B. Fortner, MD

OBJECTIVES: To compare head circumference (HC) in neonates treated for neonatal abstinence syndrome (NAS) with control neonates without antenatal opioid exposure.METHODS: Our prospective cohort study ran from April 1, 2014, through December 31, 2016. Newborns treated for NAS delivered from well-dated pregnancies ≥34 weeks’ gestation were compared with newborns who were nonopioid exposed and matched for race, parity, mode of delivery, and gestational age. All mothers underwent serial antenatal urine drug testing. A minimum of 754 study participants were needed (377 in each group) to demonstrate an increase in the proportion of newborns with HCs less than or equal to the 10th percentile from 10% in controls to a minimum of 20% in NAS newborns with 90% power.RESULTS: A total of 858 neonates were enrolled (429 NAS cases and 429 controls). Mean HC for cases was 33.04 cm (±1.9 cm) compared with 33.99 cm (±2.0 cm) for controls (P < .0001). Among the 429 NAS cases, the mothers of 372 (87%) were on opioid medication-assisted treatment. For NAS cases, 30.1% (95% confidence interval: 25.8%–34.7%) had an HC less than or equal to the 10th percentile (129 of 429 neonates), and 8.2% (95% confidence interval: 5.8%–11.2%) had an HC less than or equal to the third percentile (35 of 429 neonates). Multivariate analysis was used and determined that only chronic opioid use during gestation resulting in a neonate who was NAS treated was a significant risk factor for the observed smaller HC.CONCLUSIONS: Chronic opioid use during pregnancy sufficient to cause NAS was associated with smaller HCs at birth. Most mothers were on opioid agonist medication-assisted treatment, which is currently the recommended treatment option during pregnancy.

abstract

Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Tennessee Medical Center, Knoxville, Tennessee

Dr Towers conceptualized and codesigned the study, coordinated and supervised the maternal and neonatal data collection, conducted the initial analyses, and drafted the initial manuscript; Dr Hyatt supervised the maternal and neonatal data collection and critically reviewed and revised the manuscript; Ms Chernicky and Ms Chattin conducted the maternal and neonatal data collection and critically reviewed the manuscript; Drs Visconti and Fortner codesigned the study, supervised the maternal data collection, and critically reviewed and revised the manuscript; and all authors approved the final manuscript as submitted.

This work was presented at the 38th Annual Pregnancy Meeting of the Society for Maternal-Fetal Medicine; January 29–February 3, 2018; Dallas, Texas.

DOI: https:// doi. org/ 10. 1542/ peds. 2018- 0541

Accepted for publication Oct 16, 2018

PEDIATRICS Volume 143, number 1, January 2019:e20180541

WHAT’S KNOWN ON THIS SUBJECT: In a few published studies, authors have suggested that chronic opioid drug use during pregnancy is associated with smaller newborn head circumferences at birth. However, in these retrospective studies, researchers did not fully account for other potentially confounding antenatal drug exposures.

WHAT THIS STUDY ADDS: In this prospective study in a large series of well-dated pregnancies, we found that antenatal opioid exposure was associated with reduced head circumference at birth after controlling for other antenatal drug exposures as verified by maternal drug testing.

To cite: Towers CV, Hyatt BW, Visconti KC, et al. Neonatal Head Circumference in Newborns With Neonatal Abstinence Syndrome. Pediatrics. 2019;143(1):e20180541

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Opioid use disorder (OUD) in pregnancy has risen in the United States, resulting in an increase in neonatal abstinence syndrome (NAS).1 The current American College of Obstetricians and Gynecologists Committee Opinion recommendation for treating OUD in pregnancy is to manage the patient with medication-assisted treatment (MAT) by using either methadone or buprenorphine.2 The rationale for opioid MAT stems from evidence of maternal benefit (eg, decreased withdrawal symptoms, improved prenatal care, and reduced risk of recidivism), although neonates have a high risk of NAS, a treatable newborn condition.2 In a few studies, however, researchers have reported smaller newborn head circumferences (HCs) at delivery and smaller brain volumes in the chronic opioid–exposed newborn compared with controls, 3 – 7 which might adversely affect the newborn’s long-term neurodevelopmental outcome.

