毒理性
以下是在哺乳期间使用的概要：硬脊膜外吗啡用于剖宫产后母亲的镇痛，导致初乳和乳汁中吗啡含量微不足道。在产后早期通过静脉或口服给予母亲的吗啡剂量，比硬脊膜外吗啡导致乳汁中的吗啡水平更高。分娩疼痛药物可能会延迟哺乳的开始。哺乳期间口服麻醉剂可能会导致婴儿嗜睡，严重的中枢神经系统抑制，尽管低剂量的吗啡可能比其他鸦片类药物更可取。新生婴儿似乎对即使是小剂量的麻醉性镇痛药也特别敏感。一旦母亲的乳汁开始分泌，最好使用非麻醉性镇痛药来控制疼痛，并限制母亲的吗啡摄入量为2到3天，低剂量，并密切监测婴儿，特别是在门诊环境中。如果婴儿表现出过度嗜睡（比平时多）、哺乳困难、呼吸困难或母亲使用吗啡时的无力，应立即联系医生。一些证据表明，与基于患者控制的静脉吗啡镇痛相比，静脉注射酮咯酸、口服布洛芬和对乙酰氨基酚作为剖宫产后多模式镇痛的一部分，可以减少未能进行纯母乳喂养的母亲比例。
对哺乳婴儿的影响：一名足月婴儿在生命的第一个星期住院期间出现无法解释的呼吸暂停和心动过缓伴发绀，测量婴儿血浆中的吗啡浓度为1.2微克/升。该测量是在母亲最后一次吗啡剂量108小时后进行的，未在乳汁中检测到吗啡。母亲的剂量未报告。
与使用静脉PCA美沙酮进行剖宫产镇痛的母亲相比，使用静脉PCA吗啡的母亲在产后第3天后的新生儿更加警觉和定向，与非哺乳对照组婴儿相比。新生儿的呼吸速率没有差异。作者指出，非哺乳婴儿的母亲比哺乳母亲有更多的生育次数，这与假定对哺乳的欲望较低相结合，可能导致了非哺乳新生儿的行为和警觉性评分较低。
一项研究追踪了在维也纳一家诊所接受口服缓释吗啡治疗的孕妇及其新生儿。与未进行母乳喂养的婴儿（n = 91）相比，母乳喂养的婴儿（n = 21）的新生儿戒断症状测量值较低，吗啡剂量需求较低（5.23毫克对8.75毫克），治疗新生儿戒断症状的时间较短（10.2对18.1天）且住院时间较短（19.7对31天）。
对美国所有毒物控制中心共享数据库进行了搜索，时间为2001年至2017年，涉及哺乳期间药物使用的电话。在2319个电话中，有一个婴儿通过母乳接触了物质，其中7个被归类为导致严重不良影响，其中一个是吗啡。一名一个月大的婴儿接触了芬太尼、吗啡、氧可酮和未指定的苯二氮卓类药物。婴儿被送入重症监护室，并被描述为烦躁不安、心动过速、混淆、嗜睡、无力、瞳孔缩小、呼吸抑制、酸中毒和高血糖。剂量、给药途径和哺乳程度未报告，婴儿存活下来。
一名母亲因阿片类药物使用障碍，每天静脉注射高达2克的芬太尼。在医院，她转为静脉注射氢吗啡酮120毫克，每日三次，口服氢吗啡酮32毫克，必要时每小时一次，以及口服美沙酮70毫克，每日一次。在口服吗啡剂量逐渐减少9天后，给婴儿喂了72毫升母亲的挤奶。在第十天，婴儿接受了两次0.1毫克口服吗啡的剂量，然后在母亲注射110毫克静脉氢吗啡酮3小时后哺乳了30分钟。婴儿警觉活泼，喂养和睡眠良好，婴儿的吗啡被停用。没有出现临床相关的呼吸暂停、心动过缓、血氧饱和度下降、呼吸抑制的迹象或过度镇静。婴儿继续接受配方奶加上母乳喂养或挤奶，没有重要的不良影响。母亲的氢吗啡酮剂量在47天内逐渐减少，而口服美沙酮和口服缓释吗啡的剂量分别增加到190毫克和1200毫克/天，她在产后第58天出院。出院后母乳喂养的程度未报告。在4个月大时，婴儿在所有发展领域都高于平均水平。
在加拿大安大略省的一项人口研究中，有85,852名在出院后七天内开具阿片类药物处方的母亲与538,815名未开具阿片类药物处方的母亲进行了匹配。与出生时母亲未开具阿片类药物处方的婴儿相比，出生时母亲开具阿片类药物处方的婴儿在出生后30天内住院的可能性并不更高。出生时母亲开具阿片类药物处方的婴儿在随后的30天内被送往急诊科的可能性略高（风险比1.04）。没有婴儿死亡。开具阿片类药物处方的母亲中有19%开具了吗啡。值得注意的是，药物供应的中位数是3天（IQR 2-4）。
对哺乳和母乳的影响：吗啡可以增加血清催乳
◉ Summary of Use during Lactation:Epidural morphine given to mothers for postcesarean section analgesia results in trivial amounts of morphine in their colostrum and milk. Intravenous or oral doses of maternal morphine in the immediate postpartum period result in higher milk levels than with epidural morphine. Labor pain medication may delay the onset of lactation. Maternal use of oral narcotics during breastfeeding can cause infant drowsiness, and severe central nervous system depression, although low-dose morphine might be preferred over other opiates. Newborn infants seem to be particularly sensitive to the effects of even small dosages of narcotic analgesics. Once the mother's milk comes in, it is best to provide pain control with a nonnarcotic analgesic and limit maternal intake of morphine to 2 to 3 days at a low dosage with close infant monitoring, especially in the outpatient setting. If the baby