F1000Research F1000Research 2046-1402 F1000 Research Limited London, UK 10.12688/f1000research.13350.1 Research Article Articles Health Service Delivery & Management of Anesthesia Pregnancy, Labor, Delivery & Postpartum Care Management of eight labor and delivery patients dependent on buprenorphine (Subutex™): A retrospective chart review

[version 1; peer review: 1 approved]

 Tith Solina Conceptualization Investigation Methodology Project Administration Visualization Writing – Original Draft Preparation 1 Bining Garinder Investigation Methodology Visualization Writing – Original Draft Preparation 2 Bollag Laurent A. Conceptualization Investigation Methodology Project Administration Supervision Visualization Writing – Original Draft Preparation Writing – Review & Editing https://orcid.org/0000-0002-7261-8032 a 2 Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA bollag@uw.edu

No competing interests were disclosed.

 3 1 2018 2018 7 7 13 12 2017 Copyright: © 2018 Tith S et al. 2018 This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background:

Opioid use during pregnancy is a growing concern in the United States. Buprenorphine has been recommended by “The American College of Obstetrics and Gynecology” as an alternative to methadone to decrease risks associated with the use of illicit opioids during pregnancy.

The partial μ-opioid agonists’ unique pharmacology, including its long half time and high affinity to the μ-opioid receptor, complicates patient management in a highly kinetic, and often urgent field like obstetric anesthesia. We reviewed our management and outcomes in this medically complex population.

Methods:

An Institutional Review Board (IRB) approved retrospective chart review was conducted of women admitted to the University of Washington Medical Center Labor and Delivery unit from July 2012 to November 2013 using buprenorphine. All deliveries, including intrauterine fetal demise, were included.

Results:

Eight women were admitted during this period to our L&D floor on buprenorphine.

All required peri-partum anesthetic management either for labor and/or cesarean delivery management. Analgesic management included dilaudid or fentanyl PCA and/or continued epidural infusion, and in one instance ketamine infusion, while the pre-admission buprenorphine regimen was continued. Five babies were viable, two women experienced intrauterine fetal death at 22 and 36 weeks gestational age (GSA), respectively, and one neonate died shortly after delivery due to a congenital diaphragmatic hernia.

Conclusions:

This case series illuminates the medical complexity of parturients using buprenorphine.

Different treatment modalities in the absence of evidence-based guidelines included additional opioid administration and continued epidural analgesia.

The management of post-cesarean pain in patients on partial μ-opioid agonists remains complex and variable, and evidence-based guidelines could be useful for clinicians to direct care.

 Buprenorphine Opioid tolerance Pregnancy Post Cesarean pain management Regional anesthesia Multimodal analgesia The author(s) declared that no grants were involved in supporting this work. Introduction

Opioid use during pregnancy is a growing concern in the United States. In a review of over 500,000 women, 76,742(15%) received at least one dose of an opioid during pregnancy and of these, 11,747 were dispensed opioids three or more times during pregnancy 1 . The U.S. Food and Drug Administration (FDA) highlighted the need for further investigation regarding the risks of pain medicine use during pregnancy in a recent Drug Safety Communication in order to inform clinical practice 2 . The FDA also emphasized that severe and persistent pain that is not effectively treated during pregnancy can result in maternal depression, anxiety, and high blood pressure 2 .

The American College of Obstetrics and Gynecology (ACOG) released their opinion regarding opioid abuse, dependence, and addiction in pregnancy. They recommended buprenorphine as an alternative to methadone to decrease risks associated with the use of illicit opioids during pregnancy 3 .

Buprenorphine (Subutex TM) is a partial μ-opioid agonist and, at high doses, a weak κ-antagonist that is taken as a sublingual tablet 4 . Suggested advantages of buprenorphine over methadone in pregnancy include less severe withdrawal symptoms, a lower risk of opioid overdose, fewer drug interactions, better ability to be treated on an outpatient basis without daily visits to a treatment program, less severe neonatal abstinence syndrome (NAS), and possibly less analgesic pain medications postpartum 3, 5– 7 . On average, parturients taking buprenorphine did so for 131.6 (SD 98.7) days of their pregnancy 1 .

