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MONKEYPOX INFECTION, VACCINATION AND TREATMENT IN PREGNANCY

Date of issue: June 2022
Version: 1

This is a UKTIS monograph for use by health care professionals. For case-specific advice please contact UKTIS on 0344 892 0909. To report an exposure please download and complete a pregnancy reporting form. Please encourage all women to complete an online reporting form.

Summary

Monkeypox belongs to the Orthopoxvirus genus in the Poxviridae family. Monkeypox infection produces a disease which clinically resembles smallpox. Monkeypox has two known distinct genetic clades, central African (Congo Basin) clade and the West African clade. Historically, the Congo Basin clade has caused more severe disease and is thought to be more transmissible. In the 2022 UK outbreak, all reported cases have been identified as the West African clade.

Data regarding monkeypox infection during pregnancy are highly limited, consisting of a single case report and a small case series (n=4). All reported cases were therefore likely infected with the Congo Basin clade. All but one of the reports describe an adverse outcome, including miscarriage (n=3), and a neonatal death with features suggestive of vertical transmission. There is an absence of information relating to birth outcomes following infection with the West African clade which is circulating in the UK. Therefore, due to the lack of data and the clinical similarity between monkeypox and smallpox infection, a significant risk of adverse maternal and pregnancy outcomes cannot be excluded following infection with either clade.

A non-replicating smallpox vaccine, Modified Vaccinia Ankara – Bavarian Nordic (MVA-BN) is effective against monkeypox infection. The manufacturer of MVA-BN does not report associations with adverse pregnancy outcomes in the product literature. However, data are limited to animal studies (three pregnant rat models) and spontaneous reports of fewer than 300 exposed human pregnancies. Potential maternal adverse effects following administration of MVA-BN are expected to be similar to those in the non-pregnant population. Any theoretical risk from vaccination needs to be weighed against the maternal risk of more severe disease from viral infections in the third trimester, and the fetal risks of infection: fetal demise, preterm delivery, and vertical transmission. The UK Health Security Agency (UKHSA) therefore conclude that pregnancy is NOT a contraindication for MVA-BN vaccine.

No human pregnancy data are available for the two antiviral medications (cidofovir and tecovirimat) suggested as possible treatment options by the UKHSA. Animal data and in vitro mutagenicity assays have raised some potential concerns with regards to cidofovir and its use in pregnancy is therefore not recommended. Pregnancy outcome data from animals following tecovirimat exposure is more reassuring, and it may be preferred for use in pregnant women with monkeypox. The decision to use either treatment should be made on a case-by-case basis.

Due to the potential risk of more severe disease from viral infections occurring during the third trimester, and the potentially increased risk of adverse fetal effects, additional monitoring may be required. Discussion with UKTIS and a regional fetal medicine unit is advised.

This document is regularly reviewed and updated. Only use full UKTIS monographs downloaded directly from TOXBASE.org to be sure you are using the most up-to-date version. The summaries of these monographs are openly available on UKTIS.org.

Monkeypox infection
Monkeypox is a member of the Orthopoxvirus genus in the Poxviridae family,[1] named due to the discovery of the virus in laboratory monkeys in 1958. In 1970, human infection with monkeypox was first identified as the cause of a smallpox-like illness in the Democratic Republic of the Congo.[2,3] Monkeypox has two known distinct genetic clades, central African (Congo Basin) clade and the West African clade. Historically, the Congo Basin clade has caused more severe disease and is thought to be more transmissible.[1] In the 2022 UK outbreak, all reported cases have been identified as the West African clade.[4]

Monkeypox infection is clinically similar to smallpox infection. Following an incubation period of up to three weeks, symptoms including fever, headache, backache, fatigue, lymphadenopathy (swelling of the lymph nodes), and a rash including macules, papules, vesicles, pustules, and crusts develop.[1,2]

Infection with smallpox, a related Orthopoxvirus, has been associated with an increased risk of morbidity and mortality in pregnant women[5] and an increased rate of miscarriage, preterm delivery, and stillbirth compared to non-pregnant women.[5,6]

Human data
Data regarding monkeypox infection during pregnancy are limited to a single case report,[7] summarised by Jamieson et al.[3] and Kisalu & Mokili,[8] and a small case series (n=4).[9] All reported cases originated from the Democratic Republic of Congo and were therefore likely infected with the more severe Congo Basin clade.

The case report describes a pregnant woman who developed symptoms of monkeypox infection at ~24 weeks gestation. She delivered a preterm infant at ~30 weeks gestation with a generalised skin rash suggestive of monkeypox disease. The infant died at 6 weeks old due to malnutrition.[7] No laboratory analysis was performed, therefore neonatal monkeypox infection was not confirmed.

