MEDICATIONS USED TO TREAT COVID 19 IN PREGNANCY

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] Most women who are infected during pregnancy will be asymptomatic (70-80%)[3], and the majority of those who do become symptomatic will only ever experience mild to moderate symptoms.[3] However, natural physiological adaptations to pregnancy result in changes to the immune and respiratory systems, cardiovascular function, and coagulation, which may in turn affect the progression of COVID-19. Intensive care admission and invasive ventilation have been shown to 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) identified increased rates of intensive care admission among pregnant women with COVID-19 in comparison with uninfected pregnant women.[6] Risk factors associated with severe COVID-19, 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] Pregnant women also appear to be at increased risk of complications in their third trimester when compared to earlier in pregnancy.[3]

COVID-19 vaccination has proven highly effective at decreasing hospitalisation and ICU admission in pregnancy, with UKHSA data demonstrating that a very small proportion (<1%) of pregnant women admitted to hospital with COVID-19 had received two doses of the vaccine.[7] More information about COVID-19 vaccination in pregnancy can be found on the ‘Use of non-live vaccines in pregnancy’ summary.

The available data do not currently demonstrate an association between COVID-19 infection in pregnancy and an increased risk of congenital anomalies, and limited evidence has not shown any association with an increased risk of miscarriage. However, COVID-19 in pregnancy has been associated with impaired fetal growth and an approximate 2-fold increased risk of stillbirth. Symptomatic COVID-19 has been associated with an approximate 3-fold increased risk of preterm birth (likely influenced by iatrogenic deliveries). Excluding complications which arise as a result of prematurity, the risk of neonatal complications does not appear to be increased with COVID-19 infection in pregnancy.[3]

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 image 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 RCOG recommends prednisolone 40mg orally once daily (or methylprednisolone 32 mg once daily), and, in women unable to take oral medicine, hydrocortisone 80mg intravenously twice daily instead of dexamethasone treatment.[3] Hydrocortisone and prednisolone are extensively metabolised by the placenta, whilst dexamethasone crosses the placenta. It is reasonable to assume that prednisolone or methylprednisolone are as equally effective as hydrocortisone at treating the inflammation associated with COVID-19 and these substitutions are reasonable to prevent unnecessary fetal exposure to dexamethasone. The RECOVERY trial has recently initiated a comparison of high dose corticosteroids (prednisolone 130 mg or hydrocortisone 540 mg in four divided doses or intravenous methylprednisolone 100mg IV for five days; followed by prednisolone 65 mg or hydrocortisone 270 mg in four divided doses or intravenous methylprednisolone 50 mg for five days).[11]

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.[12] 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.[13]

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.[14] 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%).[15] 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, tocilizumab may be subject to availability issues. 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.[16]

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.[16] No adverse effects on the mother, embryo, fetus or neonate (up to 1 month after birth) were described.[16]

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 unknown 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[17]. The spike protein is a key mediator of viral infectivity required for attachment and entry into target cells by binding the ACE2 receptor.[18]

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.[19] Another randomised controlled trial described decreased mortality among hospitalised seronegative COVID-19 patients treated with Ronapreve in comparison with those allocated to standard care.[17]

The available pregnancy safety data are highly limited. Six case reports of exposure in pregnancy describe successful single dose administration of Ronapreve. Progression of COVID-19 symptoms (from mild to moderate – shortness of breath) beyond those observed at initial administration was only observed in one patient. Two of the women were exposed in the first trimester, one in the second trimester, and three in the third.[20, 21]Pregnancy outcome information has been described for three of the exposed pregnancies (one second trimester exposed, two third trimester exposed); (i) an uneventful labour with uncomplicated spontaneous vaginal delivery; (ii) preterm delivery (36 weeks) of a healthy fetus; and (iii) term delivery (37 weeks) of a healthy fetus.[20, 21] One of the neonates 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.[20] Of the remaining pregnancies, no adverse pregnancy events were reported at the time of the case report publications.

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.

Sotrovimab

Sotrovimab is an IgG1 monoclonal antibody that binds to a conserved epitope on the spike protein receptor binding domain of SARS-CoV-2.[22] In the UK it is licensed for the treatment of symptomatic adults and adolescents with acute COVID-19 infection who do not require oxygen supplementation, and who are at increased risk of progressing to severe COVID infection.