At our institution, it is not uncommon for parturients to present for delivery while currently taking buprenorphine. Managing such patients, who generally have a long history of opioid abuse and addiction, is challenging, particularly when addressing post-cesarean pain management. Perfect anticipation of labor and delivery timing is not always possible. Buprenorphine’s long duration of action conflicts with the desired goal of tapering to a pure μ-opioid agonist prior to delivery.

This case series illustrates a range of presentations and multimodal treatments for patients taking buprenorphine on the labor and delivery ward, and explores the role of alternative pain management options, including epidural catheters, in these challenging cases.

 Materials and methods

After receiving Institutional Review Board (IRB) approval from the University of Washington Human Subjects Division (IRB #51693, Committee D), we performed a retrospective chart review to find parturients using buprenorphine or neonates, who received postnatal morphine to determine if their mother had been taking buprenorphine during pregnancy. We included all deliveries, including intrauterine fetal demise, from July 2012 to November 2013, on the University of Washington Medical Center Labor and Delivery unit.

 Results

There were 2521 deliveries from 7/1/2012 through 11/30/2013, of which, 152 (6%) received neonatal morphine. A chart review of the biological mothers of each of these neonates found that eight had been taking buprenorphine during pregnancy. Table 1 to Table 4 show the demographic, labor analgesia, Obstetric/Maternal outcome and neonatal outcome data of the eight patients identified. Individual cases are presented below.

Demographic Data.
1 2 3 4 5 6 7 8
Age (years) 37 27 34 28 21 22 35 34
Gravity and Parity G3P1 G1PO G5P2 G6P1 G4P3 G1PO G4P2 G1P0
Gestational Age (weeks and days) 39 1/7 39 1/7 22 5/7 36 3/7 39 30 6/7 37 1/7 37 3/7
Buprenorphine use upon L&D admission (mg/day) 8 8 8 24 4 16 16 2
Drug Use Heroin Benzos Cocaine Heroin Opiates Heroin Benzos Opiates Heroin Heroin Meth THC Opiates Meth Opiates
BMI (kg/m2) 58 33.7 46 44.1 45 33.8 31.1 30
Labor Analgesia Data.
Patient 1 2 3 4 5 6 7 8
Labor Analgesia CSE CSE CSE N/A CSE N/A CSE CSE
VAS score range - while having labor analgesia 0 0-3 0-7 0-6 0-4 0-4
Epidural Top-Ups administered 0 0 2 2 0 1
Obstetric/Maternal Outcome Data.
Patient 1 2 3 4 5 6 7 8
Mode of Delivery CS CS NSVD (D&C) CS NSVD CS NSVD CS
Indication Fetal Distress Fetal Distress Elective Repeat Fetal Distress Failure To Progress
Anesthetic used for C/S if applicable GA after failed SPA and CSE GA after failed labor analgesia conversion N/A GA per patient request N/A CSE N/A Labor analgesia converted
Post Delivery Analgesia regimen LEP IV HM PO: APAP IBP OXY HM BUP HM PCA PO: APAP IBP OXY BUP PO: APAP IBP OXY SUB FEN. PCA IV KETAMINEIV BENZO. PO: APAP IBP HM BUP PO: APAP IBP OXY BUP LEP HM PCA PO: APAP IBP HM BUP PO: APAP IBP BUP LEP HM PCA PO: APAP IBP OXY BUP
24 hrs. post delivery VAS Pain score range 0-5 0-8 0-7 6-8 0-4 2-8 2-7 3-9
Respiratory Depression during post- partum period - - - - - - - -

•  24 hrs. Post Delivery Pain scores are presented as a range of lowest to highest reported pain score

