Jean B. Nachega，醫師、博士、公共衛生碩士；Emma L. Mohr，醫師、博士；Pradip Dashraath，醫師、理學士、醫學碩士；Placide Mbala Kingebeni，醫師、博士；Jean R . Anderson，醫師；Landon Myer，醫師、博士；Monica Gandhi，醫師；David Baud，醫師、博士、Lynne M. Mofenson，醫師；和Jean Jacques Muyembe Tamfum，醫師、博士；mpox研究聯盟(MpoxReC) /  2024 年 8 月 28 日 / n engl j med nejm.org

猴痘病毒 (MPXV) 感染在人與人之間傳播的驚人激增，特別是在高風險、性活躍和育齡人群中，以及已知的 MPXV 感染與不良產科結局之間的關聯，凸顯了迫切需要獲取數據以增強我們的了解並降低懷孕期間MPXV 感染的風險。

Mpox 是由痘病毒科正痘病毒屬 MPXV 引起的人畜共通傳染病，與天花有密切關係。儘管 MPXV 於 1958 年被發現，但第一例人類病例於 1970 年在剛果民主共和國 (DRC) 報告。該病毒有兩個進化枝：進化枝 I（以前的剛果盆地進化枝）和進化枝 II（以前的西非進化枝，現在細分為 IIa 和 IIb）。進化枝 I 的毒力更強，致死率高達 10%，而進化枝 II 的致死率為 0% 至 3.6%。剛果民主共和國2024年1月1日至5月26日期間向世界衛生組織（WHO）報告的mpox數據（N=7,851）顯示，1歲以下兒童的致死率為8.6%，而兒童的致死率為2.4%。此外，CD4 數較低的 HIV 感染者可能面臨超過 10% 的致死率。

從歷史上看，mpox 病例主要由中非和西非國家的人畜共通傳染病溢出引起，MPXV 在這些國家的野生囓齒動物和非靈長類宿主中傳播。 2022年，一場與性傳播有關的人類IIb型疫情爆發，導致全球流行，致死率低於0.2%，主要影響男男性行為者。透過對高風險族群進行疫苗接種，疫情得到控制。

最近的報告引起了人們對剛果民主共和國爆發更具致命性的 MPXV I 分支的擔憂。 2023年，向世界衛生組織報告了超過12,000例病例和600例死亡。 2023 年9 月至2024 年1 月期間，我們的mpox 研究聯盟（MpoxReC；有關研究人員和合作者的完整列表，請參閱補充附錄，可在NEJM.org 上取得）記錄了剛果民主共和國東部的金礦小鎮Kamituga 發生了241 例I型病例的大規模爆發，影響了流動性強的移工群體。基因組分析在分離的 MPXV 中發現了一種新的突變模式，現在被認為是獨特的 I 分支菌株，建議命名為 Ib。在透過即時聚合酶鏈反應（RT-PCR）確診的108名MPXV感染患者中，感染時的中位年齡為22歲； 51.9%的患者為女性，29.0%為性工作者，提示了性傳播。令人震驚的是，盧安達、烏干達、蒲隆地和肯亞現已通報感染病例。鑑於最近的病例激增，世界衛生組織於 8 月 14 日宣布mpox為國際關注的突發公共衛生事件。關於懷孕期間天花的歷史數據顯示，流產、早產和孕產婦死亡率很高。在涉及 830 名天花妊娠患者的 15 項研究中，331 名（39.9%）流產或早產； 16 項研究中的 1,074 名孕婦中，有 368 人死亡（致死率為 34.3%）。 2024 年對七項mpox研究進行的系統性回顧發現，32 名孕婦在妊娠 6 至 31 週期間感染了 IIb 支 MPXV。在報告妊娠結局的 12 次懷孕中，有一半導致胎兒子宮內死亡。

與天花一樣，MPXV 可以從母親傳播給胎兒，在胎兒和母胎界面組織中發現高病毒量（一例每毫升 106 個拷貝），可能是懷孕，因為它含有複製型減毒病毒。然而，由於這兩種疫苗的功效都是根據天花所需的中和抗體水平推斷出來的，因此需要進行臨床試驗來確認它們在預防I 型和II 型MPXV 感染方面的有效性，特別是在包括孕婦在內的高危險群中導致流產。非人類靈長類動物的數據進一步支持了子宮內傳播的可能性：獼猴模型顯示感染後6 至14 天出現垂直傳播，隨後胎兒很快死亡。 MPXV 是否存在於母乳中尚不清楚；一名 MPXV 感染婦女的母乳經 PCR 檢測 MPXV DNA 呈陰性。所有人都被感染，其中一人死亡。