To our knowledge, there are limited prospective data on neonatal HC of newborns who develop NAS in which researchers have controlled for the type of maternal opioid drug as well as other antenatal drug exposures. Pregnant women may have coexposures to sedatives, stimulants, marijuana, gabapentin, alcohol, tobacco, selective serotonin reuptake inhibitors (SSRIs), and common antiemetics. In a previous retrospective study from our institution, researchers did find an association of smaller HCs in newborns treated for NAS compared with controls; but, because of the retrospective nature of the investigation, accurate information in which authors detailed the type of maternal opioid and other coexposures and provided better pregnancy dating were lacking.6

We report results of a prospective study we designed to determine if chronic opioid use during pregnancy, sufficient enough for the neonate to require treatment for signs of

NAS, is associated with smaller HCs compared with newborns who are not exposed to opioids.

METHODS

Our prospective cohort study included births from April 1, 2014, to December 31, 2016. The case and control populations came from the same clinic pregnancy population managed and delivered at the University of Tennessee Medical Center, Knoxville. Because NAS is a reportable condition in Tennessee, we standardized our case definition for a diagnosis of NAS using the Finnegan score.8 The criteria for starting pharmacologic treatment of NAS in our NICU consisted of any 2 consecutive Finnegan scores ≥10 or a single Finnegan score ≥12. The Institutional Review Board of the University of Tennessee Medical Center, Knoxville, approved creation of a database of all clinic pregnancies receiving their care and delivery at our institution that included delivery and newborn data. Each case was a neonate from the cohort, with a well-dated pregnancy that delivered at ≥34 weeks’ gestation, who was diagnosed with and treated for NAS in the NICU. Each control newborn was selected from the clinic pregnancy cohort that delivered shortly before or after the case newborn and was matched for race, parity, mode of delivery, and gestational age at delivery (±4 days). Control mothers did not have any illicit substance use on the basis of history and urine drug testing, had well-dated pregnancies, and delivered at ≥34 weeks’ gestation.

All pregnant women in the cohort had urine drug testing performed during prenatal care and at delivery. The mothers of the newborn NAS cases had a median of 6 tests, and mothers of controls had a median of 3 tests. Maternal data collection included demographics, medical and social history, and details about the

delivery. We obtained information specific to the use of illicit drugs, tobacco, and alcohol as well as other antenatal medications, including gabapentin, SSRIs, and antiemetics, and confirmed reported drug and medication use by toxicology studies. Collected newborn data included sex, birth weight, and HC at birth.

Mothers of all cases and controls had several ultrasounds before delivery. Pregnancy dating for both cases and controls was based on the best obstetric estimate as recommended by the American College of Obstetricians and Gynecologists Committee Opinion.9 Only patients with an ultrasound before 20 weeks’ gestation were included. We used the American Academy of Pediatrics’ sex-specific nomograms of birth weight and HC by gestational age, which allowed categorization of infants with respect to the 10th and third percentiles as well as the determination of individual z scores.10 After delivery, all newborns were examined by a single group of physicians and pediatric nurse practitioners who employed a standardized approach for measuring HC. Specifically, if an infant demonstrated caput or molding, an examiner obtained the HC after these conditions had resolved. We excluded newborns with aneuploidy and major fetal anomalies.

The primary planned study end point was a comparison of neonatal HC between the cases and controls. Using data from the previous published retrospective study from the same institution, 6 we determined that 754 study participants (377 in each group) were needed to detect a minimum increase in the percentage of neonates with an HC less than the 10th percentile from 10% in controls to 20% in infants with NAS by using an α (type I error) of .01 with 90% power. On the basis of the average number of NAS cases managed at our institution each month before study initiation, we anticipated that this

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investigation would span a minimum of 30 months. Given a study start date of April 1, 2014, we decided to enroll infants through December 31, 2016.