•  Respiratory Depression assessed by continuous pulse oximetry

 Neonatal Outcome Data.
Baby Patient 1 2 3 4 5 6 7 8
APGAR scores at 1 and 5 minutes 4,8 4,7 IUFD IUFD 5,6 8,6 8,9 8,9
Cord Gas: Uterine Artery (UA) and Uterine Vein (UV) pH/pCO2/pO2/HCO3/ Base Excess (BE) Base Deficit (BD) UA: 7.09/87/6/27/ BD:4.3 UV: 7.14/78/3/27/ BD 3.5 UA: 7.23/61/19/25/ BD: 3.6 UV: 7.25/56/30/24/ BD 4.0 N/A N/A UA: 7.26/61/21/27/ BD 2.2 UV: 7.31/48/30/24/ BD 2.7 UA: 7.33/58/21/30/ BE 3.6. UV: 7.39/47/33/28/ BE 2.8 UA 7.32/52/24/26/ BD 0.2 UV: 7.35/444/35/25/ BD 1.1. UA 7.34/49/25/26/ BD 0.3 UV: 7.33/53/20/28/ BE 1.0
Baby weight (grams) 3414 3758 N/A N/A 4036 1335 2533 3108
Neonatal Interventions & NAS monitoring Routine newborn care, Photo Therapy. NAS monitoring negative NICU admission due to Respiratory failure NAS monitoring positive NICU admission due to CDH, severe pulmonary Hypoplasia. Palliative care and demise day 1 NICU admission due to VATER association w. subsequent corrective surgeries Routine Newborn care NAS monitoring positive Routine Newborn care NAS monitoring positive
NAS Diagnosed No Yes N/A N/A No No Yes Yes
Legend for text and Tables 1–4.
APAP = Tylenol
BD = Base Deficit
BE = Base Excess
Benzo = Benzodiazepine
BUP = Buprenophrine
CDH = Congenital diaphragmatic hernia
CS = Cesarean Section
CSE = Combined Spinal Epidural Labor Analgesia
D&C = Dilation and Curettage surgery
GA = General Anesthesia
HM/Fent = Hydromorphone or Fentanyl
IBU = Ibuprofen
IOL = induction of labor
IUFD = Intra uterine fetal demise
IV = Intravenous administration
LEP = Lumbar Epidural Analgesia
Meth = Methamphetamine
MVA = motor vehicle accident
NAS = Neonatal Abstinence Syndrome
NICU = Neonatal Intensive care unit
NSVD = Normal vaginal delivery
OXY = Oxycodone
PCA = patient-controlled analgesia
PEA = pulseless electrical activity
PF = preservative free
PMH = past medical history
PO = Per OS once cleared for orals
POD = postoperative day
PRN = as needed by patient
PROM = premature rupture of membranes
s/p = status post
SROM = spontaneous rupture of membranes
SSEPS = somatosensory evoked potential
SUB = Suboxone
THC = Cannabis
UA/V = uterine Artery/Vein
VAS = 11-point (0–10) Visual Analog Pain Score
VATER = Vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities
Patient 1

37yo G3P1 at 39-1/7 weeks gestational age (GSA) who presented with vaginal bleeding and genital herpes. She had a history of polysubstance abuse and was started on buprenorphine (BUP) 8mg PO daily by an outside provider. On the day of admission (DOA), she had an urgent Cesarean section (CS) for possible abruption and fetal intolerance. Intraoperatively, a single shot spinal (SSS) with 100mcg of preservative-free (PF) morphine added to 12 mg of bupivacaine and 10mcg of fentanyl failed to provide adequate anesthesia. Subsequently, a combined spinal-epidural (CSE) using only 10mg of bupivacaine for the repeat spinal anesthesia was placed. Unfortunately, the patient complained of sharp incisional pain despite a negative Allis test to the T4 dermatome. She was then converted to a general anesthetic (GA).

Her post CS pain management included BUP at her admission dose, PO OXY (15mg Q3H), APAP, and IBP. The patient additionally received three doses of 0.4mg IV HM to treat breakthrough pain. Her epidural was continued for 24 hours postoperatively with 0.0625% bupivacaine at 10ml/H. At this point, the patient had successfully transitioned to a PO pain regimen and the epidural was removed. She was discharged on POD 6 (reportedly with inadequate pain control) on her pre-operative BUP dose along with a 10-day supply of HM 2–4 mg PO Q4hrs (120 pills).

