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MEDICATIONS USED TO TREAT COVID 19 IN PREGNANCY

Date of issue: May 2020
Version: 1.2

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, in itself, is therefore not a contraindication to any of the treatment options discussed below, however safety data are lacking for some treatments, and efficacy is yet to be established for all 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]

Although pregnant women are not currently believed to be more at risk of contracting COVID-19[3], respiratory illnesses which occur during pregnancy typically result in increased morbidity and higher maternal mortality rates.[1] As a precautionary approach, the UK Government announced that pregnant women were considered to be a vulnerable population during the COVID-19 outbreak. However, the current evidence relating to COVID-19 infection during pregnancy does not suggest that maternal symptomatology is any more severe than that of the general population.[1,2]

Due to the limited data available, it is currently unknown whether infection with the virus itself exerts direct teratogenic or fetotoxic effects.[2] 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 50 mGy, 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 100 mGy 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 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)[4] or have been listed as investigational medicinal products in COVID-19 clinical trials that are recorded on the EU register.[5]

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.

Hydroxychloroquine

Hydroxychloroquine is a quinine derivative that shares many of the pharmacologic properties of chloroquine, an antimalarial and anti-inflammatory agent, although hydroxychloroquine is slightly more potent.[6] In vitro studies have shown that chloroquine may act to increase the endosomal pH required for cell fusion and interrupts the glycosylation of cellular receptors of SARS-CoV-2.[1]

Evidence relating to hydroxychloroquine use in pregnancy is mainly provided from controlled studies investigating its use as an antirheumatic or in the treatment of lupus erythematosus.[6] A meta-analysis (MA) published in 2016 pooled data from seven observational cohorts and one randomized-controlled trial, including a total of 740 HCQ-exposed infants and 1,130 unexposed controls.[7] This study found no significant increased risk of major malformations in general, as well as craniofacial, cardiovascular, nervous system and genitourinary malformations specifically, and no significant increase in stillbirth, low birth weight or prematurity risks. However, the MA did show an increase in miscarriage risk (1.85-fold) for which confounding by indication and methodological bias in the raw data is likely.[7] Retinopathy is a known adverse-effect of chloroquine/hydroxychloroquine, and therefore theoretical concerns previously existed regarding the risk of retinopathy among infants exposed to chloroquine/hydroxychloroquine in utero. However, several small controlled studies have not found evidence of such an association.[23]

Additional data which may be of relevance for hydroxychloroquine exposure in pregnancy are provided from studies investigating chloroquine use, mainly in the treatment or prophylaxis of malaria in pregnancy. The UKTIS monograph ‘Use of Chloroquine in Pregnancy’ describes approximately 8,400 exposed pregnancies, which taken together do not suggest increased risks of miscarriage, malformation (although T1 data are limited), stillbirth/IUD, prematurity, growth restriction or neonatal complication.

Azithromycin

Azithromycin is a macrolide antibiotic. In addition to their antimicrobial properties, macrolides also possess immunomodulatory effects such as decreasing the production of pro-inflammatory cytokines and inhibition of neutrophil activation, and are widely used in the treatment of infectious pneumonia and chronic inflammatory lung disease.[4] Azithromycin is also thought to possess stronger immunomodulatory effects than other macrolides.[4]

There is considerable evidence available regarding both macrolides as a class and specifically azithromycin use in pregnancy. The UKTIS monograph ‘Use of Macrolide Antibiotics in Pregnancy’ describes >10,000 azithromycin exposed pregnancies, with approximately 7,600 exposed in at least the first trimester.

A small number of studies investigating macrolide antibiotic use as a class have described increased risks of malformation (both overall and cardiac specifically) and miscarriage. However, the evidence is conflicting with several robust studies failing to confirm these associations, and the findings of increased malformation and miscarriage risks may have been produced as a consequence of methodological biases and/or data confounding. Furthermore, the increase in absolute malformation risk that was indicated by these studies is small.