Preclinical animal studies have not evaluated the risk of reproductive toxicity. However, the manufacturer reports no off-target binding in a cross-reactive binding assay that used a protein array enriched for human embryofetal proteins.[22]

As the binding target for sotrovimab is likely unique to COVID-19 viral proteins, it is not expected that the administration of sotrovimab in pregnancy would affect fetal development. Therefore, sotrovimab could be considered for use in women with COVID-19 where the benefits are expected to outweigh the risks. Discussion with UKTIS is encouraged, in order to collect pregnancy outcome data.

COVID-19 antivirals

A number of COVID-19 antiviral medications are under development. As these are newly developed medications, there is a lack of human pregnancy safety information for all these treatment options.

Molnupiravir is licensed 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.[23] Preclinical animal reproductive toxicity studies have indicated possible teratogenic effects[23], and as such, molnupiravir is not recommended for use 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, or became pregnant shortly after taking it, should be referred to UKTIS for further counselling and follow-up of the pregnancy outcome. Please see the UKTIS monograph, ‘Use of molnupiravir in pregnancy,’ for more information.

Paxlovid (nirmatrelvir/ritonavir) is licensed for the treatment of COVID-19 in adults who do not require supplemental oxygen, but who are at increased risk of developing severe illness.[24] Nirmatrelvir is a peptidomimetic inhibitor of the coronavirus 3C-like (3CL) protease which prevents viral replication.[24] Ritonavir is included in the formulation as a pharmacokinetic enhancer, to inhibit CYP3A mediated metabolism of nirmatrelvir, and does not possess pharmacodynamic activity against SARS-CoV-2 3CL protease.[24] Preclinical animal reproductive toxicity studies have not identified adverse effects on fetal morphology or embryo-fetal viability in rat or rabbit models with doses of nirmatrelvir up to 12 times the human dose (equivalence based on predicted AUC concentrations).The offspring of pregnant rabbits administered 24 times the equivalent human dose, lower fetal body weights were observed but evidence of maternal toxicity was described (impact on weight gain/food consumption).[24] There is a large amount of published evidence relating to the safety of ritonavir in human pregnancy, collected from antiretroviral and HIV/AIDS pregnancy registries. Overall, these data do not provide evidence that ritonavir use in the first trimester is associated with an increased risk of malformation above the expected background rate of 2-3%.[25] There is also no evidence that liponavir/ritonavir combination therapy in pregnancy had any detectable impact on postnatal development.[26] Data investigating other adverse pregnancy outcomes (such as miscarriage, preterm delivery, fetal growth impairment or stillbirth risks) are lacking. Due to a lack of human pregnancy safety data, the manufacturer of Paxlovid does not recommend use in pregnancy. However, the benefits of use could outweigh the risks in some circumstances (see paragraph below). As CYP3A4 metabolic activity and glomerular filtration increase during pregnancy, it is unclear whether pregnancy may impact the pharmacokinetics of Paxlovid. Further research into the efficacy of this medication in pregnancy is required.

Despite the lack of human pregnancy safety data for COVID-19 antivirals, there may be specific circumstances where the benefits of use during pregnancy could outweigh the risks. Such circumstances may include the use in women at high risk of developing severe disease (due to non-vaccination status or clinical vulnerabilities), or in women experiencing severe symptoms of COVID-19 where other more established treatments have failed. However, the efficacy of these treatments may not have been proven in all such clinical scenarios. Where COVID-19 antivirals are being considered for use during pregnancy, the risks and benefits should be discussed on an individual patient basis. Alternative early treatment options that do not pose theoretical risks of fetal harm, such as casirivimab/imdevimab (Ronapreve) or sotrovimab monoclonal antibodies may be preferred for pregnant women. Discussion with UKTIS is recommended in all cases where COVID-19 antiviral treatment is being considered in pregnancy.

In collaboration with the MHRA, UKTIS is currently conducting enhanced safety monitoring of pregnancies exposed to COVID-19 antiviral medications (including molnupiravir and Paxlovid). If you are aware of any women who have used COVID-19 antivirals during pregnancy, or became pregnant shortly after finishing treatment, please report these pregnancies to UKTIS (telephone 0344 892 0909, available Monday to Friday excluding Bank Holidays, 9am to 5pm).