Statistical analysis involved simple percentages with Poisson binomial 95% confidence intervals (CIs). For comparisons, χ2 test, Fisher’s exact test, and Student’s t test were performed when applicable, with significance considered at P < .05. All comparisons were analyzed against a 2-sided alternative hypothesis. We planned to conduct multivariate analysis with the use of stepwise logistic regression if >1 significant factor were to be identified through univariate analysis. This would be performed with respect to determining which drug exposures occurred significantly more often in cases than controls and then with respect to determining which of these exposures might have been associated with the defined difference in HC. The study was reviewed and approved by the institutional review board at the University of Tennessee Medical Center, Knoxville.

RESULTS

We enrolled and assessed 858 neonates (429 cases with NAS and 429 controls). With the data in Table 1, we show that mean HC in neonates with NAS was significantly less, by 9.5 mm, compared with controls. In addition, the proportions of NAS infants with HCs less than or equal to the 10th and third percentiles were significantly greater compared with control newborns. No other comparison was significantly different other than the length of newborn stay, which was anticipated because all of the cases by definition were treated in the NICU for NAS.

By study design, none of the controls were born to mothers with a history of antenatal exposure to opioids, sedatives, or stimulants, as validated by maternal urine drug testing.

In Table 2, we show that through univariate analysis, we identified a significantly higher exposure to antenatal marijuana, gabapentin, tobacco, and SSRIs among the NAS cases. Cases and controls had similar exposure to promethazine and alcohol. Using NAS as the constant dependent variable, we performed a backward stepwise multivariate regression analysis to determine if any individual exposure was a significant independent risk factor for neonates treated for NAS. The model included opioid drug use in general, buprenorphine, methadone, benzodiazepine, stimulant, marijuana, gabapentin,

SSRI, and tobacco usage. The analysis revealed that opioid drug exposure in general and buprenorphine, methadone, benzodiazepine, and marijuana exposure were significantly associated with NAS at P < .01. Tobacco, SSRI, stimulant, and gabapentin exposure were not significant independent risk factors.

In examining the 429 NAS cases, 372 (87%) were on opioid agonist MAT (320 [75%] on buprenorphine and 52 [12%] on methadone), with the remaining 13% on other opioid drugs. There were 35 newborns with an HC less than or equal to the third percentile (8.2%; 95% CI: 5.8%–11.2%). There were 129 cases

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TABLE 1 Demographics and Outcome Parameters of NAS Cases Compared With Controls (858 Total Neonates)

Cases Controls P

No. 429 429 —Maternal age in y, mean (±SD) 28.1 (±5.7) 27.4 (±5.8) .08White, n (%) 410 (95.6) 410 (95.6) 1.0Multiparity, n (%) 343 (80) 343 (80) 1.0Mode of delivery: vaginal, n (%) 299 (69.7) 299 (69.7) 1.0Gestational age at delivery in wk, mean (±SD) 38.3 (±1.5) 38.2 (±1.6) .35Gestational age range in wk 340/7–424/7 340/7–420/7 —Gestational age <36 wk, n (%) 39 (9.1) 38 (8.9) .90Male fetus, n (%) 232 (54.1) 217 (50.6) .34Birth weight in g, mean (±SD) 2938 (±478) 3004 (±492) .047Birth weight ≤10th percentile, n (%) 61 (14.2) 45 (10.5) .12Birth weight ≤3rd percentile, n (%) 18 (4.2) 8 (1.9) .07NICU length of stay in d, mean (±SD) 21.3 (±5.7) 3.1 (±1.0) <.0001Neonatal HC in cm, mean (±SD) 33.04 (±1.9) 33.99 (±2.0) <.0001Neonatal HC ≤10th percentile, n (%) 129 (30.1) 51 (11.9) <.0001Neonatal HC ≤3rd percentile, n (%) 35 (8.2) 8 (1.9) <.0001Chronic maternal medical disordersa, n (%) 71 (16.6) 93 (21.7) .07Gestational or pregestational diabetes, n (%) 33 (7.7) 44 (10.3) .23

—, not applicable.a Includes hypertensive conditions, lupus, chronic renal disease, and others.

