Clinical Commander

Back to dossier
peds.neonatal-abstinence-syndrome.v1PRODUCTION
peds.neonatal-abstinence-syndrome.v1

Neonatal Abstinence Syndrome (NAS) / Neonatal Opioid Withdrawal Syndrome (NOWS)

pediatricsacutesubacuteneonatal
Hard-required inputs
0 / 15
Care setting:

Encounter flow

12/12 authored

Canonical 12-phase frame with authored status for this dossier.

Current phase

Frame

Detailed

Confirm in-utero opioid (or sedative / SSRI / polysubstance) exposure; onset-timing window per substance pharmacokinetics (heroin 24-72 h, methadone 2-7 d, buprenorphine 36-60 h, SSRI/SNRI 1-3 d, benzo variable/delayed); differentiate NAS from sepsis / hypoglycemia / hypocalcemia / hyperthyroidism / HSV / IVH / structural CNS; mild-moderate-severe stratification by ESC function impairment (NOT Finnegan score per AAP 2024)

Inputs
3
Actions
0
Advance rule
Set
Advance when

Exposure axis confirmed + onset window framed + ESC function status assessed

Patient inputs (23)

Preterm < 37 wk may have blunted/atypical NAS presentation; impacts ESC interpretation

All neonatal weight-based dosing (mg/kg, mL/kg); morphine, methadone, buprenorphine, clonidine, phenobarbital all weight-based

Methadone vs buprenorphine maternal MAT impacts NAS severity (methadone-NAS often more severe + prolonged per Welle-Strand 2013); informs pharm choice + LOS expectations + postpartum MAT continuity (ACOG 711 2017; SAMHSA TIP 63)

Opioid + benzo polysubstance → delayed / prolonged / atypical NAS + phenobarbital adjunct consideration (Hudak AAP 2012)

Maternal HIV → breastfeeding contraindicated in developed countries; AAP Red Book 2024 + WHO infant feeding guidance

MAT (methadone or buprenorphine) compatible with breastfeeding (low milk transfer); HIV / illicit poly / codeine / oxycodone / tramadol contraindicate (ACOG 711 2017; FDA boxed warnings)

Tachycardia in NAS autonomic axis; severe tachycardia + tremor + sweating → severe_autonomic_instability_in_nas trigger (clonidine consideration)

Tachypnea in NAS; severe tachypnea → sepsis differential / cardiac differential

State-specific statute: automatic notification of in-utero substance exposure (MN, MA, KY, ND, SD, UT, VA, WI) vs discretionary; document + social work + perinatal navigator

Discharge planning: NAS-trained foster / kinship care + early intervention referral + developmental Q3 mo × 1 yr then annual × 5 yr (AAP 2024)

Age × substance-PK coupling defines onset window: heroin 24-72 h, methadone 2-7 d, buprenorphine 36-60 h, SSRI/SNRI 1-3 d (Hudak AAP 2012)

Objective documentation of recent maternal exposure (timing-dependent yield)

Objective documentation of in-utero exposure: heroin metabolites 2-4 d, methadone 3-7 d in UDS; meconium / cord tissue cover last-trimester regardless of recent UDS negativity

Hypoglycaemia < 47 mg/dL can mimic NAS (irritability); D10W 2-3 mL/kg bolus if < 47; rule out as primary

Hypothermia or fever in NAS infant → sepsis differential; NAS itself can cause low-grade temperature instability (Hudak AAP 2012)

Hyperthyroidism (Graves baby) can mimic severe NAS autonomic instability; check if features atypical

Cranial US if seizure in NAS (atypical — IVH / structural CNS rule-out) or preterm baseline

HSV PCR + acyclovir empiric if seizure / vesicles / encephalopathy / maternal HSV — do not attribute to NAS alone (AAP Red Book 2024; Kimberlin 2013 PMID 23359576)

Hypoxaemia not typical of NAS — directs to sepsis / cardiac / pulmonary differential

Hypocalcaemia + hypomagnesaemia can mimic NAS (tremor, irritability); rule out as primary

Baseline + sepsis differential; thrombocytopenia raises Candida / NEC concern not NAS

Bilirubin baseline; severe NAS feeding intolerance can prolong jaundice

Baseline QTc before clonidine; clonidine + bradycardia / QT-prolongation monitoring

* = hard-required. Engine cannot meaningfully run until these are filled.