Two weeks after delivery, the patient was found pulseless and cold at a downtown hotel, and CPR was initiated for PEA arrest. The patient recovered to spontaneous circulation, and therapeutic hypothermia for 24 hours was initiated. Her MRI was consistent with anoxic brain injury demonstrating infarcts in the brainstem and cerebellum. A lumbar puncture was performed and creatine kinase bands (CK-BB) were exceptionally high. SSEPS noted an absence of cortical response. The patient was placed on comfort care and died 22 days after delivery. Donation of organs after cardiac death was declined. Opioid overdose was deemed the most likely etiology, based on the patient's history of heroin abuse and accounts from bystanders. OXY was identified in a post-arrest urine drug screen.

 Patient 2

27yo G1P0 at 39-1/7 weeks GSA with a history of opioid dependence. She successfully completed an inpatient addiction treatment and was on BUP 8mg daily for one year. She was admitted for IOL in the setting of premature rupture of membranes (PROM). A CSE was placed on the DOA for labor analgesia and later an urgent CS was called for fetal distress. The epidural in situ was dosed for anesthesia in the operating room, but the patient reported a positive Allis test and consequently required a GA.

Post-operatively, the epidural was removed immediately since the epidural did not appear to provide operative anesthesia. She was not administered epidural morphine. Additional post-CS pain management included her pre-operative dose of BUP 8mg daily and a HM PCA; she was transitioned to PO OXY on POD 2. In addition, she did receive PO APAP and IBP throughout. On POD 1 she ambulated, met goals for symptom relief and was satisfied with her pain control. On POD 3, elevated blood pressures in the range of 120–150 mmHg systolic and 80–90 mmHg diastolic were measured and required treatment with furosemide and nifedipine.

She was discharged on POD 4 after a negative work-up of her hypertension. Discharge medications included a 7-day supply of OXY 5–15mg Q3H PRN (168 pills).

 Patient 3

34yo G5P2 at 22-5/7 weeks GSA with a history of bipolar disorder, morbid obesity, bicorneate uterus, and heroin abuse on buprenorphine-naloxone (Suboxone TM) 8mg daily. Her obstetric history included two prior CS’s and an IUFD. She was admitted for IOL with an IUFD at 22 weeks GSA. A CSE was placed for labor analgesia on the DOA and provided adequate pain relief, but as her labor progressed, she required multiple top-up boluses.

After an uneventful NSVD the patient required a dilation and curettage for retained products. Her epidural catheter in situ was successfully used for the surgery, and removed afterwards. Epidural morphine was not administered.

Post-op pain management included PO OXY, APAP, and IBP and her home dose of Suboxone was re-initiated; the patient had discontinued it upon hospital admission.

On POD 1 the patient was diagnosed with a post-dural puncture headache and received an epidural blood patch with good effect. She required 10mg of PO OXY on 3 occasions during her hospital stay; however, at discharge on POD 1 she was not prescribed opioids.

 Patient 4

28yo G6P1 at 36 weeks GSA with cervical shortening, vaginal bleeding and pelvic pressure. She had a PMH significant for four years of BUP 8mg TID and alprazolam 1mg BID, opiate and benzo dependence, several 2nd trimester losses, and a CS at 40 weeks for 2nd stage arrest. She was diagnosed with an IUFD, and continued on her home dose of BUP and alprazolam while inpatient. The patient strongly desired GA for her CS.

Her post CS pain management included a ketamine infusion that was started intra-operatively at 8mg/H and continued post-op for 24H, a fentanyl PCA, PO APAP and IBP, as well as PRN IV lorazepam for anxiety. The patient’s PCA use of fentanyl included 4500mcg (1st 24H), 2600mcg (next 24H) and 3–6 mg IV lorazepam per day. On POD 2 the PCA was discontinued and PO HM was started. BUP was continued throughout her stay. The patient met goals for symptom relief and was satisfied with her pain control. She was discharged on POD 2 with a 10-day supply of HM 4mg PO Q6H (120 pills).