Remdesivir

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] A 2020 NICE evidence review concluded that there was some evidence to support the benefit of remdesivir use in decreasing the need for supportive measures, including mechanical ventilation, and reducing the time to recovery in patients with mild/moderate to severe COVID-19 receiving supplemental oxygen.[27] A 2021 study has also shown that use of remdesivir within seven days of symptom onset among patients at high risk for severe disease progression resulted in an 87% reduction in risk of hospitalisation or death.[28]

Remdesivir is not considered highly effective in the treatment of acute COVID-19. Clinical guidelines for the UK state that remdesivir may be used in patients requiring low-flow supplemental oxygen.[27] Remdesivir may also be used as a prophylactic treatment in patients with hospital onset of COVID-19, where treatment is being initiated within seven days of symptom onset and where a neutralising monoclonal antibody (nMAB) is either contraindicated or otherwise unavailable.[29]

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.[30]

More recent case reports have not identified any particular concerns,[31-33] 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.[34]

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.[35] 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).[35] 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.[36-42] Two cases of renal anomalies in exposed infants were reported, one renal agenesis in a twin with a genetic mutation[37] 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.[40] In addition, two cases of oligohydramnios were also seen in five pregnancies from a registry.[39] 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.[43][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.[44]

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, 45] 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.[46]

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, 45] 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.[47]]

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.[47] Studies investigating neurodevelopmental outcomes have also provided reassuring findings.[47] 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.[45] 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.[48] 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.[49] Its anti-inflammatory effect has been attributed to the disruption of microtubules in neutrophils, which in turn inhibit migration toward the chemotactic factors.[50] 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.[49] 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.[51] 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.[52]

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.[53] Although malformations including combinations of exomphalos, renal agenesis,[54, 55] scoliosis and hemivertebrae[55] 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.[56] Tofacitinib is another Janus kinase inhibitor; although data are limited with approximately 60 exposed pregnancies published in a small number of uncontrolled case series[57, 58] and a case report[59], 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.