由於在正痘病毒家族中觀察到廣泛的交叉免疫，世衛組織免疫策略諮詢專家小組建議使用兩種天花疫苗中的一種來預防猴痘：由巴伐利亞北歐公司(MVA-BN) 開發的改良安卡拉牛痘疫苗；另一種或稱為LC16m8的疫苗，則由日本KM Biologics開發。 MVA-BN 疫苗含有活的非複製病毒，以多種名稱銷售——美國的 JYNNEOS、歐盟的 Imvanex 和加拿大的 Imvamune——並被批准（包括在剛果民主共和國）用於 18 歲（含）以上有感染mpox風險的人群，包括孕婦或哺乳期婦女。 MVA-BN 對雌性大鼠和兔子的發育毒性研究顯示對胎兒沒有傷害。 LC16m8 疫苗在日本和剛果民主共和國批准用於成人和兒童，通常禁止免疫功能低下的患者和懷孕期間使用，因為它含有複製的減毒病毒。然而，由於這兩種疫苗的功效都是根據天花所需的中和抗體水平推斷的，因此需要進行臨床試驗來確認它們在預防進化枝I 和進化枝II MPXV 感染方面的有效性，特別是在包括孕婦在內的高危險群中。

在美國，抗病毒藥物tecovirimat獲得食品藥物管理局批准，根據美國疾病管制與預防中心 (CDC) 的擴大使用研究新藥授權，可用於治療天花，並可用於治療嚴重的猴痘。儘管沒有與人類妊娠或母乳餵養相關的藥理學數據，但當以人類建議劑量的約 23 倍劑量給予小鼠和兔子時，沒有發現胚胎毒性或致畸作用。在動物母乳中檢測到替科維馬特 (tecovirimat)，但是否會進入人類母乳或胎盤尚不清楚。由於懷孕期間嚴重疾病的風險增加以及新生兒嚴重感染的可能性，替考維馬在美國被推薦作為懷孕或哺乳期 MPXV 感染者的治療方法。在一項納入 23 名患有 mpox 的美國孕婦的研究中，其中 11 人接受了替考維馬（包括懷孕早期使用），並且沒有報告與藥物相關的不良事件。

Tecovirimat 可從 CDC 獲得，主要針對由美國國家衛生研究院和美國國家過敏和傳染病研究所 (NIH/NIAID) 資助的 STOMP 試驗的參與者，該試驗允許招募孕婦和哺乳期患者。

PALM007 試驗是與 NIH/NIAID 和剛果民主共和國國家生物醫學研究所合作在剛果民主共和國啟動的，旨在評估 tecovirimat 對 600 名實驗室確診的 MPXV 兒童和成人（包括孕婦）的安全性和有效性。 NIH/NIAID 於 2024 年 8 月 15 日發布了關於初步結果的新聞稿：儘管該研究未達到病灶消退時間有統計學上顯著改善的主要終點，但在不良事件方面與安慰劑對照沒有差異。然而，計畫進行更多分析，其他試驗正在美國 (STOMP)、加拿大和英國 (PLATINUM)、瑞士和巴西 (UNITY) 評估 tecovirimat 用於治療 mpox，其中一些試驗允許孕婦或哺乳期婦女加入組中。由於 PALM007 試驗僅招募了 11 名孕婦，因此它提供的有關妊娠結果的資訊有限。需要進行更大規模的研究來評估替考維馬 (tecovirimat) 在懷孕期間的安全性並評估懷孕特定的結果。

MpoxReC 啟動了一項 MPXV 研究計畫，包括評估 MPXV（進化枝 I 和 II）可用診斷工具的準確性、識別 MPXV 儲存庫以及評估現有疫苗和治療方法的臨床療效。該表概述了以懷孕為重點的研究議程，旨在提高我們對流行病學因素、傳播機制、臨床結果以及疫苗和抗病毒藥物有效性的了解。迫切需要這些數據來為有關妊娠期間 MPXV 感染的循證臨床指南和公共衛生政策提供資訊。

