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USE OF MOLNUPIRAVIR IN PREGNANCY

Date of issue: December 2021
Version: 1.0

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

Molnupiravir is an antiviral pro-drug that inhibits viral replication through the active metabolite being incorporated into the viral RNA, resulting in an accumulation of errors in the viral genome. In the UK, it is licensed as a five-day course for the treatment of mild to moderate COVID-19 in adults with a positive SARS-COV-2 diagnostic test, who have at least one risk factor for developing severe illness.

Preclinical animal reproductive toxicity data are conflicting, with high maternal doses administered in the rat model demonstrating possible teratogenic effects, but no evidence of similar effects observed in the rabbit model. There are currently no human data regarding the safety of molnupiravir in pregnancy. UKTIS are collecting outcome data for all pregnancies with maternal or paternal exposure to molnupiravir (more information can be found here).

Although COVID-19 in pregnancy presents a significant risk to both the woman and her baby, both the mechanism of action of molnupiravir and the preclinical animal data warrant a cautious approach towards its use in pregnancy. Molnupiravir is not to be routinely recommended in pregnancy until further studies have established its effectiveness and safety. The manufacturer of molnupiravir recommends that women of childbearing potential should use effective contraception for the duration of treatment and for four days after the final dose. Pregnant women who have received molnupiravir at any stage in pregnancy should be referred to UKTIS for further counselling and follow-up of the pregnancy outcome.

In circumstances where the woman is experiencing severe symptoms of COVID-19, and where other more established treatments have failed, the risks and benefits of molnupiravir may need to be considered and discussed on an individual patient basis. However, the efficacy of molnupiravir has not been proven in such clinical scenarios, and alternative early treatment options that do not pose theoretical risks of fetal harm, such as casirivimab/imdevimab (Ronapreve) monoclonal antibodies, may be preferred for pregnant women. Discussion with UKTIS is recommended in all cases where molnupiravir treatment is being considered in pregnancy.

Owing to the lack of data regarding malformation risks, routine detailed fetal anomaly scans are recommended for all pregnancies with exposure to molnupiravir in the first trimester, or where there was paternal exposure to molnupiravir around the time of conception. Exposure to molnupiravir at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy. However, other risk factors may be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case specific risk assessments.

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.

Background

Molnupiravir is an antiviral pro-drug medication that is metabolised into ribonucleoside triphosphate, which is subsequently incorporated into viral RNA by the viral RNA polymerase, resulting in an accumulation of errors in the viral genome leading to inhibition of replication.[1]

Molnupiravir is licensed for the treatment of mild to moderate coronavirus disease 2019 (COVID-19) in adults with a positive SARS-COV-2 diagnostic test, who have at least one risk factor for developing severe illness.[1] The product literature defines these risk factors as age 60 years or older, diabetes, obesity (BMI >30), chronic kidney disease, serious heart conditions, chronic obstructive pulmonary disease, or active cancer.[1] In non-pregnant, high-risk populations, molnupiravir has been shown to be efficacious at reducing hospitalisation or death (as a composite outcome).[1] The standard dosing regimen involves a five day treatment course.[1]

COVID-19 in pregnancy
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection during pregnancy is known to increase the risk of adverse outcomes for both the woman and her baby. Women who are overweight or obese, 35 years old or older, of Black, Asian or any other minority ethnic background, or who have co-morbidities such as diabetes, hypertension and asthma are more likely to experience severe COVID-19.[2, 3] A meta-analysis conducted in 2020[2] indicated that approximately 10% of pregnant women with laboratory confirmed COVID-19 are admitted to hospital, up to 7% require admission to intensive care units and up to 5% require mechanical ventilation (more recent data have suggested these risks may be increased with newer SARS-CoV-2 variants[4]). Increased risks of preterm delivery, neonatal intensive care admission and stillbirth have also been described.[2]

Preclinical (animal) data

Preclinical animal reproductive toxicity data are conflicting, with high maternal doses administered in the rat model demonstrating possible teratogenic effects, but no evidence of similar effects observed in the rabbit model.