shows signs of increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness during maternal morphine use, a physician should be contacted immediately. Some evidence suggests that IV ketorolac, oral ibuprofen and acetaminophen as part of a multimodal post-cesarean section analgesia reduces percentage of mothers who fail exclusive breastfeeding compared to patient-controlled IV morphine-based analgesia.
◉ Effects in Breastfed Infants:In a term infant with unexplained apnea and bradycardia with cyanosis while hospitalized in the first week of life, the measured plasma morphine in the infant was 1.2 mcg/L. The measurement was taken 108 hours after the mother's last dose of morphine and no morphine was detected in her milk. The mother's dose was not reported.
Breastfed newborns of mothers using intravenous PCA morphine for postcesarean analgesia were more alert and better oriented after postpartum day 3 than infants of mothers using intravenous PCA meperidine and nonbreastfed control infants. There was no difference in newborn respiratory rates. The authors stated that the mothers of nonbreastfed infants had greater parity than the breastfeeding mothers which, combined with a presumed lower desire to breastfeed, may have contributed to the lower behavioral and alertness scores in the nonbreastfed newborns.
A study of pregnant women being treated for opiate dependency with slow-release oral morphine at a clinic in Vienna were followed as were their newborn infants. Compared to infants who were not breastfed (n = 91), breastfed infants (n = 21) had lower average measures of neonatal abstinence, lower dosage requirements of morphine (5.23 mg vs 8.75 mg), shorter durations of treatment for neonatal abstinence (10.2 vs 18.1 days) and shorter hospital stays (19.7 vs 31 days).
A search was performed of the shared database of all U.S. poison control centers for the time period of 2001 to 2017 for calls regarding medications and breastfeeding. Of 2319 calls in which an infant was exposed to a substance via breastmilk, 7 were classified as resulting in a major adverse effect, and one of these involved morphine. A one-month-old infant was exposed to fentanyl, morphine, oxycodone, and unspecified benzodiazepines. The infant was admitted to the intensive care unit and described as being agitated and irritable and having tachycardia, confusion, drowsiness, lethargy, miosis, respiratory depression, acidosis, and hyperglycemia. The dosages, routes of administration, and extent of breastfeeding were not reported and the infant survived.