Severity triggers (10)

10 need judgement
  • informationallife_threateningnas_seizure_atypical_consider_hsv
    Seizure in NAS infant is ATYPICAL — must rule out HSV / sepsis / metabolic (hypoglycaemia, hypocalcaemia, hypomagnesaemia, hyperammonaemia, organic acidaemias) / IVH / structural CNS; empiric acyclovir 60 mg/kg/day q8h IV + HSV PCR + sepsis workup + neuroimaging + EEG + anti-epileptic loading (AAP Red Book 2024; Kimberlin Pediatrics 2013 PMID 23359576)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseveresevere_nas_requiring_pharmacotherapy_per_esc
    ESC function impaired (unable to eat ≥ 1 oz per feed OR sleep ≥ 1 h after feed OR console within 10 min with non-pharm) × ≥ 3 consecutive feed cycles AFTER adequate non-pharm trial — initiate oral morphine 0.04-0.08 mg/kg q3-4h OR methadone 0.05-0.1 mg/kg q6-12h OR oral buprenorphine 5-10 mcg/kg q8h (Kraft BBORN); non-pharm continued (AAP 2024; Young NEJM 2023 PMID 37125831)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverepolysubstance_withdrawal_opioid_plus_benzo
    Documented maternal opioid + benzodiazepine in-utero exposure → delayed / prolonged / atypical withdrawal course; add phenobarbital 5 mg/kg load then 2-5 mg/kg/day to opioid pharm regimen; closer monitoring of CNS depression + cumulative respiratory depression risk (Hudak AAP 2012 PMID 22291123)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseveresevere_autonomic_instability_in_nas
    Severe NAS autonomic features persisting on Tier 2 monotherapy: tachycardia (HR > 180 sustained) + sweating + tremor severe + irritability not responsive to non-pharm + escalating opioid dose → add clonidine 1 mcg/kg q4-6h PO/IV; rule out non-NAS etiologies first (sepsis, hyperthyroidism / Graves baby, pheochromocytoma rare); BP / HR / QT monitoring (AAP 2024; Hudak AAP 2012 PMID 22291123)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverenas_with_feeding_intolerance_or_dehydration
    NAS infant with feeding intolerance (vomiting, refusal, gagging) + weight loss > 10% birth weight + poor UO + signs of dehydration — IV hydration + careful feeding plan + NICU; do not discharge until tolerating feeds reliably (AAP 2024)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmoderatecps_notification_per_state_law
    State-specific statutory CPS reporting of in-utero substance exposure: automatic notification in MN, MA, KY, ND, SD, UT, VA, WI; discretionary in others. Document + social work + perinatal navigator; non-punitive engagement framework per ACOG 711 2017
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmoderatenas_discharge_to_foster_or_kinship_care
    Discharge to NAS-trained foster or kinship caregiver when home maternal placement not viable: NAS-trained caregiver education (ESC principles, non-pharm techniques, return precautions, safe sleep, feeding cues) + early intervention referral + developmental follow-up Q3 mo × 1 yr then annual × 5 yr (AAP 2024)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmildmaternal_mat_continuation_postpartum
    Maternal methadone or buprenorphine MAT continued postpartum; coordinate with addiction medicine; breastfeeding compatible with MAT (low milk transfer; clinical effect minimal) (ACOG 711 2017; SAMHSA TIP 63 2021)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmildnaloxone_unindicated_in_chronic_nas
    Naloxone is for ACUTE opioid intoxication, NOT chronic NAS; can precipitate severe withdrawal in chronic-exposed neonate; do NOT administer routinely (Hudak AAP 2012 PMID 22291123; AAP 2024)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmildeat_sleep_console_first_line_per_aap_2024
    Eat-Sleep-Console (ESC) function-based assessment is the AAP 2024 first-line standard, supplanting Finnegan scoring; non-pharm care first; pharm only if function-impaired AFTER adequate non-pharm trial; reduces LOS + opioid-treatment exposure per Young NEJM 2023 (AAP 2024; Young NEJM 2023 PMID 37125831)
    Trigger could not be auto-evaluated — needs clinician judgement.

