妊娠期使用丁基原啡因後的新生兒結局
Elizabeth E. Krans，醫學博士 / 社論 / n engl j med 387;22 / 2022 年 12 月 1 日 /
財團法人台灣紅絲帶基金會編譯
美國的阿片類藥物危機對孕婦及其子女產生了深遠影響。 在過去十年中，幾乎所有州和人口群體在懷孕期間對阿片類藥物相關的診斷率都有所增加，現在過量服用是懷孕相關死亡的主要原因。在懷孕期間，使用美沙酮和用於阿片類藥物使用障礙的丁基原啡因等藥物可降低藥物過量和早產的風險，並且是針對患有該障礙的孕婦推薦的循證治療方法。
30 多年來，美沙酮是主要用於治療懷孕期間阿片類藥物使用障礙的藥物。 儘管在減輕戒斷和渴望方面極其有效，但用於治療阿片類藥物使用障礙的美沙酮只能由獲得聯邦許可的藥物和酒精治療計畫分發。患者通常需要每天參加治療計畫以觀察藥物給藥情況，這可能會對治療參與造成障礙。限制性法規和政策阻礙了美沙酮治療方案的擴展以滿足患者的需求，尤其是在農村地區，而且提供者無法透過聯邦許可方案以外的方式開出美沙酮處方，這使這種高效治療與常規產科照護脫節。
2010 年，母親阿片類藥物治療：人類實驗研究 (MOTHER) 試驗極大地改變了患有阿片類藥物使用障礙的孕婦的治療前景。 MOTHER 試驗是一項國際性、雙盲、雙模擬、隨機、對照試驗，分析了妊娠期間丁基原啡因的使用與美沙酮的使用對新生兒戒斷症狀群（觀察到的臨床戒斷症狀群）相關結局的影響，暴露於丁基原啡因的嬰兒治療新生兒戒斷症狀群的嗎啡明顯減少，新生兒戒斷症候群的治療時間更短，住院時間也短於暴露於美沙酮嬰兒。在新生兒戒斷症狀群比率不斷上升的情況下發表，這項試驗的結果為產科社區提供了一種有效的美沙酮治療替代品——一種可以由丁基原啡因豁免 (buprenorphine waiver，註) 之提供者於任何門診環境中開出的處方藥，具有較低的呼吸抑制風險，並可降低新生兒戒斷症候群的嚴重程度。
儘管 MOTHER 試驗的結果透過擴大到對主流醫學中經常被邊緣化人群的治療選擇，重新定義了對患有阿片類藥物使用障礙的孕婦的照護，但它有幾個重要的局限性。 在接受隨機分組的 175 名參與者中，只有 131 名完成了試驗； 與美沙酮組 (18%) 相比，丁基原啡因組 (33%) 的失訪率存在差異，這可能會導致偏倚。 MOTHER 試驗的小樣本量也限制了對與出生相關的不良結局的組間差異之檢測，包括早產、胎齡兒體型較小和低出生體重，以及在接受新生兒戒斷症候群治療的各組中嬰兒數量的差異，這是 MOTHER 試驗的主要結果之一。
在新英格蘭本期期刊中，Suarez 和同事試圖透過採用人群水準的方法來評估與懷孕期間使用丁基原啡因或美沙酮相關的結果，來解決 MOTHER 試驗的許多局限性。作者使用了一個大型的國家醫療補助數據集來創建一個回顧性世代，研究對象是使用丁基原啡因（13,255 人）或美沙酮（6,019 人）之患有阿片類藥物使用障礙的孕婦。 根據孕期暴露時間（懷孕早期、懷孕晚期、分娩前30天）評估藥物暴露。
在分娩前 30 天內接觸過美沙酮的嬰兒中，有 69% 發生新生兒戒斷症候群，而同期接觸丁基原啡因的嬰兒中，這一比例為 52%。 在本研究中，暴露於丁基原啡因的嬰兒中新生兒戒斷症候群的發生率相對低於暴露於美沙酮的嬰兒，其差異幅度與接受新生兒戒斷治療的嬰兒數量的組間差異相似 MOTHER 試驗中的症候群。Suarez 等人的研究中樣本數量較大，因而對時間間隔的估計具有更窄的信賴區間。無論暴露發生在何時，與使用美沙酮相比，使用丁基原啡因可降低早產、胎齡兒體型較小和低出生體重的風險。
這項研究的優勢包括樣本量大和對可能混淆研究結果的協同變量的仔細關注，包括對每個暴露窗口使用傾向評分分析 (propensity-score analysis)，旨在平衡暴露組中所有測量的共變量。以及敏感性分析以解決可能的暴露和結果之錯誤分類，當未測量的干擾時不會去改變對結果的解釋。
丁基原啡因現在是患有阿片類藥物使用障礙的孕婦最常用的藥物。雖然 Suarez 等人的研究結果。 為了進一步加強丁基原啡因作為許多孕婦一線治療選擇的作用，隨著芬太尼等合成阿片類藥物的使用升級，丁基原啡因的使用變得更具挑戰性。丁基原啡因是一種部分的 μ-阿片受體激動劑，可能不足以減輕使用芬太尼的患者對阿片類藥物的渴望和加速戒斷，芬太尼的效力是嗎啡的 50 到 100 倍。 因此，在懷孕期間選擇使用美沙酮還是丁基原啡因應該是患者和提供者之間共同決策過程的結果，其中包括患者偏好、既往治療經驗和藥物可用性等因素。 諸如此類的研究強調了評估懷孕和哺乳期間藥物使用情況的研究的重要性。迫切需要此類研究來擴大對患有阿片類藥物使用障礙的孕婦的治療選擇，尤其是在阿片類藥物危機繼續蔓延的情況下。