TABLE 2 Other Medication or Drug Use in NAS Cases Compared With Controls (858 Total Neonates)

Cases Controls P

No. 429 429 —Opioid drug use, n (%) 429 (100) 0 (0) <.0001 Buprenorphine 320 (74.6) 0 (0) <.0001 Methadone 52 (12.1) 0 (0) <.0001Benzodiazepine usage, n (%) 90 (21.0) 0 (0) <.0001Stimulant usage, n (%) 27 (6.3) 0 (0) <.0001Marijuana usage, n (%) 199 (46.4) 112 (26.1) <.0001Gabapentin usage, n (%) 61 (14.2) 14 (3.3) <.0001SSRI usage, n (%) 54 (12.6) 33 (7.7) .02Promethazine usage, n (%) 118 (27.5) 97 (22.6) .12Smoking, n (%) 314 (73.2) 221 (51.5) <.0001Positive alcohol screen result, n (%) 21 (4.9) 19 (4.4) .87

By study design, the control group was negative for opioid drugs, benzodiazepine, and stimulant usage.

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(30.1%; 95% CI: 25.8%–34.7%) with an HC less than the 10th percentile. Comparing these with the 300 NAS cases with a normal HC, we found no differences in exposure to buprenorphine, methadone, other opioid drugs, amphetamines, cocaine, benzodiazepines, marijuana, gabapentin, SSRIs, tobacco, or alcohol (Table 3).

We then performed a forward stepwise logistic analysis of the primary outcome variable (HC ≤10th percentile) using each of the exposures that was found to be significantly different between the cases and controls in the backward multivariate analysis. The only exposure that was associated with a significant risk of an HC less than or equal to the 10th percentile was chronic antenatal opioid exposure resulting in a neonate treated for NAS. The relative risk for an HC less than or equal to the 10th percentile was 2.53, with an adjusted odds ratio of 3.19 (95% CI: 2.23–4.56; P < .0001), whereas the relative risk for an HC less than or equal to the third percentile was 4.38, with an adjusted OR of 4.67 (95% CI: 2.14–10.20; P < .0001).

In many studies, researchers analyze HC solely as a continuous variable. In this study, however, we prospectively made the primary outcome measure (for HC with respect to the 10th and third percentiles) a dichotomous value. However, to provide the fullest depiction of the differences in HC between the NAS and control newborns, we also determined the z score for the HC of each infant on the basis of gestational age at delivery and plotted the data for the cases and controls to create Gaussian curves (Fig 1). In the distribution of HC among NAS cases, a simple shift to the left was demonstrated, compared with controls. With this finding, the possibility is raised that antenatal exposure to opioids sufficient enough to result in NAS might have a deleterious effect of similar

magnitude on HC in every NAS case, even if HC was in the normal range.

We designed our study to compare neonates who sustained chronic opioid exposure that resulted in NAS treatment with control newborns who were not exposed to opioids. In this prospective study, we did not include 216 neonates with antenatal exposure to opioids who did not develop NAS. These latter newborns were born to mothers

on full-maintenance opioid MAT, to mothers on other opioid drugs, and to mothers who were tapering their opioid drug dosage but remained on a reduced dose of opioid at the time of delivery. The demographics and the gestational age at delivery (38.1 ± 1.6 weeks) did not differ between these infants and the NAS cases in this study. The rates of benzodiazepine, gabapentin, marijuana, and tobacco usage were

TOWERS et al4

TABLE 3 Substance Use in the 429 NAS Cases Comparing the Small HC Group With the Normal HC Group (N = 429)

HC <10th Percentile Normal HC P

No. 129 300 —Opioid agonist MAT, n (%) 114 (88.4) 258 (86.0) .61 Buprenorphine 94/114 (82.5) 226/258 (87.6) .25 Methadone 20/114 (17.5) 32/258 (12.4) .25Opioid street drug usage, n (%) 15 (11.6) 42 (14.0) .61Benzodiazepine usage, n (%) 24 (18.6) 66 (22.0) .51Amphetamine usage, n (%) 6 (4.7) 11 (3.7) .83Cocaine usage, n (%) 3 (2.3) 7 (2.3) .99Marijuana usage, n (%) 58 (45.0) 141 (47.0) .77Gabapentin usage, n (%) 20 (15.5) 41 (13.7) .73SSRI usage, n (%) 18 (14) 36 (12.0) .69Smoking, n (%) 96 (74.4) 218 (72.7) .80Positive alcohol screen result, n (%) 5 (3.9) 16 (5.3) .63

FIGURE 1Comparison of z scores for HC between controls and cases.