Workflow calculators

Run this disease's risk and dosing calculators inline.

TREATMENToptionalDrives dose adjustment
Loading…

Recommended regimen

NAS / NOWS acute management — Eat-Sleep-Console function-first per AAP 2024 + Young NEJM 2023
axis: nas_acute_function_firststep 1 - Tier 1 — Non-pharmacologic care (ALWAYS, regardless of severity)
Selected step "Tier 1 — Non-pharmacologic care (ALWAYS, regardless of severity)" — ANY opioid-exposed neonate, ANY severity; non-pharm is the substrate on which pharm is layered ONLY if function-impaired
  • rooming-in_with_caregiver
    first line
    non_pharmacologic_care
    24-hour rooming-in with caregiver throughout NAS observation • environmental • continuous
    triggers: opioid_exposed_neonate
    AAP 2024; Young NEJM 2023 PMID 37125831 — rooming-in is core to ESC function-based approach; reduces LOS + pharm exposure
  • breastfeeding_when_eligible
    first line
    non_pharmacologic_care
    On-demand breastfeeding when maternal HIV negative AND not on contraindicated meds (codeine, oxycodone, tramadol) AND no illicit poly-substance use • oral_maternal_milk • on-demand
    triggers: breastfeeding_eligible
    ACOG 711 2017; LactMed — methadone + buprenorphine compatible with breastfeeding (low milk transfer); reduces NAS severity in dyad cohorts
  • swaddling
    first line
    non_pharmacologic_care
    Snug swaddling with hands midline when not feeding / skin-to-skin • environmental • between feeds
    triggers: opioid_exposed_neonate
    AAP 2024 — reduces sensory overload + improves consolability
  • low_stimulation_environment
    first line
    non_pharmacologic_care
    Dim lighting + minimal noise + cluster cares + minimal handling • environmental • continuous
    triggers: opioid_exposed_neonate
    AAP 2024 — reduces autonomic activation; improves sleep + console axes of ESC
  • kangaroo_care_skin_to_skin
    first line
    non_pharmacologic_care
    Multiple daily skin-to-skin sessions with caregiver • environmental • multiple times daily
    triggers: opioid_exposed_neonate
    AAP 2024 — improves autonomic regulation + feeding + caregiver bonding
  • on_demand_feeding
    first line
    non_pharmacologic_care
    Feed on cues rather than scheduled; advance volume as tolerated • oral • on-demand q2-4 h typical
    triggers: opioid_exposed_neonate
    AAP 2024 — supports Eat axis of ESC; do not over-feed (vomiting / discomfort)

outpatient playbook — drug actions (3)

  1. 1. NO routine outpatient pharm continuation for NAS — pharm wean is completed inpatient before discharge
    N/A • N/A • N/A
    trigger: Standard NAS discharge — wean complete
    AAP 2024 — NAS pharm taper completed inpatient before discharge; rare exceptions documented case-by-case
  2. 2. PCV15 / PCV20 + Hib + Hep B per ACIP age-appropriate schedule
    Per ACIP • IM • per ACIP
    trigger: Standard immunization schedule begins at 2 mo
    AAP Red Book 2024 + ACIP — NAS history does not modify schedule
  3. 3. Maternal MAT continuation supported (postpartum dose adjustment per addiction medicine; not infant-side pharm)
    Per psych.opioid_use_disorder.core.v1 maternal regimen • maternal_oral / SL • per maternal regimen
    trigger: Maternal MAT continuity
    ACOG 711 2017 + SAMHSA TIP 63 2021 — postpartum MAT continuation reduces relapse and dyad outcome improved

Auto-drafted A&P note

outpatient

Subjective

- Possible entry pathways: Maternal in-utero opioid exposure (methadone OR buprenorphine MAT, heroin, prescription opioids) — applies to ~ 60-90% of opioid-exposed infants (Hudak AAP 2012 PMID 22291123); Maternal polysubstance: opioid + benzodiazepines OR opioid + SSRI/SNRI OR illicit poly (cocaine, methamphetamine) — drives delayed / prolonged / atypical course (Hudak AAP 2012); Tremor / hypertonia / hyperreflexia / autonomic instability (tachycardia, sweating, sneezing, yawning) / GI features (poor feeding, loose stools, vomiting) / sleep disturbance / inconsolable cry in opioid-exposed neonate (AAP 2024 NAS/NOWS update).