作者提供的披露表格與這篇社論的全文可在 NEJM.org 上獲取。
來自匹茲堡大學婦產科和生殖科學系以及馬吉婦女研究所——均位於匹茲堡。
（註）丁基原啡因豁免 (buprenorphine waiver) ：是指美國藥物成癮治療法 (DATA 2000) 之「豁免」立法，該立法授權門診患者使用丁基原啡因治療阿片類藥物使用障礙。2021 年 4 月 28 日法規更新，任何臨床醫生都可以在醫院對出現阿片類藥物戒斷症狀的患者使用丁基原啡因。 但是，為了開出丁基原啡因的處方，臨床醫生必須獲得「 豁免」。以前要求在申請豁免之前醫生需進行 8 小時培訓。而這項規定已經改變，不再需要培訓證書。但臨床醫生仍然需要申請豁免。醫師、執業護士 (NP)、醫師助理 (PA)、臨床護士專家 (CNS)、認證註冊護士麻醉師 (CRNA) 和認證助產士 (CNM) 無需完成培訓即可申請獲得豁免。但是，免費的培訓仍然在線上提供。
Neonatal Outcomes after Use of Buprenorphine during Pregnancy
Elizabeth E. Krans, M.D / Editorials / n engl j med 387;22 / December 1, 2022
The opioid crisis in the United States has had profound effects on pregnant persons and their children. Over the past decade, the rate of opioid-related diagnoses during pregnancy has increased across nearly all states and demographic groups, and overdose is now a leading cause of pregnancy-related deaths. In pregnancy, the use of medications such as methadone and buprenorphine for opioid use disorder reduces the risks of overdose and preterm birth and is the recommended evidence-based treatment approach for pregnant persons with the disorder.
For more than 30 years, methadone was the medication that was predominantly used to treat opioid use disorder during pregnancy. Although extremely effective in mitigating withdrawal and cravings, methadone for use in the treatment of opioid use disorder can only be dispensed by federally licensed drug and alcohol treatment programs. Patients are often required to present to a treatment program daily for observed medication administration, which can create barriers to treatment engagement. Restrictive regulations and policies have hindered the expansion of methadone treatment programs to meet patient demands, especially in rural areas, and the inability of providers to prescribe methadone other than through the federally licensed programs has disconnected this highly effective treatment from routine obstetrical care.