An infant was born to a mother with opioid use disorder who was taking up to 2 grams of intravenous fentanyl daily. In the hospital she was transitioned to intravenous hydromorphone 120 mg three times daily, oral hydromorphone 32 mg every hour as needed, and methadone 70 mg daily by mouth. After 9 days of tapering the oral morphine dosage, the infant was given 72 mL of the mother’s expressed milk. On day 10, the infant received two doses of 0.1 mg of oral morphine and then breastfed for 30 minutes 3 hours after a maternal dose of 110 mg of intravenous hydromorphone. The infant was alert and active, feeding and sleeping well, and the infant’s morphine was discontinued. There were no clinically relevant episodes of apnea, bradycardia, desaturation, signs of respiratory depression, or excessive sedation. The infant continued to receive formula plus either breastfeeding or expressed milk with no clinically important adverse effects. The mother’s hydromorphone dose was tapered over 47 days while oral methadone and oral slow-release morphine were increased to 190 mg and 1200 mg daily, respectively, and she was discharged on day 58 postpartum. The extent of breastfeeding after hospital discharge was not reported. At 4 months of age, the infant scored above average on all developmental domains.
In population study in the province of Ontario, Canada, 85,852 who filled an opioid prescription within seven days of discharge after delivery were matched to 538,815 did not. Compared with infants born to mothers who were not prescribed an opioid, those born to mothers prescribed an opioid were no more likely to be admitted to hospital in the 30 days after the index date. Infants born to mothers prescribed opioids after delivery were slightly more likely to be taken to the emergency department in the subsequent 30 days (hazard ratio 1.04). No infant deaths occurred. Nineteen percent of the mothers prescribed an opioid were prescribed morphine. Of note is that the median drug supply was for 3 days (IQR 2-4).
◉ Effects on Lactation and Breastmilk:Morphine can increase serum prolactin. However, the prolactin level in a mother with established lactation may not affect her ability to breastfeed.
A national survey of women and their infants from late pregnancy through 12 months postpartum compared the time of lactogenesis II in mothers who did and did not receive pain medication during labor. Categories of medication were spinal or epidural only, spinal or epidural plus another medication, and other pain medication only. Women who received medications from any of the categories had about twice the risk of having delayed lactogenesis II (>72 hours) compared to women who received no labor pain medication.
A randomized, blinded study in 250 women receiving a cesarean section at term compared the effects on breastfeeding of postpartum intrathecal morphine 300 to 500 mcg to a control group who received a non-opiate for pain. Systemic morphine or meperidine could be given to control mothers for severe breakthrough pain. All mothers also received midazolam 2 mg after cord clamping and oxytocin. At 2 months of age, there was no difference in the breastfeeding rates between the two groups, although infant weight gain was about 5% lower in the spinal morphine group.
A prospective study in an Australian hospital compared mothers who received epidural fentanyl analgesia, subcutaneous morphine or neither during labor and delivery. When controlled for labor induction, instrumental delivery and special care nursery admission, no difference was seen between the 3 groups in breastfeeding rates at discharge or at 6 weeks postpartum.
A multicenter, prospective cohort study in Hong Kong of 1277 women who gave birth found that women who received epidural analgesia with either fentanyl or morphine had no decreased frequency breastfeeding in the first hour compared to mothers who did not receive epidural analgesia. All epidural injections were combined with a local anesthetic, but the exact dosages were not given.
A prospective cohort study of postcesarean pain control compared (1) morphine PCA and scheduled ibuprofen for the first 12 hours followed by continued scheduled ibuprofen with hydrocodone-acetaminophen as needed to a multimodal pain management regimen consisting of (2) acetaminophen 1000 mg orally every 8 hours, ketorolac 30 mg IV once initially, then 15 mg IV every 8 hours for 24 hours, then ibuprofen 600 mg orally every 8 hours for the remainder of the postoperative course with opioids given only as needed. Of women who planned to exclusively breastfeed on admission, fewer women used formula prior to discharge in the multimodal group compared to the traditional group (9% vs. 12%).
来源:Drugs and Lactation Database (LactMed)