Objective

- No vitals, labs, or imaging entered for this encounter.

Assessment

**Neonatal Abstinence Syndrome (NAS) / Neonatal Opioid Withdrawal Syndrome (NOWS)** (peds.neonatal-abstinence-syndrome.v1).
Phenotype framing: NAS (opioid) vs SSRI/SNRI-induced neonatal adaptation syndrome (milder, 1-3 d, self-limited) vs benzo withdrawal (variable, delayed) vs polysubstance vs sepsis vs HSV vs hypoglycemia / hypocalcemia / hypomagnesemia vs hyperthyroidism (Graves baby) vs IVH vs metabolic vs structural CNS vs colic (older)
Scope: Confirm in-utero opioid (or sedative / SSRI / polysubstance) exposure; onset-timing window per substance pharmacokinetics (heroin 24-72 h, methadone 2-7 d, buprenorphine 36-60 h, SSRI/SNRI 1-3 d, benzo variable/delayed); differentiate NAS from sepsis / hypoglycemia / hypocalcemia / hyperthyroidism / HSV / IVH / structural CNS; mild-moderate-severe stratification by ESC function impairment (NOT Finnegan score per AAP 2024)

No severity triggers fired against current inputs.

Plan

Regimen axis: **NAS / NOWS acute management — Eat-Sleep-Console function-first per AAP 2024 + Young NEJM 2023** — step "Tier 1 — Non-pharmacologic care (ALWAYS, regardless of severity)".
1. rooming-in_with_caregiver 24-hour rooming-in with caregiver throughout NAS observation environmental continuous (non_pharmacologic_care, first line) — AAP 2024; Young NEJM 2023 PMID 37125831 — rooming-in is core to ESC function-based approach; reduces LOS + pharm exposure
2. breastfeeding_when_eligible On-demand breastfeeding when maternal HIV negative AND not on contraindicated meds (codeine, oxycodone, tramadol) AND no illicit poly-substance use oral_maternal_milk on-demand (non_pharmacologic_care, first line) — ACOG 711 2017; LactMed — methadone + buprenorphine compatible with breastfeeding (low milk transfer); reduces NAS severity in dyad cohorts
3. swaddling Snug swaddling with hands midline when not feeding / skin-to-skin environmental between feeds (non_pharmacologic_care, first line) — AAP 2024 — reduces sensory overload + improves consolability
4. low_stimulation_environment Dim lighting + minimal noise + cluster cares + minimal handling environmental continuous (non_pharmacologic_care, first line) — AAP 2024 — reduces autonomic activation; improves sleep + console axes of ESC
5. kangaroo_care_skin_to_skin Multiple daily skin-to-skin sessions with caregiver environmental multiple times daily (non_pharmacologic_care, first line) — AAP 2024 — improves autonomic regulation + feeding + caregiver bonding
6. on_demand_feeding Feed on cues rather than scheduled; advance volume as tolerated oral on-demand q2-4 h typical (non_pharmacologic_care, first line) — AAP 2024 — supports Eat axis of ESC; do not over-feed (vomiting / discomfort)

Setting playbook (outpatient) — Post-discharge primary care + developmental + perinatal-navigator continuity; Q3 mo developmental surveillance × 1 yr then annually × 5 yr per AAP 2024; early intervention engagement; maternal MAT coordination postpartum; family support; CPS follow-through
7. NO routine outpatient pharm continuation for NAS — pharm wean is completed inpatient before discharge N/A N/A N/A — Standard NAS discharge — wean complete (AAP 2024 — NAS pharm taper completed inpatient before discharge; rare exceptions documented case-by-case)
8. PCV15 / PCV20 + Hib + Hep B per ACIP age-appropriate schedule Per ACIP IM per ACIP — Standard immunization schedule begins at 2 mo (AAP Red Book 2024 + ACIP — NAS history does not modify schedule)
9. Maternal MAT continuation supported (postpartum dose adjustment per addiction medicine; not infant-side pharm) Per psych.opioid_use_disorder.core.v1 maternal regimen maternal_oral / SL per maternal regimen — Maternal MAT continuity (ACOG 711 2017 + SAMHSA TIP 63 2021 — postpartum MAT continuation reduces relapse and dyad outcome improved)