The small case series described four pregnant women who presented to hospital with monkeypox symptoms. Two patients presented with symptoms in the first trimester (6 to 7 weeks gestation) with both pregnancies ending in miscarriage. The third case presented in the second trimester (14 weeks gestation) and delivered a healthy neonate at term. The fourth case was a woman who also developed symptoms in the second trimester (18 weeks gestation); fetal death occurred at 21 weeks gestation. At post-mortem, hydrops fetalis was detected (marked hepatomegaly and peritoneal effusion), which the authors suggested was due to monkeypox-induced cellular injury. Cutaneous maculopapillary lesions involving the scalp, trunk, and extremities, including the palms of the hands and soles of the feet, were also observed.[9]

The available data, although highly limited, suggest the possibility of fetal demise and vertical transmission-associated poor neonatal outcomes. The available data likely describe the risks associated with Congo Basin clade infection during pregnancy, whereas in the 2022 UK outbreak, all reported cases have been identified as the West African clade.[4] However, due to the clinical similarity between monkeypox and smallpox infection, a significant risk of adverse maternal and pregnancy outcomes cannot be excluded following infection with either clade.

Vaccination
Modified Vaccinia Ankara - Bavarian Nordic (MVA-BN) vaccine is a smallpox vaccine containing a live, replication-deficient, modified vaccinia virus (vaccinia Ankara).[10,11] MVA-BN has previously been used in used in the UK in response to monkeypox incidents.[12]

The manufacturer of MVA-BN does not report associations with adverse pregnancy outcomes in the product literature.[10] However, the available data are limited to animal studies (three pregnant rat models) and spontaneous reports of fewer than 300 exposed human pregnancies.

Although the manufacturer of MVA-BN does not recommend the vaccine is administered during pregnancy,[10] as MVA-BN is a non-replicating vaccine any potential maternal adverse effects are expected to be similar to those in the non-pregnant population.[12] Any theoretical risk from vaccination needs to be weighed against the maternal risk of more severe disease from viral infections in the third trimester, and fetal risks: fetal demise, preterm delivery, and vertical transmission. UKHSA conclude that pregnancy is NOT a contraindication for MVA-BN vaccine.[12]

Treatment of monkeypox infection
At the time of writing, the UK Health Security Agency (UKHSA) have listed cidofovir, and tecovirimat as antivirals that can be used to control outbreaks of monkeypox.[13] However, no specific advice for pregnant women is provided. Readers are advised to check for updated guidelines from the UK government website.

Cidofovir
Cidofovir is an antiviral licensed for the treatment of cytomegalovirus (CMV) retinitis in adults with acquired immunodeficiency syndrome (AIDS).[14] Animal models and in vitro tests have found cidofovir to have activity against various orthopox viruses, including monkeypox.[15]

Intravenous administration to pregnant rats resulted in decreased litter sizes and live births per litter, increased early resorptions (1.2 mg/kg/week or higher once weekly; 0.09 times the human dose based on AUC), and reduced fetal body weights (1.5 mg/kg/day; dose equivalence not provided). Intravenous administration of 1.0 mg/kg/day (dose equivalence not provided) to pregnant rabbits resulted in a significantly increased incidence of external, soft tissue and skeletal anomalies, and reduced fetal body weights, as well as maternal toxicity.[14,16]

No human pregnancy data are available, however, due to the animal reproductive toxicology data and in vitro genotoxic potential of cidofovir the manufacturer recommends against its use in women of childbearing potential not using contraception.[14]

Tecovirimat
Tecovirimat is an antiviral developed for the treatment of smallpox which was licensed by the European Medicines Agency (EMA) for monkeypox in 2022.[1,17]

No embryo or fetal toxicities were observed in mice or rabbits administered doses of tecovirimat up to 1,000 mg/kg/day in mice (~23 times the human dose) and 100 mg/kg/day (0.4 times the human dose), respectively. Maternal toxicity (mortality and decreases in body weight) was reported in rabbits administered doses of 100 mg/kg/day.[17]

No human pregnancy data are available.

Conclusions
Data regarding monkeypox infection during pregnancy are highly limited, consisting of a single case report and a small case series (n=4). All reported cases originated from the Democratic Republic of Congo and were therefore likely infected with the more severe Congo Basin clade. All but one of the cases describe adverse outcomes, including miscarriage (n=3), and a neonatal death with features suggestive of vertical transmission. There is an absence of information relating to birth outcomes following infection with the West African clade which is circulating in the UK. Therefore, due to the lack of data and the clinical similarity between monkeypox and smallpox infection, a significant risk of adverse maternal and pregnancy outcomes cannot be excluded following infection with either clade.

The manufacturer of MVA-BN does not report associations with adverse pregnancy outcomes in the product literature; however, the available data are limited to animal studies (three pregnant rat models) and spontaneous reports of fewer than 300 exposed human pregnancies. As MVA-BN is a non-replicating vaccine any potential maternal adverse effects are expected to be similar to those in the non-pregnant population. Any theoretical risk from vaccination needs to be weighed against the maternal risk of more severe disease from viral infections in the third trimester, and the fetal risks of infection: fetal demise, preterm delivery, and vertical transmission. The UKHSA therefore conclude that pregnancy is NOT a contraindication for MVA-BN vaccine.