Although individual studies have described increased risks of miscarriage and overall malformation following azithromycin use in pregnancy, the majority of studies do not support these findings. Furthermore, where studies have indicated increased risks of miscarriage and malformation, these data may have been impacted by methodological biases and/or data confounding. Also, five studies that included ~7,500 first trimester azithromycin exposed pregnancies all found no increased risk of cardiac malformation specifically. The available data relating to risks of intrauterine death, preterm delivery, low birth weight, and neonatal complications do not suggest increased risks for macrolides as a class, although for these outcomes, there are no or very limited data relating specifically to azithromycin-exposed pregnancies.

Tocilizumab

The UKTIS monograph ‘Use of Tocilizumab in Pregnancy’ provides an overview of the fetal risks following maternal exposure. Tocilizumab is a humanized monoclonal IgG1 antibody which binds and inhibits both soluble and membrane-bound IL-6 receptors, thereby inhibiting the pro-inflammatory activity of IL-6.[8] Evidence relating to the fetal effects following maternal use in pregnancy are limited, currently consisting of uncontrolled case reports/series’ which together describe <300 exposed pregnancies.[9] 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%).[9] 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.

Lopinavir/ritonavir

Lopinavir and ritonavir are both HIV-protease inhibitors.[10] Typically, ritonavir is administered alongside other protease inhibitors to act as a competitive inhibitor of CYP3A4, thereby enhancing bioavailability and prolonging pharmacodynamic activity.[10] All betacoronaviruses contain two cysteine proteases that process viral polypeptides during replication, therefore lopinavir and ritonavir may offer some benefit in the adjunctive management of COVID-19.[1]

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.[10] Studies investigating neurodevelopmental outcomes have also provided reassuring findings.[10] However, cases of preterm delivery, low birth weight and stillbirth have also been described.[24] Due to data limitations, the risk of these outcomes following maternal lopinavir/ritonavir use in pregnancy is currently undetermined.

Interferon beta-1a

Interferons are a family of naturally occurring cytokines that are produced in response to viral infection, and mediate antiviral, antiproliferative and immunomodulatory activities.[11] 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. Although the number of interferon beta-exposed pregnancies appears substantial, the majority are derived from a large uncontrolled mixed case series of prospective and retrospective cases spontaneously reported to the manufacturer. Furthermore, most of the available controlled cohort studies only provide small numbers of exposed pregnancies, which limits their statistical power to detect differences in adverse pregnancy outcome rates. Nonetheless, the available data do not currently suggest increased risks of miscarriage, congenital malformation, low infant birth weight or impaired neurodevelopment following in utero interferon beta exposure. The evidence relating to preterm delivery risk is conflicting, but also likely confounded by the underlying condition for which interferon beta was administered. Due to a lack of any controlled data the risk of intrauterine death is currently unquantifiable.

Corticosteroids

Low dose dexamethasone has been suggested as a possible anti-inflammatory corticosteroid for COVID-19 patients.[4] 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.

Remedesivir

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.[12]

Colchicine

Colchicine is a mitotic spindle fibre inhibitor which induces metaphase arrest in cells undergoing mitosis.[13] Its anti-inflammatory effect has been attributed to the disruption of microtubules in neutrophils, which in turn inhibit migration toward the chemotactic factors.[14] 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.[13] 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.[15] 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.[16]

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.[17] Although malformations including combinations of exomphalos, renal agenesis,[18,19] scoliosis[18] and hemivertebrae 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.[20] Tofacitinib is another Janus kinase inhibitor; although data are limited with approximately 60 exposed pregnancies published in a small number of uncontrolled case series,[21,22] 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,[5] including camostat mesilate (a serine protease inhibitor), sarilumab (a recombinant human granulocyte-macrophage colony stimulating growth factor) and sargramostim (IgG1 IL-6 receptor antibody). No pregnancy exposure data (human or animal) were located for these medications.