Non-pharmacologic actions:
- Perinatal navigator continuity — weekly to monthly contact
- Early intervention engagement (PT / OT / speech as indicated by Bayley / ASQ)
- Lactation continued support if breastfeeding
- Family / foster / kinship support + caregiver respite resources
- Mental health support for caregiver (postpartum depression / anxiety / OUD recovery)
- CPS follow-through + supportive services audit
- Safe sleep / car seat / breastfeeding reinforcement at every visit
- Driving / dating / college transition discussion — N/A at this engine age; encoded only in chronic engines
- Sibling exposure + family OUD prevention discussion

AVOID / contraindication checks:
- Naloxone CONTRAINDICATED in chronic NAS precipitates severe withdrawal (Hudak AAP 2012 PMID 22291123; AAP 2024)
- ESC function first pharm only after adequate non pharm trial (AAP 2024; Young NEJM 2023 PMID 37125831)
- Phenobarbital reserved for polysubstance with benzo not for opioid only NAS (Hudak AAP 2012)
- Clonidine monitor BP HR QT (AAP 2024)
- Breastfeeding contraindicated maternal HIV or illicit polysubstance or codeine oxycodone tramadol (ACOG 711; AAP Red Book 2024; FDA boxed warnings)
- Seizure in NAS is atypical rule out HSV sepsis metabolic (AAP Red Book 2024; AAP 2024)

Monitoring

Regimen monitoring:
- ESC function assessment q3-4h with feeds — first-line per AAP 2024 + Young NEJM 2023
- Vitals q4h (continuous monitoring while on clonidine or phenobarbital)
- Daily weight + strict I/O (feeding intolerance / dehydration risk)
- ECG baseline + during clonidine (BP / HR / QT monitoring)
- Phenobarbital level if used > 5 d (target 15-30 mcg/mL; watch cumulative sedation)
- Morphine / methadone / buprenorphine wean per protocol (10% q24-48 h morphine; 10-20% q3-7 d methadone; 10-15% q24-48 h buprenorphine)
- HSV / sepsis workup repeat if new features (atypical course)
- Family / foster bonding observation; perinatal navigator + social work weekly minimum

Setting (outpatient) monitoring:
- Peds visit at 24-48 h, 1 wk, 1 mo, 3 mo, 6 mo, 9 mo, 12 mo, then annually × 5 yr
- Neurodevelopmental re-assessment at 3 mo + 6 mo + 12 mo + 24 mo (Bayley III / ASQ-3)
- Caregiver mental health re-screen at every visit
- Immunization status audit at every visit until catch-up complete
- Maternal MAT continuity audit

Follow-up plan: Pediatric primary care within 24-48 h of discharge; perinatal navigator continuity; early intervention referral; developmental surveillance Q3 mo × 1 yr then annually × 5 yr; maternal MAT coordination postpartum (ACOG 711 2017; SAMHSA TIP 63 2021); breastfeeding support if continuing; ophthalmology if perinatal substance + CNS features; audiology if HSV / meningitis differential triggered; mental health for caregiver
- Close-out criterion: Outpatient plan + EI referral + perinatal navigator + family education documented

Monitoring phase: ESC function assessment q3-4 h (with feeds) per AAP 2024; vitals q4 h; daily weight + I/O; ECG baseline + during clonidine; phenobarbital level if used > 5 d; HSV / sepsis workup repeat if new features; family / foster bonding observation; wean schedule (morphine 10% q24-48 h; methadone 10-20% q3-7 d; buprenorphine 10-15% q24-48 h) once stable function × 48-72 h

Disposition

Current setting: outpatient — Post-discharge primary care + developmental + perinatal-navigator continuity; Q3 mo developmental surveillance × 1 yr then annually × 5 yr per AAP 2024; early intervention engagement; maternal MAT coordination postpartum; family support; CPS follow-through