No human pregnancy data are available for the two antiviral medications (cidofovir and tecovirimat) suggested as possible treatment options by the UKHSA. Animal data and in vitro mutagenicity assays have raised some potential concerns with regards to cidofovir and its use in pregnancy is therefore not recommended. Pregnancy outcome data from animals following tecovirimat exposure is more reassuring, and it may be preferred for use in pregnant women with monkeypox. The decision to use either treatment should be made on a case-by-case basis.

Due to the potential risk of more severe disease from viral infections occurring during the third trimester, and the potentially increased risk of adverse fetal effects, additional monitoring may be required. Discussion with UKTIS and a regional fetal medicine unit is advised.

References
1.  World Health Organization. Monkeypox. Fact Sheets. 2022. Available from: https://www.who.int/news-room/fact-sheets/detail/monkeypox
2.  Centers for Disease Control and Prevention (CDC). Multistate outbreak of monkeypox--Illinois, Indiana, and Wisconsin, 2003. MMWR Morb Mortal Wkly Rep. 2003 Jun 13;52(23):537–40.
3.  Jamieson DJ, Jernigan DB, Ellis JE, Treadwell TA. Emerging infections and pregnancy: West Nile virus, monkeypox, severe acute respiratory syndrome, and bioterrorism. Clin Perinatol. 2005 Sep;32(3):765–76.
4.  UK Health Security Agency (UKHSA) PHSPHW and PHANI. Principles for monkeypox control in the UK: 4 nations consensus statement. 2022. Available from:
https://www.gov.uk/government/publications/principles-for-monkeypox-control-in-the-uk-4-nations-consensus-statement/principles-for-monkeypox-control-in-the-uk-4-nations-consensus-statement
5.  Constantin CM, Martinelli AM, Foster SO, Bonney EA, Strickland OL. Smallpox: a disease of the past? Consideration for midwives. J Midwifery Womens Health. 48(4):258–67, 302–4.
6.  Waterson AP. Virus infections (other than rubella) during pregnancy. Br Med J. 1979 Sep 8;2(6190):564–6.
7.  Jezek Z, Fenner F. Human Monkeypox. In: Melnick JL, editor. Monographs in Virology. Houston: Karger; 1988.
8.  Kisalu NK, Mokili JL. Toward Understanding the Outcomes of Monkeypox Infection in Human Pregnancy. J Infect Dis. 2017;216(7):795–7.
9.  Mbala PK, Huggins JW, Riu-Rovira T, Ahuka SM, Mulembakani P, Rimoin AW, et al. Maternal and Fetal Outcomes Among Pregnant Women With Human Monkeypox Infection in the Democratic Republic of Congo. J Infect Dis. 2017;216(7):824–8.
10.  Bavarian Nordic A/S. IMVANEX suspension for injection Smallpox vaccine (Live Modified Vaccinia Virus Ankara). SmPC. 2022. Available from:
https://www.ema.europa.eu/en/medicines/human/EPAR/imvanex
11.  EMA. Imvanex smallpox vaccine (Live Modified Vaccinia Virus Ankara). European public assessment report (EPAR). 2019. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/imvanex
12.  UK Health Security Agency. Recommendations for the use of pre and post exposure vaccination during a monkeypox incident. 2022. Available from: https://www.gov.uk/government/publications/monkeypox-vaccination
13.  UK Health Security Agency. Monkeypox: background information. 2022. Available from: https://www.gov.uk/guidance/monkeypox
14.  Tillomed Laboratories Ltd. Cidofovir 75 mg/ml Concentrate for Solution for Infusion. SmPC. 2022. Available from: https://www.medicines.org.uk/emc/product/11151
15.  Andrei G, Snoeck R. Cidofovir Activity against Poxvirus Infections. Viruses. 2010;2(12):2803–30.
16.  Gilead Sciences Inc. VISTIDE (cidofovir injection). FDA. 2000. Available from:
https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/020638s003lbl.pdf
17.  SIGA Technologies Netherlands B.V. Tecovirimat SIGA 200 mg hard capsules. SmPC. 2022. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/tecovirimat-siga

This is a summary of the full UKTIS monograph for health care professionals and should not be used in isolation. The full UKTIS monograph and access to any hyperlinked related documents is available to health care professionals at www.toxbase.org.

If you have a patient with exposure to a drug or chemical and require assistance in making a patient-specific risk assessment, please telephone UKTIS on 0344 892 0909 to discuss the case with a teratology specialist.

If you would like to report a pregnancy to UKTIS please click here to download our pregnancy reporting form. Please encourage all women to complete an online reporting form.

Disclaimer: Every effort has been made to ensure that this monograph was accurate and up-to-date at the time of writing, however it cannot cover every eventuality and the information providers cannot be held responsible for any adverse outcomes of the measures recommended. The final decision regarding which treatment is used for an individual patient remains the clinical responsibility of the prescriber. This material may be freely reproduced for education and not for profit purposes within the UK National Health Service, however no linking to this website or reproduction by or for commercial organisations is permitted without the express written permission of this service. This document is regularly reviewed and updated. Only use UKTIS monographs downloaded directly from TOXBASE.org or UKTIS.org to ensure you are using the most up-to-date version.