 Patient 5

21yo G4P3 at 39 weeks GSA with a body mass index (BMI) of 44, a history of previous low transverse CS, followed by successful vaginal birth after CS (VBAC) twice before. She had a history of heroin abuse and was on BUP 4mg/day. In this pregnancy the fetus had been diagnosed with CDH (congenital diaphragmatic hernia). The patient desired a trial of labor after C-section (TOLAC) and received a CSE for labor analgesia. She remained on her pre-admission dose of BUP throughout her hospital stay. Due to the fetus’ likely poor prognosis, medical staff decided that expediting birth of the fetus would be the safest course of action. After the rupture of membranes and labor augmentation she delivered on the DOA. Unfortunately, the infant died within hours of birth due to complications from CDH.

Her postpartum pain management included PO OXY, APAP and IBP, as well as her outpatient dose of BUP. Pain remained well controlled with this regimen. Her mood was somber and she was grieving appropriately. Postpartum complications included elevated blood pressures without features of pre-eclampsia on post-partum day 1 (PPD). With well controlled pain and appropriate functional status, she was discharged three days after delivery. By the end of the hospital stay, she only required scheduled PO APAP and IBP for pain; she was discharged with no additional short acting opioids.

 Patient 6

22yo G1PO at 30-6/7 weeks GSA who presented with preterm PROM. The pregnancy was complicated by heroin and methamphetamine abuse during the first trimester. After admission to the antepartum unit, her home dose of daily BUP 16mg for the remainder of her pregnancy was ordered. On the third day of the hospitalization, prolonged fetal decelerations prompted an urgent CS. A routine CSE was placed for CS anesthesia, and the surgery proceeded uneventfully. The spinal dose included bupivacaine 12.5mg, PF morphine 100mcg, and fentanyl 10mcg. Ketorolac 30mg IV was administered at the end of the case per routine protocol.

Her post CS pain management included an epidural infusion of bupivacaine 0.0625% at 10cc/H, a HM PCA, PO APAP and IBP and her daily home dose BUP. The patient’s pain was well-controlled and she was fully satisfied with pain management. After successful transition to PO HM the epidural was removed. The patient remained satisfied with her pain relief and was discharged on POD 2 with 36 tabs of 2mg HM.

The neonate was newly diagnosed with congenital anomalies including imperforate anus and esophageal atresia, with a VATER association. The patient stayed with her baby at the local children’s hospital and was unable to visit her distant provider for BUP refills. It was noted that she subsequently relapsed into her previous abuse pattern, within three months postpartum.

 Patient 7

35yo G4P2 at 37-1/7 weeks GSA who presented for IOL in the setting of term IUFD in a previous pregnancy. She had a history of opioid dependence following an injury in the military requiring multiple reconstructive knee surgeries. She was placed on BUP 16mg daily for the remainder of her pregnancy and received this also throughout her hospital stay. During her IOL she received a CSE for labor analgesia, followed by an uncomplicated vaginal delivery 2 days after admission.

Her postpartum pain management included PO APAP and IBP and her daily home dose BUP; epidural was removed after delivery. She did not require additional PO opioids during her hospital stay and was discharged without any additional short acting opioids on POD 2.

 Patient 8

34yo G1PO at 37-3/7 weeks GSA who presented with SROM. She had a history of opioid dependence following an MVA, in addition to current methamphetamine use. Her PMH was also significant for a congenital ventricular septal defect s/p surgery at age 1yo, with secondary pulmonary stenosis and a dilated right ventricle with mild dysfunction. In addition, the patient had a complex partial seizure disorder, tobacco use, and poor compliance with pregnancy care. She had been on BUP 2mg BID throughout the pregnancy, which was continued during her L&D stay. She received a CSE on the DOA for labor analgesia and required a CS for second stage arrest a day later; the epidural catheter in situ was successfully converted to provide anesthesia. She was not given epidural morphine.

Her post CS pain management included a HM PCA, an epidural infusion (0.1% bupivacaine at 8cc/H), PO APAP, IBP and her home dose of BUP. On POD 2 the epidural infusion was discontinued. On POD 3 she was transitioned to PO OXY and the PCA stopped. She was counseled not to use amphetamines while breastfeeding. On POD 5 she was discharged to home with 30 tabs of 5mg OXY, with the plan of continuing BUP in the outpatient setting. In the following days, she returned to clinic requesting additional opioids due to breast pain; she was subsequently prescribed 20 tabs of 5mg OXY.