Disposition criteria:
- Sustained recovery — developmental milestones at age norms, caregiver demonstrating ongoing competence, no recurrent serious medical / developmental concerns over 5 yr (then transition to standard peds care)

Escalation triggers (move to higher acuity):
- Recurrent NAS-like features (rare after wean) → urgent peds + addiction-medicine + meconium re-test
- Developmental delay > 1 SD below age norms on ASQ / Bayley → developmental peds + early intervention intensify
- Caregiver mental health crisis (EPDS / PHQ-9 elevated) → urgent mental-health referral + perinatal navigator
- CPS / foster placement disruption → emergency social work + multi-disciplinary care meeting
- New seizures OR neuro deterioration → urgent neuro + neuroimaging + HSV / sepsis differential
- Failure to thrive → urgent peds + GI + nutritional assessment

Earlier-Return Triggers

Return-precaution thresholds (watch for):
- [LIFE_THREATENING] Seizure in NAS infant is ATYPICAL — must rule out HSV / sepsis / metabolic (hypoglycaemia, hypocalcaemia, hypomagnesaemia, hyperammonaemia, organic acidaemias) / IVH / structural CNS; empiric acyclovir 60 mg/kg/day q8h IV + HSV PCR + sepsis workup + neuroimaging + EEG + anti-epileptic loading (AAP Red Book 2024; Kimberlin Pediatrics 2013 PMID 23359576)
- [SEVERE] ESC function impaired (unable to eat ≥ 1 oz per feed OR sleep ≥ 1 h after feed OR console within 10 min with non-pharm) × ≥ 3 consecutive feed cycles AFTER adequate non-pharm trial — initiate oral morphine 0.04-0.08 mg/kg q3-4h OR methadone 0.05-0.1 mg/kg q6-12h OR oral buprenorphine 5-10 mcg/kg q8h (Kraft BBORN); non-pharm continued (AAP 2024; Young NEJM 2023 PMID 37125831)
- [SEVERE] Documented maternal opioid + benzodiazepine in-utero exposure → delayed / prolonged / atypical withdrawal course; add phenobarbital 5 mg/kg load then 2-5 mg/kg/day to opioid pharm regimen; closer monitoring of CNS depression + cumulative respiratory depression risk (Hudak AAP 2012 PMID 22291123)

Citations

- AAP Clinical Report 2024 NAS / NOWS update (Eat-Sleep-Console first-line) + Young et al, NEJM 2023 (ACT NOW ESC cluster RCT) PMID 37125831 + Hudak ML, Tan RC, AAP Clinical Report on Neonatal Drug Withdrawal, Pediatrics 2012 PMID 22291123 + Kraft WK et al, BBORN buprenorphine NEJM 2017 PMID 28468518 + ACOG Committee Opinion 711 (2017) maternal OUD in pregnancy + SAMHSA TIP 63 (2021) MOUD in pregnancy + AAP Red Book 2024 [PMID:37125831](https://pubmed.ncbi.nlm.nih.gov/37125831/)
- Cited evidence (PMID 22291123) [PMID:22291123](https://pubmed.ncbi.nlm.nih.gov/22291123/)
- Cited evidence (PMID 28468518) [PMID:28468518](https://pubmed.ncbi.nlm.nih.gov/28468518/)
- Cited evidence (PMID 23359576) [PMID:23359576](https://pubmed.ncbi.nlm.nih.gov/23359576/)

Last reconciled with current guidelines: 2026-05-25.
References
  • AAP Clinical Report 2024 NAS / NOWS update (Eat-Sleep-Console first-line) + Young et al, NEJM 2023 (ACT NOW ESC cluster RCT) PMID 37125831 + Hudak ML, Tan RC, AAP Clinical Report on Neonatal Drug Withdrawal, Pediatrics 2012 PMID 22291123 + Kraft WK et al, BBORN buprenorphine NEJM 2017 PMID 28468518 + ACOG Committee Opinion 711 (2017) maternal OUD in pregnancy + SAMHSA TIP 63 (2021) MOUD in pregnancy + AAP Red Book 2024 — PMID:37125831
  • Cited evidence (PMID 22291123) — PMID:22291123
  • Cited evidence (PMID 28468518) — PMID:28468518
  • Cited evidence (PMID 23359576) — PMID:23359576