作者提供的揭露表格可在 NEJM.org 上取得。

來自匹茲堡大學醫學院流行病學、傳染病和微生物學系，匹茲堡 (J.B.N.)；約翰霍普金斯大學彭博公共衛生學院 (J.B.N.) ；流行病學和國際衛生糸以及約翰霍普金斯大學醫學院婦產科— 均位於巴爾摩 (J.R.A.)；斯泰倫博斯大學醫學與健康科學學院醫學系傳染病系 (J.B.N.) 和開普敦大學公共衛生學院流行病學與生物統計學系 (L.M.) — 均位於南非開普敦非洲; 威斯康辛大學麥迪遜分校兒科系，麥迪遜 (E.L.M.)；新加坡國立大學醫院楊潞齡醫學院婦產科母胎醫學科，新加坡 (P.D.)；國家生物醫學研究所 (INRB) 和金薩沙大學醫學院微生物學和病毒學系 — 均位於剛果民主共和國金沙薩 (P.M. K.、J. J.M. T.)；加州大學舊金山分校醫學系愛滋病毒、傳染病和全球醫學科，舊金山 (M.G.)；瑞士洛桑洛桑大學醫院「Femme Mère Enfant」科母體胎兒與產科研究室（D.B.）；和伊麗莎白·格拉澤兒科愛滋病基金會，華盛頓特區 (L.L.M.)。

Mofenson 和 Muyembe Tamfum 對本文做出了同等貢獻。

參考文獻：

1. Vakaniaki EH、Kacita C、Kinganda-Lusa maki E 等人。在剛果民主共和國東部，新的 MPXV 演化支 I 譜系在人類中持續爆發。 《自然醫學》Nat Med ，2024 年 6 月 13 日（印刷前的電子版）。

2. Nishiura H. 。妊娠期間的天花和孕產婦結局。《突發感染症》， 2006；12：1119-21。

3. Sanchez Clemente N、Coles C、Paixao ES 等人。兒科、孕產婦和先天性猴痘：系統性評價和薈萃分析。 《刺胳針全球健康》，2024 年； 12(4)：e572-e588。

4. Krabbe NP、Mitzey AM、Bhattacharya S 等人。 Mpox 病毒 (MPXV) 在懷孕恒河猴模型中的垂直傳播和胎兒死亡。 2024 年 5 月 31 日（https://www.biorxiv.org/content/10.1101/2024.05.29 .596240v1）。預印本。

5. Oakley LP、Hufstetler K、O’Shea J 等人。順性別婦女和孕婦中的 mpox 病例 — 美國，2022 年 5 月 11 日，11 月 7 日。《發病率和死亡率周報》，2023;72:9-14.

DOI：10.1056/NEJMp2410045

Mpox in Pregnancy — Risks, Vertical Transmission, Prevention, and Treatment

Jean B. Nachega, M.D., Ph.D., M.P.H., Emma L. Mohr, M.D., Ph.D., Pradip Dashraath, M.B., B.S., M.Med., Placide Mbala‑Kingebeni, M.D., Ph.D., Jean R. Anderson, M.D., Landon Myer, M.D., Ph.D., Monica Gandhi, M.D., David Baud, M.D., Ph.D., Lynne M. Mofenson, M.D., and Jean‑Jacques Muyembe‑Tamfum, M.D., Ph.D., for the Mpox Research Consortium (MpoxReC) / n engl j med nejm.org

The alarming surge in human-to-human transmission of monkeypox virus (MPXV) infections, particularly in high-risk, sexually active, and reproductive-age populations, along with the known association between MPXV infection and adverse obstetrical outcomes, highlights the urgent need for data to enhance our understanding and mitigate the risks of MPXV infection during pregnancy.

Mpox is a zoonotic disease caused by MPXV, a DNA virus of the orthopoxvirus genus in the family poxviridae, and is closely related to smallpox. Although MPXV was discovered in 1958, the first human case was reported in 1970 in the Democratic Republic of Congo (DRC). The virus has two clades: clade I (formerly Congo Basin clade) and clade II (formerly West African clade, now subdivided into IIa and IIb). Clade I is more virulent, with a case fatality ratio as high as 10%, as compared with 0 to 3.6% for clade II. Mpox data from the DRC reported to the World Health Organization (WHO) between January 1 and May 26, 2024 (N = 7851) indicate that the case fatality ratio among children under 1 year of age is 8.6%, as compared with 2.4% among per sons 15 years of age or older. Furthermore, people living with HIV and low CD4 counts may face a case fatality ratio greater than 10%.

Historically, mpox cases have predominantly arisen from zoonotic spillover in Central and West African countries, where MPXV circulates among wild rodents and nonprimate hosts. In 2022, a human clade IIb outbreak linked to sexual transmission led to a global epidemic, with a case fatality ratio of less than 0.2%, primarily affecting men who have sex with men. The outbreak was controlled by vaccination of high-risk groups.