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also similar to the NAS cases. The mean HC was 33.27 ± 2.0 cm, the rate of an HC less than or equal to the 10th percentile was 26.9%, and the rate of an HC less than or equal to the third percentile was 6.9%. For the subset of infants without NAS whose mothers were on MAT, 71 were on buprenorphine, and 42 were on methadone.

DISCUSSION

We found that chronic opioid use during pregnancy sufficient enough to result in NAS was associated with a significant decrease in HC at birth. Newborns with NAS had more frequent coexposures to benzodiazepines, stimulants, marijuana, gabapentin, tobacco, and SSRIs than did non-NAS controls. However, when we assessed these individual drug exposure relationships within the NAS newborn population alone, we found that none of the coexposures was a significant risk factor for a smaller HC at birth. It is noteworthy that the majority of NAS cases were born to mothers on opioid agonist MAT, which is currently the recommended treatment option during pregnancy.

To our knowledge, this is the first large prospective study in which researchers compare HC in newborns treated for NAS with well-matched controls in which all mothers had well-dated pregnancies and in which determinations of exposure were made by using both history and multiple urine drug tests. Our findings were similar to the retrospective material previously reported from our institution that had stimulated the current, more-rigorous, and prospective investigation.6 In that previous study, 332 neonates treated for NAS were compared with controls, and greater proportions of infants with NAS had a newborn HC less than or equal to the 10th and less than or equal to the third percentiles. In

that study, authors were unable to make a definitive conclusion about the possible effect of antenatal opioid exposure on neonatal HC because data pertaining to other possible confounding drugs and exposures were incomplete. Arlettaz et al, 3 in a retrospective study of 86 newborns exposed to methadone, reported a 13% incidence of HC less than the third percentile, but 62% were also exposed to additional drugs, primarily cocaine. Bier et al11 reported significantly smaller HC z scores for neonates exposed to a high dose of methadone (>100 mg daily dose) compared with newborns exposed to a low dose of methadone or buprenorphine. Additionally, in a few small studies, researchers have reported smaller brain volumes and abnormal white matter development in older children (ages 9–14) who received treatment of NAS after birth compared with controls, suggesting that children may not experience “catch-up” growth in HC through early adolescence.4, 5, 7

Many intrauterine perturbations that affect fetal growth elicit a variety of compensatory mechanisms that allow the fetus to preserve the development and growth of the central nervous system. To the contrary, our data revealed a significant 2.8% reduction in mean HC and a smaller proportional reduction of 2.2% in mean birth weight. Because newborn HC is an indirect measure of brain volume, further research is necessary to determine if this finding increases the risk for long-term neurodevelopmental delay. Current data on the long-term neurodevelopmental effects of antenatal opioid exposure are conflicting. Authors of recent studies involving brain imaging have suggested that there is abnormal neural tract development and myelination in newborns assessed at 2 to 6 weeks of age as well as at 12 to 15 years of age.12, 13 In a 2008

publication, researchers reported an increased risk for neurodevelopment delay through early childhood in infants who were exposed to chronic maternal opioid use, whereas in a meta-analysis from 2014, researchers reported no significant impairment with respect to neurobehavioral outcomes in exposed children.14, 15 However, in the past 20 years, there are numerous reports of impaired psychomotor development, visual-motor disturbances, increased attention-deficit/hyperactivity disorder, lower IQ scores, lower Griffith MD scores, lower executive function, weaknesses in language and cognition, and poorer high school performance in children who were treated for NAS at birth.16 – 24