References

1.  Dashraath P, Jing Lin Jeslyn W, Mei Xian Karen L, Li Min L, Sarah L, Biswas A, et al. Coronavirus Disease 2019 (COVID-19) Pandemic and Pregnancy. Am J Obstet Gynecol. 2020 Mar;
2.  De-Haan T, Dinavitser N, Cohen R, Berkovitch M, Berlin M. The Corona Pandemic- Safety/Risk of COVID 19 During Pregnancy and Lactation. Motherisk Int J. 2020;1(8).
3.  RCOG. Coronavirus (COVID-19) infection and pregnancy [Internet]. 2020. Available from: www.rcog.org.uk/coronavirus-pregnancy
4.  University of Oxford. RECOVERY; Randomised Evaluation of COVID-19 Therapy.
5.  EU Commission. EU Clinical Trials Register. 2020.
6.  Reprotox. Hydroxychloroquine. 2020.
7.  Kaplan YC, Ozsarfati J, Nickel C, Koren G. Reproductive outcomes following hydroxychloroquine use for autoimmune diseases: a systematic review and meta-analysis. Br J Clin Pharmacol. 2016 May;81(5):835–48.
8.  Roche Products Limited. SmPC: RoActemra 162 mg Solution for Injection in Pre-Filled Pen. 2019.
9.  Reprotox. Tocilizumab. 2020.
10.  Shepard’s. Lopinavir and ritonavir. 2020.
11.  Biogen Idec Ltd. SmPC: AVONEX 30 micrograms/0.5 ml solution for injection. 2019.
12.  Mulangu S, Dodd LE, Davey RTJ, Tshiani Mbaya O, Proschan M, Mukadi D, et al. A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics. N Engl J Med. 2019 Dec;381(24):2293–303.
13.  Reprotox. Colchicine. 2020.
14.  Ben-Chetrit E, Bergmann S, Sood R. Mechanism of the anti-inflammatory effect of colchicine in rheumatic diseases: a  possible new outlook through microarray analysis. Rheumatology (Oxford). 2006 Mar;45(3):274–82.
15.  Novartis Pharmaceuticals UK Ltd. SmPC: Glivec 100 mg film-coated tablets. 2019.
16.  Aman J. COUNTER-COVID Trial Protocol [Internet]. Available from: www.clinicaltrialsregister.eu/ctr-search/trial/2020-001236-10/NL
17.  Reprotox. Imatinib. 2020.
18.  Pye SM, Cortes J, Ault P, Hatfield A, Kantarjian H, Pilot R, et al. The effects of imatinib on pregnancy outcome. Blood. 2008 Jun;111(12):5505–8.
19.  Jain N, Sharma D, Agrawal R, Jain A. A newborn with teratogenic effect of imatinib mesylate: a very rare case report. Med Princ Pract. 2015;24(3):291–3.
20.  Costanzo G, Firinu D, Losa F, Deidda M, Barca MP, Del Giacco S. Baricitinib exposure during pregnancy in rheumatoid arthritis. Vol. 12, Therapeutic advances in musculoskeletal disease. England; 2020. p. 1759720X19899296.
21.  Reprotox. Tofacitinib. 2020.
22.  Mahadevan U, Dubinsky MC, Su C, Lawendy N, Jones T V, Marren A, et al. Outcomes of Pregnancies With Maternal/Paternal Exposure in the Tofacitinib Safety Databases for Ulcerative Colitis. Inflamm Bowel Dis. 2018 Nov;24(12):2494–500.
23.  Osadchy A, Ratnapalan T, Koren G. Ocular toxicity in children exposed in utero to antimalarial drugs: review of the literature. J Rheumatol. 2011 Dec;38(12):2504–8.
24.  Pasley M V, Martinez M, Hermes A, d’Amico R, Nilius A. Safety and efficacy of lopinavir/ritonavir during pregnancy: a systematic review. AIDS Rev. 2013;15(1):38–48.

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.