MEDICATIONS USED TO TREAT COVID 19 IN PREGNANCY

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(Date of issue: October 2021, Version: 1.5)

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

The following document provides summary information for healthcare professionals, and describes the available evidence regarding the fetal risks associated with medications that are being used in patients with COVID-19.

This document is not intended to act as a clinical guideline for the pharmacological management of pregnant patients with COVID-19. The UK Royal College of Obstetricians and Gynaecologists (RCOG) are regularly updating their clinical advice to both healthcare professionals and pregnant women regarding COVID-19 in pregnancy; this information can be found here.

Owing to the potential for COVID-19 to cause significant disease and mortality in pregnant women, the benefits of maternal treatment should be carefully considered against the fetal/neonatal risks discussed below. In the context of COVID-19, pregnancy is not a contraindication to any of the treatment options discussed below. However, safety data and efficacy are yet to be established for some treatments.

Given that the scientific understanding of the coronavirus pandemic is constantly changing, this document will be updated as new information becomes available.


Background

The current outbreak of coronavirus disease 2019 (COVID-19) was declared a global pandemic by the World Health Organization (WHO) on 11th March 2020.[1]

COVID-19 is acquired following infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen, a novel enveloped RNA betacoronavirus which infects host epithelial cells via angiotensin-converting enzyme 2 (ACE2). As ACE2 is predominantly expressed on type II alveolar cells of the lung, [1] patients with COVID-19 manifest a spectrum of upper and lower respiratory tract symptoms.[1]

Pregnant women do not appear to be more likely to contract SARS-CoV-2 than the general population,[2] and most women who are infected during pregnancy will only ever experience mild to moderate symptoms.[3] However, intensive care admission and invasive ventilation may be more common among pregnant women with COVID-19 than in infected non-pregnant women of the same age.[4, 5] The UK Obstetric Surveillance Survey (UKOSS) have identified increased rates of intensive care admission among pregnant women with COVID-19 in comparison with uninfected pregnant women.[6] Risk factors which have been associated with severe COVID-19 infection, ICU admission or invasive ventilation during pregnancy include: maternal age ≥35, BMI ≥30, and pre-existing maternal comorbidity, specifically chronic hypertension and pre-pregnancy diabetes.[4]

Due to the limited data available, it is currently unknown whether infection with the virus itself exerts direct teratogenic or fetotoxic effects.[7] The limited preliminary data currently available do not suggest higher than expected rates of fetal loss or growth restriction.[1, 3] However evidence relating to pregnancy outcomes following infection in early pregnancy is currently highly limited.[1] Although higher than expected rates of preterm delivery have been described,[1] it is unclear what proportion of these have been iatrogenic due to deterioration in the maternal condition.[3]

As ACE2 is widely expressed in the human placenta, there is a theoretical risk of vertical transmission of COVID-19 to the fetus.[1] Although a small number of neonates have tested positive for the virus,[1] it is currently unclear if this has occurred as a result of transplacental infection, or whether the infants acquired the infection during or shortly following delivery.


Imaging

Diagnostic chest X-rays and chest CT scans may be required when investigating pregnant patients with COVID-19.

The UKTIS monograph ‘Exposure to Ionising Radiation in Pregnancy’ provides an overview of the fetal risks following maternal exposure to diagnostic radiation in pregnancy. In summary, national guidelines state that pregnant women should not be exposed to doses of radiation in excess of 50mGy, and a single chest X-ray or cross-sectional chest CT scan would not be expected to exceed this dose. Furthermore, results from preclinical animal studies and epidemiological human surveillance together provide evidence that exposure to total absorbed doses of less than 100mGy is unlikely to result in increased risks of dose-dependent effects (including fetal loss, malformation growth restriction or neurodevelopmental impairment). Very small increased risks of non-dose-dependent effects may exist, but these are likely to be very small and minimally raised above the background rate.

Chest X-ray and cross-sectional imaging (CT scanning or MRI) should not be withheld on fetal grounds (since the risk to the fetus is minimal) if there is a clinical need to scan pregnant women.


Treatment guidelines

Treatment guidelines for the general populations are provided by the National Institute for Health and Care Excellence.[8] Pregnancy specific treatment guidelines are provided jointly by the Royal College of Midwives and the Royal College of Obstetricians and Gynaecologists.[9] Readers are encouraged to check the latest recommendations provided in these treatment guidelines, and use these in conjunction with the safety information provided below.