 Discussion

This retrospective chart review shows the heterogeneity and complexity of peripartum pain management in patients on buprenorphine (Subutex TM) therapy. Neuraxial techniques, namely continued utilization of epidural catheters placed for labor and/or the cesarean delivery was the most common post-operative analgesic method used or offered to patients. While lumbar epidural analgesia provides effective analgesia 8– 10 , the associated motor block hinders post-cesarean mobilization, often necessitating that epidural infusions be stopped on POD 2, in comparison to other surgical populations where epidural analgesia can be used longer 11 .

In addition to our standard post-CS multimodal analgesic regimen, which includes neuraxial opioids, PO APAP, NSAIDs, and OXY, IV ketamine is utilized mainly as a rescue medication for intractable pain. One patient with a non-viable fetus received a low dose (8mg/H) ketamine infusion post-operatively. NMDA receptor antagonist infusions are rarely used on our L&D floor, in part due to uncertainty of fetal central nervous system effects 12, 13 . Similarly, gabapentinoids are reserved for cases where the pain management is complex, due to unclear fetal effects and reported maternal sedation 14 . None of our reported cases received this class of drug. Most patients received additional IV opioids after their CS’s. Fentanyl was used in one case, while HM was used in four cases. The most effective opioid in the setting of concurrent BUP remains unclear, some suggest using morphine 15 . The particular strong µ-opioid receptor affinity of BUP, however, complicates the titration of commonly used pure agonists for pain management. To allow for better titration, some suggest the use of shorter acting opioids, like fentanyl, which patient 5 received, in line with our acute pain service recommendations.

In many of the cases we described, transitioning patients from IV to PO opioid pain medication proved challenging and often required a prolonged hospital stay. OXY is our routine PO opioid and we found it to be effective in six cases; two women preferred PO HM. A retrospective study that matched patients treated with BUP to control patients found that patients maintained on BUP have similar intrapartum pain and analgesic needs during labor, yet experience more postpartum pain and use more opioid analgesia following cesarean delivery 16 . Theoretically, adding opioids to the local anesthetic epidural infusion for post-operative pain management, compared to an IV PCA system, may reduce maternal plasma levels and subsequent fetal opioid exposure. However we found this not feasible in our teaching institution setting.

All patients in our series were continued on their home dose of BUP throughout hospitalization. One key consideration is whether patients should be tapered off BUP prior to delivery when operative techniques may be necessary. One case report described a woman who tapered from 24mg of BUP starting at 14 weeks GSA 17 . The patient demonstrated increased withdrawal symptoms and her fetus showed signs of distress. The woman was re-initiated on BUP and delivered without complication. Further study is needed to investigate the appropriate tapering methods in this population, and each patient’s medical history and psychosocial background must be carefully evaluated. The potential risks of tapering, including autonomic effects and withdrawal symptoms, to both the mother and fetus may not be justified in many cases. The current evidence continues to support the relative safety of BUP; one study found that women who taper their BUP by more than 50% during pregnancy did not have significantly different neonatal outcomes compared to women who remained on the same dose. 18 . Also, fewer term NAS infants require drug treatment if exposed to BUP compared to methadone. 19 .

Three women in our series relapsed into pre-pregnancy habits of opioid abuse. One woman unfortunately overdosed and a subsequent urine sample was positive for oxycodone and its metabolites. This emphasizes the importance of post-hospital care and follow-ups in this high-risk population. To this end, the University of Washington operates a perioperative pain clinic staffed with specialized physicians and pharmacists that follow-up with high risk patients. In this setting, opioid weaning can be professionally supported until the regimen is deemed manageable by the primary provider. Utilization of this service is patient dependent, and social disarray is a risk factor for poor compliance.

The management of post-cesarean pain in patients on partial μ-opioid agonists remains complex and variable, and evidence-based guidelines could be useful for clinicians to direct care. Pre-existing protocols, customized to provide flexibility, could be extremely valuable in a setting that is by its very nature, highly kinetic and often urgent. It is crucial that health care providers dealing with these complicated patients are aware of possible options that offer safe treatment.