Recent reports have raised concerns about outbreaks of the more lethal MPXV clade I in the DRC. In 2023, more than 12,000 cases and 600 deaths were reported to the WHO. Between September 2023 and January 2024, our group, the Mpox Research Consortium (MpoxReC; for a complete list of investigators and collaborators, see the Supplementary Appen dix, available at NEJM.org), documented a substantial outbreak of 241 clade I cases in Kamituga, a gold-mining town in eastern DRC, affecting a highly mobile popula tion of migrant workers. Geno mic analyses identified a new mutation pattern in the isolated MPXV, now considered a distinct clade I strain with the proposed designation Ib. Among 108 patients with MPXV infection confirmed by real-time polymerase chain re action (RT-PCR), the median age at infection was 22 years; 51.9% of patients were female, and 29.0% were sex workers, which suggests sexual transmission. Alarmingly, infections have now been report ed in Rwanda, Uganda, Burundi, and Kenya. Given this recent up surge, the WHO declared mpox a Public Health Emergency of International Concern on August 14.

* MPXV denotes monkeypox virus, MVA‑BN Modified Vaccinia Ankara by Bavarian Nordic, and RT‑PCR real‑time polymerase chain reaction.

Historical data on smallpox during pregnancy reveal high rates of miscarriage, premature birth, and maternal death. In 15 studies involving 830 pregnant patients with smallpox, 331 (39.9%) had a miscarriage or premature birth; of 1074 pregnant patients in 16 studies, 368 died (case fatality ratio, 34.3%).2 The limited avail able data suggest that mpox, like smallpox, increases the risks of severe maternal disease, miscarriage, and stillbirth. A 2024 systematic review of seven studies identified 32 pregnant women with clade IIb MPXV infection between 6 and 31 weeks of gestation. Of the 12 pregnancies with reported gestational outcomes, half resulted in intrauterine fetal demise.

Like smallpox, MPXV can be transmitted from mother to fetus, with high viral loads (106 copies per milliliter in one case) found within fetal and maternal fetal interface tissues, possibly pregnancy because it contains a replicating attenuated virus. How ever, since both vaccines’ efficacy was extrapolated from the neutralizing antibody levels required for smallpox, clinical trials are needed to confirm their effectiveness in preventing clade I and clade II MPXV infections, particularly in high-risk groups including pregnant women. contributing to pregnancy loss. The potential for intrauterine transmission is further support ed by data from nonhuman pri mates: a macaque model showed vertical transmission 6 to 14 days after infection, followed shortly by fetal demise.4 Transmission from breast-feeding mothers with mpox to their infants can also occur, potentially by means of close contact. Whether MPXV is present in breast milk is un known; breast milk from one MPXV-infected woman tested negative for MPXV DNA on PCR.5 Outcomes were reported on three breast-feeding infants in studies of MPXV-infected mothers; all were infected, and one died.

Because of the broad cross immunity observed within the orthopoxvirus family, the WHO Strategic Advisory Group of Experts on Immunization recommends administering one of two smallpox vaccines for mpox prevention: the Modified Vaccinia Ankara vaccine, developed by Bavarian Nordic (MVA-BN), or the LC16m8 vaccine, developed by KM Biologics in Japan. The MVA-BN vaccine, containing live, nonreplicating virus, is marketed under various names — JYNNEOS in the United States, Imvanex in the European Union, and Imvamune in Canada — and is approved (including in the DRC) for persons 18 years of age or older who are at risk for mpox, including pregnant or breast-feeding women. Developmental toxicity studies of MVA-BN in female rats and rabbits have revealed no harm to fetuses. The LC16m8 vaccine, approved in Japan and the DRC for adults and children, is typically contraindicated for immunocompromised patients and during pregnancy because it contains a replicating attenuated virus. How ever, since both vaccines’ efficacy was extrapolated from the neutralizing antibody levels required for smallpox, clinical trials are needed to confirm their effectiveness in preventing clade I and clade II MPXV infections, partic ularly in high-risk groups including pregnant women.

 In the United States, the antiviral agent tecovirimat is approved by the Food and Drug

Administration for smallpox and available for treating severe mpox under an Expanded Access Investigational New Drug authorization from the Centers for Disease Control and Prevention (CDC). Although no pharmacologic data related to pregnancy or breast feeding in humans exist, no embryotoxic or teratogenic effects were found when tecovirimat was administered to mice and rabbits at doses approximately 23 times the recommended human dose. Tecovirimat was detected in animal breast milk, but whether it crosses into human breast milk or the placenta is unknown. Because of the increased risk of severe disease during pregnancy and the possibility of severe infection in newborns, tecovirimat has been recommended in the United States as therapy for MPXV infected persons who are pregnant or breast-feeding. In a study including 23 U.S. pregnant women with mpox, 11 received tecovirimat (including first-trimester use) and no medication-related adverse events were reported.