Treatment options for patients with COVID-19

The following therapies have either been identified as possible treatment options by the New and Emerging Respiratory Virus Threats Advisory Group (NERVTAG) or have been listed as investigational medicinal products in COVID-19 clinical trials that are recorded on the EU register.

Additional treatment options are likely to emerge as the scientific and clinical understanding of COVID-19 improve; these will be added to future updates of this document.
 
If there are any treatment options which this document does not discuss please contact the telephone service (0344 892 0909 – available Monday to Friday, excl. bank holidays, 9am to 5pm) for more information.

Aspirin
There is no specific information on malformation rates following use of low-dose aspirin (75-300mg/day) in pregnancy but in most cases this treatment is initiated after 12 weeks of pregnancy when fetal organogenesis is complete and there is little risk of medication-induced structural malformation. Increased risks of gastroschisis, cleft lip and palate, and neural tube defects have been reported following maternal use of aspirin during pregnancy (mainly at analgesic doses); however, data are conflicting and may also be confounded, and a causal association with aspirin has not been proven. Data relating to risk of cardiac malformations are reassuring.

The majority of evidence suggests that there is no association between the use of low-dose aspirin and miscarriage, fetal growth restriction, or preterm delivery. Stillbirth data are limited to one small randomised-controlled trial that found no increased risk following exposure to low-dose aspirin. No data are available on pregnancy outcomes following aspirin use at analgesic doses, and data on neurodevelopmental outcomes following in utero aspirin exposure at any dose are too limited to facilitate an evidence-based assessment of risk.

Please refer to the UKTIS monograph ‘Use of Aspirin in Pregnancy’ for further information regarding the use of low dose aspirin in pregnancy.

Corticosteroids
The interim results of the RECOVERY trial have demonstrated a significant reduction in 28-day mortality for individuals with COVID-19 requiring oxygen who were given steroid (dexamethasone) therapy (age-adjusted rate ratio 0.83; 95% CI 0.75–0.93; P<0.001).[10] Corticosteroids are recommended for treating COVID-19 if patients require supplementary oxygen[8].

The RECOVERY trial protocol for pregnancy recommends prednisolone 40mg orally once daily, and, in women unable to take oral medicine, hydrocortisone 80mg intravenously twice daily instead of dexamethasone treatment.[10] Hydrocortisone and prednisolone are extensively metabolised by the placenta, whilst dexamethasone crosses the placenta. It is reasonable to assume that prednisolone and hydrocortisone are equally effective at treating the inflammation associated with COVID-19 and this substitution is reasonable to prevent unnecessary fetal exposure to dexamethasone.

The UKTIS monograph ‘Use of Systemic Corticosteroids in Pregnancy’ describes approximately 7,000 exposed pregnancies reported in the literature. Many of the studies reporting pregnancy outcomes following gestational exposure to systemic corticosteroids are limited by a lack of stratification to account for differing doses, treatment duration and steroid potencies. The available data may therefore be inadequate to assess the fetal risks posed by maternal high dose/potency corticosteroid exposure, or use for extended periods during pregnancy.

Although data regarding malformation risks following first trimester exposure are conflicting, the majority of the best quality evidence does not suggest increased risks in either the overall malformation rate, or for specific malformations (including orofacial clefts and cardiac anomalies). The small number of methodologically limited studies investigating miscarriage and intrauterine death risks do not provide reliable evidence of increased risks, and similarly there is no reliable evidence indicating use of systemic corticosteroids impairs fetal growth. Some studies have shown increased risks of preterm delivery, but the evidence is likely confounded by the underlying condition for which corticosteroids were administered.