In 2010, the Maternal Opioid Treatment: Human Experimental Research (MOTHER) trial dramatically changed the treatment landscape for pregnant persons with opioid use disorder. The MOTHER trial was an international, doubleblind, double-dummy, randomized, controlled trial that analyzed buprenorphine use as compared with methadone use during pregnancy with regard to the effects on outcomes associated with neonatal abstinence syndrome, a clinical withdrawal syndrome observed in infants after opioid exposure in utero. Infants who were exposed to buprenorphine received significantly less morphine to treat the symptoms of neonatal abstinence syndrome, had a shorter duration of treatment for neonatal abstinence syndrome, and had a shorter hospital length of stay than infants exposed to methadone. Published amid escalating rates of neonatal abstinence syndrome, findings from this trial provided the obstetrical community with an effective treatment alternative to methadone — one that can be prescribed in any outpatient setting by a provider with a buprenorphine waiver, has a low risk of respiratory depression, and reduces the severity of neonatal abstinence syndrome.
Although the findings from the MOTHER trial redefined care for pregnant patients with opioid use disorder by expanding treatment options for a population that is often relegated to the margins of mainstream medicine, it had several important limitations. Of the 175 participants who underwent randomization, only 131 completed the trial; the differential loss to follow-up in the buprenorphine group (33%) as compared with the methadone group (18%) introduced the possibility of bias. The small sample size of the MOTHER trial also limited detection of between-group differences in adverse outcomes related to birth, including preterm birth, small size for gestational age, and low birth weight, as well as differences in the numbers of infants in each group who received treatment for neonatal abstinence syndrome, one of the primary outcomes of the MOTHER trial.
In this issue of the Journal, Suarez and colleagues attempt to address many of the limitations of the MOTHER trial by taking a populationlevel approach to the assessment of outcomes associated with the use of buprenorphine or methadone during pregnancy. The authors used a large national Medicaid data set to create a retrospective cohort of pregnant persons with opioid use disorder who used buprenorphine (13,255 persons) or methadone (6019 persons). Medication exposure was evaluated according to the timing of the exposure during pregnancy (early pregnancy, late pregnancy, and 30 days before delivery).
Neonatal abstinence syndrome occurred in 69% of the infants who were exposed to methadone in the 30 days before delivery, as compared with 52% of those who were exposed to buprenorphine during the same period. The relatively fewer occurrences of neonatal abstinence syndrome among the infants in this study who were exposed to buprenorphine than among those who were exposed to methadone was a difference similar in magnitude to the between group difference in the number of infants who were treated for neonatal abstinence syndrome in the MOTHER trial. However, the larger sample size in the study by Suarez et al. resulted in an estimate with much narrower confidence intervals. Regardless of when exposure occurred, buprenorphine use was associated with lower risks of preterm birth, small size for gestational age, and low birth weight than methadone use.
The strengths of this study include the large sample size and careful attention to covariates that could confound the findings, including the use of a propensity-score analysis for each exposure window that was intended to balance all measured covariates among the exposure groups. Sensitivity analyses that addressed possible exposure and outcome misclassification as well as unmeasured confounding did not change the interpretation of the findings.
Buprenorphine is now the most commonly used medication in pregnant persons with opioid use disorder.9 Although findings from the study by Suarez et al. further reinforce the role of buprenorphine as a first-line treatment option for many pregnant patients, the use of buprenorphine has become more challenging with the escalation of the use of synthetic opioids such as fentanyl. A partial mu-opioid receptor agonist, buprenorphine may insufficiently mitigate opioid cravings and precipitate withdrawal in patients who use fentanyl, which is 50 to 100 times more potent than morphine. Thus, the choice to use methadone or buprenorphine during pregnancy should be the result of a shared decisionmaking process between a patient and a provider that incorporates factors such as patient preference, previous treatment experiences, and medication availability. Studies such as this highlight the importance of research that evaluates medication use during pregnancy and lactation. Such research is desperately needed to expand treatment options for pregnant persons with opioid use disorder, especially while the opioid crisis continues to unfold.
Disclosure forms provided by the author are available with the full text of this editorial at NEJM.org.
From the Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, and the Magee– Womens Research Institute — both in Pittsburgh.