Few data are available to evaluate whether detoxification during pregnancy of patients with OUD lowers the risk for a reduced HC and what effect detoxification might have on long-term childhood outcome. Haabrekke et al25 reported a mean HC of 33.9 (±1.9) cm in 78 newborns who were substance exposed, a mean HC of 34.8 (±1.5) cm in 22 newborns delivered to mothers who underwent full detoxification during pregnancy (resulting in no NAS), and a mean HC of 35.4 (±1.2) cm in control newborns who were not exposed. The difference in mean HC was significant between the drug-exposed and control groups but not between the detoxified and control groups.25 Walhovd et al26 reported that the MRI brain volumes did not differ at a mean age of 4.5 years in 12 newborns delivered to mothers who detoxified during pregnancy, resulting in an absence of NAS, compared with 12 controls. At present, detoxification during pregnancy is not recommended in the primary management of OUD in pregnancy2 and has only been reported in a few locations (in both inpatient and outpatient settings) in the United States and other countries.27 – 31 If the practice of detoxification

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during pregnancy expands, research regarding newborn head size and long-term outcomes on these infants and children is of paramount importance.

Not all neonates chronically exposed to opioid drugs during pregnancy develop NAS postdelivery.32 The reason for this is not certain but may involve innate genetic differences, differences in placental metabolism, or other unknown factors. We did not include newborns who were born to women with OUD but who did not require treatment of NAS in this study. Our reason for not including these newborns in the current study was that we wished to ensure a minimum threshold level of antenatal opioid exposure and set that threshold as the development of NAS symptoms severe enough as to require treatment. Those neonates exposed to opioid drugs during pregnancy that do not develop NAS that requires treatment may represent a different population in which the nature of opioid exposure and its effect are more speculative. Because our study has now revealed that neonates treated for NAS have a significantly smaller mean HC compared with controls, further prospective research to assess the impact of opioid exposure in newborns who do not develop NAS is still needed. Such newborns may be born to women on maintenance MAT,

women on illicit opioids, or women who underwent partial or complete opioid detoxification. Such variable antenatal exposure may provide valuable information about whether there is a critical predelivery time period of exposure that is associated with a reduction in neonatal HC or whether the opioid effect is cumulative over time.

Any investigation in which researchers seek to define a relationship between a drug and an outcome is limited to the extent to which the exact amount and timing of drug exposure are known. Although the women in our practice did have urine drug testing performed, we could not precisely quantify the opioid dosage in all cases or know if other drugs not included in the urine drug test played a role or were consumed at a time outside the performance limitations of the test. However, 179 substances were analyzed in the urine drug test used in this study.33 Although we could not quantitate a dose-response relationship for each mother-infant dyad, we do provide the best evidence to date that chronic antenatal opioid exposure sufficient enough to lead to NAS that requires treatment is associated with a significant reduction in neonatal HC independent of other coexposures.

CONCLUSIONS

Chronic opioid use during pregnancy that results in a newborn with signs of NAS that requires treatment appears to reduce head growth in utero compared with nonopioid-exposed controls, as assessed by comparisons of mean HC, proportions of HC less than or equal to the 10th or third percentiles, or distribution of z scores of HC by gestational age. The majority of NAS cases were born to mothers receiving opioid agonist MAT, which is currently the recommended treatment option during pregnancy. Analyses of non-NAS newborns exposed to maintenance MAT, illicit opioids, or lesser doses and/or durations of MAT because of partial or complete maternal detoxification are needed to determine if the current recommended management of OUD in pregnancy should be revisited.

TOWERS et al6

Address correspondence to Craig V. Towers, MD, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Tennessee Medical Center, 1930 Alcoa Highway, Suite A-435, Knoxville, TN 37920. E-mail: ctowers@utmck.edu

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2019 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: Partially funded through the Blue Cross Blue Shield Research Foundation.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

COMPANION PAPER: A companion to this article can be found online at www. pediatrics. org/ cgi/ doi/ 10. 1542/ peds. 2018- 3376.

ABBREVIATIONS

CI:  confidence intervalHC:  head circumferenceMAT:  medication-assisted

treatmentNAS:  neonatal abstinence

syndromeOUD:  opioid use disorderSSRI:  selective serotonin

reuptake inhibitor

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