Tocilizumab
Tocilizumab is a humanised monoclonal IgG1 antibody which binds and inhibits both soluble and membrane-bound IL-6 receptors, thereby inhibiting the pro-inflammatory activity of IL-6.[11] Randomised clinical trials have demonstrated that tocilizumab given to hospitalised patients with severe COVID-19 reduces the risk of death, lessens the need for mechanical ventilation, and decreases time spent in hospital.[12]

Evidence relating to the fetal effects following maternal use in pregnancy are limited, currently consisting of uncontrolled case reports/series’ which together describe approximately 600 exposed pregnancies.[13] Although adverse pregnancy outcomes have been described (including cases of congenital anomaly, miscarriages and preterm deliveries), the crude rates of these events do not generally appear to be notably increased above the background rate. The largest case series published to date is provided from a review of the manufacturer’s global safety database, describing 180 prospective exposed pregnancies with a crude malformation rate of 4.5% (95% CI 1.50 to 10.2%) and a crude miscarriage rate of 21.6% (95% CI 16.0 to 28.5%).[14] Although these crude rates are increased in comparison to the background risks (malformation 2-3%, miscarriage 10-20%), the findings are based on small numbers of exposed and affected pregnancies which produced wide confidence limits that overlap the expected rates. Furthermore, no pattern of malformation was observed, concomitant methotrexate exposure (a known teratogen and abortifacient) was described, and methodological biases likely exist. Controlled studies are therefore required before any meaningful assessment of the teratogenic risk can be provided.

Tocilizumab should be strongly considered for pregnant women with severe COVID who have a CRP>75 or are in, or may be going to, an intensive care unit.[9]

Whilst there are no major concerns about the use of tocilizumab in pregnancy, discussion with UKTIS is recommended. Due to high demand, there is currently a global shortage of tocilizumab. The UK Department of Health and Social Care have recommended that sarilumab may be given in place of tocilizumab for adult patients hospitalised due to COVID-19, who meet the criteria for interleukin-6 receptor inhibitor treatment.

Sarilumab
Sarilumab is a human monoclonal antibody (IgG1 subtype) that specifically binds to both soluble and membrane-bound IL-6 receptors (IL-6Rα), and inhibits IL-6-mediated signalling, thereby inhibiting the pro-inflammatory activity of IL-6.[15]

There are currently no published data regarding the safety of sarilumab use in human pregnancy. Preclinical reproductive toxicity studies (using animal models) undertaken by the manufacturer have not been published in the peer-reviewed literature. Product literature states that pregnant Cynomolgus monkeys given intravenous sarilumab once-weekly from early gestation to birth experienced AUC plasma concentrations 83 times those seen in human therapy.[15] No adverse effects on the mother, embryo, fetus or neonate (up to 1 month after birth) were described.[15]

Given that monoclonal antibodies have highly selective pharmacological effects, it is anticipated that sarilumab will have a pregnancy safety profile similar to that of tocilizumab. In instances where tocilizumab is unavailable, the benefits of sarilumab treatment in hospitalised pregnant patients with severe COVID-19 who meet the requirements for IL-6 receptor inhibitor treatment will likely outweigh the risks. As no human pregnancy data are currently available for sarilumab, careful collation of pregnancy outcome data is advised. To aid this data collection, healthcare professionals are encouraged to report cases of sarilumab exposure in pregnancy to UKTIS.

Sarilumab should be considered in place of tocilizumab (in women with COVID who have CRP>75 and are in, or need ICU admission).[8]

Ronapreve (REGN-COV2)
Ronapreve (REGN-COV2) is a mixture of two monoclonal antibodies (mAbs; casirivimab (REGN10933) and imdevimab (REGN10987) targeting non-overlapping epitopes on the SARS-CoV-2 spike protein[16]. The spike protein is a key mediator of viral infectivity required for attachment and entry into target cells by binding the ACE2 receptor.[17]

Results from a double blind, placebo controlled trial of 799 non-hospitalised adults with mild to moderate COVID-19 symptoms showed viral load reduction in patients treated with Ronapreve versus placebo at day seven.[18] Another randomised controlled trial described decreased mortality among hospitalised seronegative COVID-19 patients treated with Ronapreve in comparison with those allocated to standard care.[16]

The available pregnancy safety data are highly limited. Two case reports of exposure in pregnancy describe successful single dose administration of Ronapreve to a pregnant woman in her first trimester, and a pregnant woman in her second trimester. Pregnancy outcome information was described for the second trimester exposed pregnancy; an uneventful labour with uncomplicated spontaneous vaginal delivery. The neonate was admitted to the neonatal intensive care unit owing to intermittent tachypnea and presumed transient tachypnea of the newborn (COVID-19 test result was negative) with discharge on day 2 after delivery.[19]

Ronapreve should be considered for women with COVID-19 and no SARS-CoV2 antibodies.[9]

Whilst the target for the monoclonal antibodies are unique to viral proteins and therefore unlikely to affect fetal development, minimal pregnancy exposure data (human or animal) are available for Ronapreve to establish safety. Discussion with UKTIS is encouraged, in order to collect pregnancy outcome data.