Tecovirimat can be obtained from the CDC primarily for enrollees in the STOMP trial fund ed by the National Institutes of Health and the National Institute of Allergy and Infectious Diseases (NIH/NIAID), which pe mits recruitment of pregnant and breast-feeding persons.

The PALM007 trial was launched in the DRC in partnership with the NIH/NIAID and the DRC’s National Institute for Biomedical Research to evaluate tecovirimat’s safety and efficacy in 600 children and adults, including pregnant women, with laboratory confirmed MPXV. An NIH/NIAID press release on preliminary results was posted on August 15, 2024: though the study didn’t meet the primary end point of statistically significant improvement in the time to lesion resolution, there was no difference from the placebo control in terms of adverse events. However, additional analyses are planned, and other trials are evaluating tecovirimat use for mpox in the United States (STOMP), Canada and the United Kingdom (PLATINUM), and Switzerland and Brazil (UNITY), some of which allow enrollment of pregnant or lactating persons. Since the PALM007 trial enrolled only 11 pregnant women, it will provide limited information about pregnancy outcomes. Larger studies are necessary to evaluate tecovirimat’s safety during pregnancy and assess pregnancy-specific outcomes.

The MpoxReC has launched an mpox research program, including evaluating the accuracy of available diagnostic tools for MPXV (clades I and II), identifying MPXV reser voirs, and assessing the clinical efficacy of existing vaccines and therapeutics. The table outlines a pregnancy-focused research agen da aimed at improving our under standing of epidemiologic factors, transmission mechanisms, clini cal outcomes, and the effective ness of vaccines and antivirals. Such data are urgently needed to inform evidence-based clinical guidelines and public health pol icies regarding MPXV infection during pregnancy.

Disclosure forms provided by the authors are available at NEJM.org.

From the Departments of Epidemiology, Infectious Diseases, and Microbiology, University of Pittsburgh School of Medi cine, Pittsburgh (J.B.N.); the Departments of Epidemiology and International Health, Johns Hopkins Bloomberg School of Public Health (J.B.N.), and the Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine (J.R.A.) — both in Balti more; the Department of Medicine, Division of Infectious Diseases, Stellenbosch University Faculty of Medicine and Health Sciences (J.B.N.), and the Division of Epidemiology and Biostatistics, School of Pub lic Health, University of Cape Town (L.M.) — both in Cape Town, South Africa; the Department of Pediatrics, University of Wis consin–Madison, Madison (E.L.M.); the Division of Maternal–Fetal Medicine, Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University Hospital, Singapore City, Singa n engl j med nejm.org pore (P.D.); the Institut National de Recher che Biomédicale (INRB) and the Depart ments of Microbiology and Virology, University of Kinshasa School of Medicine — both in Kinshasa, Democratic Republic of Congo (P.M.‑K., J.‑J.M.‑T.); the Division of HIV, Infectious Diseases, and Global Medi cine, Department of Medicine, University of California, San Francisco, San Francisco (M.G.); Materno‑fetal and Obstetrics Re search Unit, Department “Femme‑Mère Enfant,” Lausanne University Hospital, and University of Lausanne, Lausanne, Swit zerland (D.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.L.M.).

Drs. Mofenson and Muyembe‑Tamfum contributed equally to this article.

This article was published on August 28, 2024, at NEJM.org.

1. Vakaniaki EH, Kacita C, Kinganda-Lusa maki E, et al. Sustained human outbreak of a new MPXV clade I lineage in eastern Dem ocratic Republic of the Congo. Nat Med 2024 June 13 (Epub ahead of print).

2. Nishiura H. Smallpox during pregnancy and maternal outcomes. Emerg Infect Dis 2006;12:1119-21.

3. Sanchez Clemente N, Coles C, Paixao ES, et al. Paediatric, maternal, and congeni tal mpox: a systematic review and meta analysis. Lancet Glob Health 2024; 12(4): e572-e588.

4. Krabbe NP, Mitzey AM, Bhattacharya S, et al. Mpox virus (MPXV) vertical transmis sion and fetal demise in a pregnant rhesus macaque model. May 31, 2024 (https://www .biorxiv.org/content/10.1101/2024.05.29 .596240v1). preprint.

5. Oakley LP, Hufstetler K, O’Shea J, et al. Mpox cases among cisgender women and pregnant persons — United States, May 11 November 7, 2022. MMWR Morb Mortal Wkly Rep 2023;72:9-14.

DOI: 10.1056/NEJMp2410045

Copyright © 2024 Massachusetts Medical Society.