Pregnant rats administered doses of molnupiravir that produced active metabolite concentrations eight times larger than those observed at the human recommended daily dose experienced post-implantation losses, malformations of the eye, kidney, and axial skeleton, and rib variations. Reduced fetal body weights and delayed ossification was observed at doses equivalent to approximately three times the human recommended daily dose. It is noted that maternal toxicity was observed at the above doses. No developmental toxicity was observed at doses approximately 80% of those observed at the human recommended daily dose.[1] However, similar evidence of toxicity was not observed in the rabbit model, where doses equivalent to approximately 7 times the human recommended daily dose were administered.[1]

Human data

Often, data from observational sources or case reports, including data collected by UKTIS, may be confounded by maternal co-ingestion of a number of drugs, at varying doses, and for a range of indications.  The severity of the underlying maternal condition, where relevant, is frequently unknown and information on other potential confounding variables may be incomplete.  These factors should be considered when interpreting observational human pregnancy data.

There are currently no human data regarding the safety of molnupiravir in pregnancy. UKTIS are operating a registry to collect outcome data for all pregnancies with maternal or paternal exposure to molnupiravir (more information can be found here). NHS healthcare professionals are strongly encouraged to report such pregnancies to UKTIS.

Pharmacokinetic data

No data regarding pregnancy-specific changes in the metabolism or pharmacokinetics of molnupiravir were located. 

Miscarriage

Studies investigating relationships between gestational exposures and the occurrence of miscarriage should be interpreted with caution. Miscarriage prior to the recognition of pregnancy, or the pregnancy being reported to a clinician, is likely to be common; as such, observational studies likely underestimate true rates of early pregnancy loss. Additionally, the risk of miscarriage decreases as pregnancy progresses and elective termination acts as a competing risk. Correction for exposed and control group differences in stage of pregnancy at recruitment, and variation in the rate of elective termination, is therefore essential, but rarely performed.

No studies investigating the risk of miscarriage following maternal use of molnupiravir during pregnancy have been identified in the literature.

Congenital malformations/anomalies

No studies investigating the risk of congenital malformation following maternal use of molnupiravir during pregnancy have been identified in the literature.

Intrauterine death

No studies investigating the risk of intrauterine death/stillbirth following maternal use of molnupiravir during pregnancy have been identified in the literature.

Low birth weight/SGA

No studies investigating the risk of low birth weight following maternal use of molnupiravir during pregnancy have been identified in the literature.

Preterm delivery

No studies investigating the risk of preterm delivery following maternal use of molnupiravir during pregnancy have been identified in the literature.

Neonatal complications

No studies investigating the risk of neonatal complications following maternal use of molnupiravir during pregnancy have been identified in the literature.

Neurodevelopment

No studies investigating the risk of neurodevelopmental impairment following maternal use of molnupiravir during pregnancy have been identified in the literature.

Carcinogenicity

No studies investigating the risk of childhood cancer following maternal use of molnupiravir during pregnancy have been identified in the literature.

Paternal exposure

Only studies which examine the effects of paternal exposure on offspring congenital malformation rate, development, cancer and reproductive potential are included here. Effects on sperm quality and the reproductive health of the exposed father are NOT included.

There were no reports found regarding paternal exposure to molnupiravir. It is noted that there are no known human teratogens that affect the developing fetus via paternal exposure. However,  both molnupiravir and its active metabolite have been observed to produce mutagenic effects in preclinical in vitro studies.[1]  Although these results highlight some theoretical concerns regarding paternal molnupiravir exposure, reassuringly mutagenic or genotoxic effects have not been observed in preclinical in vivo (rat) studies.[1]  Mutagenic/genotoxic effects on sperm cell DNA are therefore unlikely following paternal molnupiravir use. Yet close monitoring of pregnancies fathered by those using molnupiravir at or around the time of conception remains warranted.