Remdesivir
Remdesivir has been shown to reduce the time taken until clinical improvement in individuals with severe COVID-19 from a median of 15 days to 11 days (rate ratio 1.32; 95% CI 1.12-1.55).[20] It has been recommended for use in patients who have been hospitalised and are on supplementary oxygen therapy.[21] However, the SOLIDARITY trial, which compared 2,750 patients with COVID-19 treated with remdesivir to 4,088 receiving standard care, showed no reduction in mortality rates, the need for invasive ventilation or duration of hospital stay.[22]

Remdesivir is a novel, broad-acting antiviral nucleotide prodrug which effectively inhibits replication of SARS-CoV-2 in vitro and that of related coronaviruses including MERS-CoV in non-human primates.[1] There are very limited animal or human pregnancy exposure data available. A single small case series of six pregnant women exposed at various (unreported) stages of pregnancy whilst being treated for Ebola did not describe any adverse pregnancy outcomes.[23]

More recent case reports have not identified any particular concerns,[24-26] but it should be noted that remdesivir was given outside of the first trimester in all these case reports. A case series of 86 women (67 were pregnant, 19 immediate postpartum) were given remdesivir on a compassionate basis for severe COVID-19 infection. Although rates of pre-term delivery were high (likely related to severe COVID-19) the study demonstrated a high rate of clinical recovery.[27]

Remdesivir can be given in pregnancy if the benefits outweigh the potential risks. Discussion with UKTIS is recommended to discuss the clinical circumstances around each individual case.

Anakinra
Anakinra is a recombinant selective IL-1 receptor antagonist. It blocks the biologic activity of natural IL-1 by competitively inhibiting the binding of IL-1 to the interleukin-1 type receptor.[28]

No observed effects were seen on embryo-fetal development in rats and rabbits at doses up to 100 time the human dose (2mg/kg/day).[28] The limited human pregnancy exposure data consist of 57 pregnancies from a number of case reports, case series and registry data; with 23 using anakinra throughout pregnancy.[29-35] Two cases of renal anomalies in exposed infants were reported, one renal agenesis in a twin with a genetic mutation[30] and one renal agenesis and ectopic neuropophysis with growth hormone deficiency in an infant exposed in utero from 9/40 until delivery at 38/40.[33] In addition, two cases of oligohydramnios were also seen in five pregnancies from a registry.[32] However, one patient was also exposed to three other DMARDs and celecoxib, a drug previously associated with low amniotic fluid levels.

Pregnancy data are currently limited, and although renal agenesis and oligohydramnios have been described in exposed infants, controlled studies are lacking, therefore any meaningful assessment of the teratogenic risk cannot currently be provided. Discussion with UKTIS is recommended prior to treatment.
 
Bamlanivimab
Bamlanivimab, also known as LY-CoV555 and LY3819253, is a neutralising monoclonal antibody that targets the receptor-binding domain of the spike protein of SARS-CoV2. Bamlanivimab has been found to be ineffective in treating hospitalised patients with COVID-19.[36][30] There are limited data available to determine bamlanivimab’s effectiveness in outpatients with mild to moderate COVID-19. Interim results from the BLAZE-1 trial in the United States indicate a potential clinical benefit but further data are required to draw conclusions.[37]

Bamlanivimab remains an investigational drug and is not licensed.  No pregnancy exposure data (human or animal) are currently available. Discussion with UKTIS is recommended prior to treatment.

Hydroxychloroquine
Hydroxychloroquine has not shown to be effective for the treatment of COVID-19[10, 22] and is therefore not recommended for treating COVID-19 in pregnancy.

Please refer to the UKTIS monograph ‘Use of Chloroquine in Pregnancy‘ for further information regarding the use of hydroxychloroquine in pregnancy.