 Data availability

All gathered data was taken directly from patient files, de-identified and entered in the tables presented.

 Ethics and consent

Approval for the study was obtained from the Institutional Review Board (IRB) of the University of Washington Human Subjects Division (IRB #51693, Committee D). For this study a waiver of consent from patients was obtained from the IRB.

 Bateman BT Hernandez-Diaz S Rathmell JP : Patterns of opioid utilization in pregnancy in a large cohort of commercial insurance beneficiaries in the United States. Anesthesiology. 2014;120(5):1216–24. 24525628 10.1097/ALN.0000000000000172 3999216 FDA Drug Safety Communication: FDA has reviewed possible risks of pain medicine use during pregnancy. Accessed March 30, 2017. Reference Source ACOG Committee on Health Care for Underserved Women; American Society of Addiction Medicine: ACOG Committee Opinion No. 524: Opioid abuse, dependence, and addiction in pregnancy. Obstet Gynecol. 2012;119(5):1070–6. 22525931 10.1097/AOG.0b013e318256496e Lutfy K Eitan S Bryant CD : Buprenorphine-induced antinociception is mediated by mu-opioid receptors and compromised by concomitant activation of opioid receptor-like receptors. J Neurosci. 2003;23(32):10331–7. 14614092 Johnson RE Jones HE Fischer G : Use of buprenorphine in pregnancy: patient management and effects on the neonate. Drug Alcohol Depend. 2003;70(2 Suppl):S87–101. 12738353 10.1016/S0376-8716(03)00062-0 Gaalema DE Scott TL Heil SH : Differences in the profile of neonatal abstinence syndrome signs in methadone- versus buprenorphine-exposed neonates. Addiction. 2012;107 Suppl 1:53–62. 23106927 10.1111/j.1360-0443.2012.04039.x 4165073 Jones HE O’Grady K Dahne J : Management of acute postpartum pain in patients maintained on methadone or buprenorphine during pregnancy. Am J Drug Alcohol Abuse. 2009;35(3):151–6. 19462298 10.1080/00952990902825413 2925397 Ramin SM Gambling DR Lucas MJ : Randomized trial of epidural versus intravenous analgesia during labor. Obstet Gynecol. 1995;86(5):783–789. 7566849 10.1016/0029-7844(95)00269-W Dickinson JE Paech MJ McDonald SJ : Maternal satisfaction with childbirth and intrapartum analgesia in nulliparous labour. Aust N Z J Obstet Gynaecol. 2003;43(6):463–468. 14712952 10.1046/j.0004-8666.2003.00152.x Sharma SK McIntire DD Wiley J : Labor analgesia and cesarean delivery: an individual patient meta-analysis of nulliparous women. Anesthesiology. 2004;100(1):142–148; discussion 6A. 14695735 10.1097/00000542-200401000-00023 Comparative Obstetric Mobile Epidural Trial (COMET) Study Group UK: Effect of low-dose mobile versus traditional epidural techniques on mode of delivery: a randomised controlled trial. Lancet. 2001;358(9275):19–23. 11454372 10.1016/S0140-6736(00)05251-X Zhao T Li Y Wei W : Ketamine administered to pregnant rats in the second trimester causes long-lasting behavioral disorders in offspring. Neurobiol Dis. 2014;68:145–55. 24780497 10.1016/j.nbd.2014.02.009 Dong C Rovnaghi CR Anand KJ : Ketamine affects the neurogenesis of rat fetal neural stem progenitor cells via the PI3K/Akt-p27 signaling pathway. Birth Defects Res B Dev Reprod Toxicol. 2014;101(5):355–63. 25231110 10.1002/bdrb.21119 4330101 Monks DT Hoppe DW Downey K : A Perioperative Course of Gabapentin Does Not Produce a Clinically Meaningful Improvement in Analgesia after Cesarean Delivery: A Randomized Controlled Trial. Anesthesiology. 2015;123(2):320–6. 26200182 10.1097/ALN.0000000000000722 SOAP 2013 Summer Newsletter: Education Committee: Post Cesarean Pain Management in the Buprenorphine (Subutex) Dependent Patient. Meyer M Paranya G Keefer Norris A : Intrapartum and postpartum analgesia for women maintained on buprenorphine during pregnancy. Eur J Pain. 2010;14(9):939–43. 20444630 10.1016/j.ejpain.2010.03.002 Well-Strand GK Kvamme O Andreassen A : A woman’s experience of tapering from buprenorphine during pregnancy. BMJ Case Rep. 2014;2014: pii: bcr2014207207. 25540212 10.1136/bcr-2014-207207 4281552 Welle-Strand GK Skurtveit S Tanum L : Tapering from Methadone or Buprenorphine during Pregnancy: Maternal and Neonatal Outcomes in Norway 1996–2009. Eur Addict Res. 2015;21(5):253–261. 25967268 10.1159/000381670 Nanda S Brant R Regier M : Buprenorphine: a new player in neonatal withdrawal syndrome. W V Med J. 2015;111(1):16–21. 25665273 10.5256/f1000research.14490.r29456 Reviewer response for version 1 Baird Emily J. 1 Referee Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR, USA