UKTIS are operating a registry to collect outcome data for all pregnancies with maternal or paternal exposure to molnupiravir (more information can be found here). NHS healthcare professionals are strongly encouraged to report such pregnancies to UKTIS.

Lactation

For information on the therapeutic use of medicines during breastfeeding, please consult the UK Drugs in Lactation Advisory Service (UKDILAS) online lactation safety information (available from www.sps.nhs.uk) or contact the UKDILAS enquiry line (details can be found here). If you have concerns regarding toxicity in the child as a consequence of exposure to a drug or chemical during lactation please consult TOXBASE or contact the National Poisons Information Service on 0344 892 0111.

UKTIS data

UKTIS have not followed up any cases of molnupiravir exposure during pregnancy.

Conclusions

Although COVID-19 in pregnancy presents a significant risk to both the woman and her baby, both the mechanism of action of molnupiravir and the preclinical animal data warrant a cautious approach towards its use in pregnancy. The manufacturer of molnupiravir recommends that women of childbearing potential should use effective contraception for the duration of treatment and for four days after the final dose.[1]

In circumstances where a pregnant woman is experiencing severe symptoms of COVID-19, and where other more established treatments have failed, the risks and benefits of molnupiravir may need to be considered and discussed on an individual patient basis. However, the efficacy of molnupiravir has not been proven in such clinical scenarios, and alternative early treatment options that do not pose theoretical risks of fetal harm, such as casirivimab/imdevimab (Ronapreve) monoclonal antibodies, may be preferred for pregnant women. Discussion with UKTIS is recommended in all cases where molnupiravir treatment is being considered in pregnancy.

Molnupiravir is not routinely recommended in pregnancy until further studies have established its effectiveness and safety. Pregnant women who have received molnupiravir at any stage in pregnancy should be referred to UKTIS for further counselling and follow-up of the pregnancy outcome.

References

1. Merck Sharp & Dohme (UK) Limited. Summary of Product Characteristics: Lagevrio 200 mg hard capsules. 2021; Available from: www.medicines.org.uk/emc/product/13044.
2. Allotey, J., E. Stallings, M. Bonet, M. Yap, S. Chatterjee, T. Kew, L. Debenham, A.C. Llavall, A. Dixit, D. Zhou, R. Balaji, S.I. Lee, X. Qiu, M. Yuan, D. Coomar, J. Sheikh, H. Lawson, K. Ansari, M. van Wely, E. van Leeuwen, E. Kostova, H. Kunst, A. Khalil, S. Tiberi, V. Brizuela, N. Broutet, E. Kara, C.R. Kim, A. Thorson, O.T. Oladapo, L. Mofenson, J. Zamora, S. Thangaratinam, and C.O.V.L.S.R.C. for Preg, Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis. BMJ, 2020. 370: p. m3320. PMID: 32873575.
3. Vousden, N., K. Bunch, E. Morris, N. Simpson, C. Gale, P. O'Brien, M. Quigley, P. Brocklehurst, J.J. Kurinczuk, and M. Knight, The incidence, characteristics and outcomes of pregnant women hospitalized with symptomatic and asymptomatic SARS-CoV-2 infection in the UK from March to September 2020: A national cohort study using the UK Obstetric Surveillance System (UKOSS). PLoS One, 2021. 16(5): p. e0251123. PMID: 33951100.
4. Vousden, N., R. Ramakrishnan, K. Bunch, E. Morris, N. Simpson, C. Gale, P. O’Brien, M. Quigley, P. Brocklehurst, J.J. Kurinczuk, and M. Knight, Impact of SARS-CoV-2 variant on the severity of maternal infection and perinatal outcomes: Data from the UK Obstetric Surveillance System national cohort. medRxiv, 2021: p. 2021.07.22.21261000. PMID: NA (pre-print)

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.