Azithromycin
Azithromycin has not been shown to benefit clinical outcome including clinical status or mortality, when added to standard care (which included hydroxychloroquine) in treating patients admitted to hospital with COVID-19.[38]

Please refer to the UKTIS monograph ‘Use of Macrolide Antibiotics in Pregnancy’ for further information regarding the use of azithromycin in pregnancy.

Lopinavir/ritonavir
Lopinavir/ritonavir has not been shown to be effective for the treatment of COVID-19[10, 22] and is therefore not recommended for treating COVID-19 in pregnancy.

Lopinavir and ritonavir are both HIV-protease inhibitors. Typically, ritonavir is administered alongside other protease inhibitors to act as a competitive inhibitor of CYP3A4, thereby enhancing bioavailability and prolonging pharmacodynamic activity.[39]

Evidence relating to the fetal effects following maternal use in pregnancy is mainly provided from large uncontrolled case series collected from antiretroviral pregnancy registries. Together these data provide outcomes for approximately 3,000 exposed pregnancies and do not suggest an increased risk of malformation.[39] Studies investigating neurodevelopmental outcomes have also provided reassuring findings.[39] However, data concerning other adverse pregnancy outcomes are lacking.

Interferon beta-1a
The SOLIDARITY trial showed no reduction in mortality (in unventilated patients or any other subgroup), initiation of ventilation or hospitalisation duration in COVID-19 patients treated with interferon beta-1a (n=1,412) or with interferon beta -1a and lopinavir (n=651) when compared to 4,088 receiving standard care.[22] Beta interferon is not currently recommended by the NHS.

Interferons are a family of naturally occurring cytokines that are produced in response to viral infection, and mediate antiviral, antiproliferative and immunomodulatory activities.[40] Studies assessing teratogenic or fetotoxic risks have typically assessed exposure to any interferon beta (including 1a and 1b subtypes) in the treatment of multiple sclerosis.

The UKTIS monograph ‘Use of Interferon Beta in Pregnancy’ describes approximately 2,750 exposed pregnancies reported in the literature.

Colchicine
Colchicine is a mitotic spindle fibre inhibitor that induces metaphase arrest in cells undergoing mitosis.[41] Its anti-inflammatory effect has been attributed to the disruption of microtubules in neutrophils, which in turn inhibit migration toward the chemotactic factors.[42] Pregnancy exposure data are mainly provided from uncontrolled case reports of patients treated for Familial Mediterranean Fever and together describe approximately 2,100 exposed pregnancies.[41]  These data do not currently indicate an increased risk of miscarriage, congenital malformation or chromosomal anomalies.

Imatinib
Imatinib is a tyrosine kinase inhibitor that potently inhibits the activity of the Bcr-Abl tyrosine kinase, as well as several receptor tyrosine kinases, and is typically used in the treatment of haematological malignancies.[43] A clinical trial is under way in the Netherlands investigating whether early imatinib use can prevent hypoxemic respiratory failure through preventing extensive vascular leakage and pulmonary oedema in patients with COVID-19.[44]

Data regarding imatinib use in human pregnancy are limited to retrospective case reports and case series describing approximately 300 pregnancies exposed in the treatment of CML, with around half exposed in the first trimester.[45] Although malformations including combinations of exomphalos, renal agenesis,[46, 47] scoliosis and hemivertebrae[47] have been described in exposed infants, controlled studies are lacking, therefore any meaningful assessment of the teratogenic risk cannot currently be provided.

Baricitinib
Baricitinib is a Janus kinase inhibitor which machine learning has identified as a potential drug for the treatment of COVID-19 by inhibiting the endocytosis of SARS-CoV-2 into pulmonary cells.[1] A case report was located in the literature which described a patient with rheumatoid arthritis who was exposed to baricitinib from conception to 17 weeks. The outcome was a healthy infant born at 38 weeks.[48] Tofacitinib is another Janus kinase inhibitor; although data are limited with approximately 60 exposed pregnancies published in a small number of uncontrolled case series,[49, 50] crude rates of adverse pregnancy outcomes do not appear to be increased in comparison with their respective expected background rates.

Other treatment options
Clinical trials of several other treatment options are recorded in the EU register, including camostat mesilate (a serine protease inhibitor) and sargramostim (a recombinant human granulocyte-macrophage colony stimulating growth factor). No pregnancy exposure data (human or animal) were located for these medications.


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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.