Competing interests: No competing interests were disclosed.

 1 2 2018 Copyright: © 2018 Baird EJ 2018 This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. recommendation approve

Tith et al. highlight the complexity of the analgesic management of labor and delivery in parturients receiving buprenorphine. The retrospective chart review details the peripartum course of 8 women on buprenorphine maintenance. Given the heterogeneity in patient demographics, buprenorphine dose, analgesic regimen, mode of delivery, and neonatal outcomes, it is difficult to extract meaningful conclusions. The vast disparateness of the peripartum management of parturients on buprenorphine vividly demonstrates the need for evidence-based practice guidelines.

Although the details of the individual patient’s peripartum course are interesting, the comprehensiveness of each description is distracting. Since the focus of the review is the analgesic management of labor and delivery on patients receiving buprenorphine, consider omitting extraneous maternal and neonatal details. The patients’ descriptions should conclude with discharge. Details such as “two weeks after delivery, patient was found pulseless…,” “patient stayed with her baby at the local children’s hospital…,” and “in the following days, she returned to clinic requesting opioids due to breast pain” detract from the intention of the review. Similarly, the specifics of the neonate’s postdelivery course (i.e. diagnosis of imperforate anus) are irrelevant. Concise reconstruction of the results section will highlight the focus of this review.

Tables 1-4 are not referred to in the text. Without further explanation of the tables in the text, it is unclear what information the table is intended to convey.

Table 2 (Labor Analgesia Data) is a bit misleading. For patient 1, the table indicates the patient had a CSE for labor that required no “top-ups” and resulted in a VAS score of zero. According to the results section, patient 1 had a failed single shot spinal, followed by a CSE, and ultimately needed a general anesthetic for cesarean delivery. This seems to suggest that the patient never received labor analgesia but rather the CSE was placed for surgical anesthesia.

The absences of a comprehensive legend for Table 3 makes it challenging to interpret. Twelve abbreviations are used in Table 3 which are not defined until the following page. Consider including a key to the abbreviations in the table legend. In addition, since respiratory depression did not occur in any parturient, consider removing it from the table.

The discussion section would be more meaningful if it offered some interpretation of the data rather than summarizing the results presented in the previous section. Specifically, why did 3 of the 5 women undergoing cesarean delivery have a general anesthetic? Based on the limited experience, what is the optimal labor analgesia regimen? Post vaginal delivery pain regimen? Post-operative regimen? Neonatal implications of intrauterine exposure to buprenorphine?

Tith et al.’s retrospective review of the periparturm course of parturients dependent on buprenorphine illustrates the heterogeneity of analgesic regimens for labor and delivery. The review highlights the need for research to help develop protocols and standards.

Is the work clearly and accurately presented and does it cite the current literature?

Partly

If applicable, is the statistical analysis and its interpretation appropriate?

Not applicable

Are all the source data underlying the results available to ensure full reproducibility?

No source data required

Is the study design appropriate and is the work technically sound?

Partly

Are the conclusions drawn adequately supported by the results?

Partly

Are sufficient details of methods and analysis provided to allow replication by others?

Partly

Reviewer Expertise:

NA

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.