References

1. Dashraath, P., W. Jing Lin Jeslyn, L. Mei Xian Karen, L. Li Min, L. Sarah, A. Biswas, M. Arjandas Choolani, C. Mattar, and S.L. Lin, Coronavirus Disease 2019 (COVID-19) Pandemic and Pregnancy. American journal of obstetrics and gynecology, 2020.
2. Docherty, A.B., E.M. Harrison, C.A. Green, H.E. Hardwick, R. Pius, L. Norman, K.A. Holden, J.M. Read, F. Dondelinger, G. Carson, L. Merson, J. Lee, D. Plotkin, L. Sigfrid, S. Halpin, C. Jackson, C. Gamble, P.W. Horby, J.S. Nguyen-Van-Tam, A. Ho, C.D. Russell, J. Dunning, P.J.M. Openshaw, J.K. Baillie, and M.G. Semple, Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ, 2020: p. m1985.
3. Royal College of Obstetricians and Gynaecologists. Coronavirus (COVID-19) infection and pregnancy. 2021; Available from: www.rcog.org.uk/coronavirus-pregnancy.
4. 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, 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, and S. Thangaratinam, Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: Living systematic review and meta-analysis. The BMJ, 2020. 370.
5. Collin, J., E. Byström, A. Carnahan, and M. Ahrne, Public Health Agency of Sweden’s Brief Report: Pregnant and postpartum women with severe acute respiratory syndrome coronavirus 2 infection in intensive care in Sweden. Acta Obstetricia et Gynecologica Scandinavica, 2020. 99(7): p. 819-822.
6. Knight, M., K. Bunch, N. Vousden, E. Morris, N. Simpson, C. Gale, P. Obrien, M. Quigley, P. Brocklehurst, and J.J. Kurinczuk, Characteristics and outcomes of pregnant women admitted to hospital with confirmed SARS-CoV-2 infection in UK: National population based cohort study. The BMJ, 2020. 369.
7. UK Health Security Agency. New UKHSA study provides more safety data on COVID-19 vaccines in pregnancy. 2021; Available from: www.gov.uk/government/news/new-ukhsa-study-provides-more-safety-data-on-covid-19-vaccines-in-pregnancy#:~:text=Analysis%20by%20the%20UK%20Health,safety%20record%20in%20pregnant%20women.&text=This%20is%20the%20first%20data,vaccination%20had%20good%20birth%20outcomes.
8. National Institute for Health and Care Excellence. COVID-19 rapid guideline: Managing COVID-19 2021; Available from: https://app.magicapp.org/#/guideline/L4Qb5n/section/LAJvRn.
9. Royal College of Midwives and Royal College of Obstetricians Gynaecologists. Coronavirus (COVID-19) Infection in Pregnancy. 2021; Available from: www.rcog.org.uk/globalassets/documents/guidelines/2021-08-25-coronavirus-covid-19-infection-in-pregnancy-v14.pdf.
10. University of Oxford, RECOVERY; Randomised Evaluation of COVID-19 Therapy. 2020.
11. RECOVERY Trial. RECOVERY Trial to investigate whether higher doses of dexamethasone deliver greater benefit for patients with severe COVID-19. 2021; Available from: www.recoverytrial.net/news/recovery-trial-to-investigate-whether-higher-doses-of-dexamethasone-deliver-greater-benefit-for-patients-with-severe-covid-19.
12. Roche Products Limited. RoActemra 162 mg Solution for Injection in Pre-Filled Pen. 2021 September 2021]; Available from: www.medicines.org.uk/emc/product/9086/smpc.
13. RECOVERY Trail. Tocilizumab reduces deaths in patients hospitalised with COVID-19. 2021 September 2021]; Available from: www.recoverytrial.net/news/tocilizumab-reduces-deaths-in-patients-hospitalised-with-covid-19.
14. Jorgensen, S.C.J. and S.E. Lapinsky, Tocilizumab for coronavirus disease 2019 in pregnancy and lactation: a narrative review. Clin Microbiol Infect, 2021. PMID: 34438068.
15. Reprotox, Tocilizumab. 2020.
16. Sanofi Genzyme. Kevzara 200 mg solution for injection in pre-filled pen. 2021 September 2021]; Available from: www.medicines.org.uk/emc/product/8145/smpc.
17. RECOVERY Collaborative Group, P.W. Horby, M. Mafham, L. Peto, M. Campbell, G. Pessoa-Amorim, E. Spata, N. Staplin, J.R. Emberson, B. Prudon, P. Hine, T. Brown, C.A. Green, R. Sarkar, P. Desai, B. Yates, T. Bewick, S. Tiberi, T. Felton, J.K. Baillie, M.H. Buch, L.C. Chappell, J.N. Day, S.N. Faust, T. Jaki, K. Jeffery, E. Juszczak, W.S. Lim, A. Montgomery, A. Mumford, K. Rowan, G. Thwaites, D.M. Weinreich, R. Haynes, and M.J. Landray, Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. medRxiv, 2021: p. 2021.06.15.21258542-2021.06.15.21258542.
18. Wang, Q., Y. Zhang, L. Wu, S. Niu, C. Song, Z. Zhang, G. Lu, C. Qiao, Y. Hu, K.-Y. Yuen, Q. Wang, H. Zhou, J. Yan, and J. Qi, Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2. Cell, 2020. 181(4): p. 894-904.e9.
19. FDA. Coronavirus (COVID-19) Update: FDA Authorizes Monoclonal Antibodies for Treatment of COVID-19. Press Announcements. 2020; Available from: www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-monoclonal-antibodies-treatment-covid-19.
20. Mayer, C., K. VanHise, R. Caskey, M. Naqvi, and R.M. Burwick, Monoclonal Antibodies Casirivimab and Imdevimab in Pregnancy for Coronavirus Disease 2019 (COVID-19). Obstet Gynecol, 2021. PMID: 34583385.
21. Hirshberg, J.S., E. Cooke, M.C. Oakes, A.O. Odibo, N. Raghuraman, and J.C. Kelly, Monoclonal antibody treatment of symptomatic COVID-19 in pregnancy: initial report. Am J Obstet Gynecol, 2021. 225(6): p. 688-689. PMID: 34453934.
22. GlaxoSmithKline UK. Xevudy 500 mg concentrate for solution for infusion. 2021; Available from: www.medicines.org.uk/emc/product/13097.
23. Merck Sharp & Dohme (UK) Limited. Lagevrio 200 mg hard capsules. 2021; Available from: www.medicines.org.uk/emc/product/13044.
24. Pfizer Limited. Paxlovid 150 mg/100 mg film-coated tablets. 2022; Available from: www.medicines.org.uk/emc/product/13145.
25. TERIS Teratology Information System. Ritonavir. 2022; Available from: www.micromedexsolutions.com.
26. Van Dyke, R.B., E.G. Chadwick, R. Hazra, P.L. Williams, and G.R. Seage, 3rd, The PHACS SMARTT Study: Assessment of the Safety of In Utero Exposure to Antiretroviral Drugs. Front Immunol, 2016. 7: p. 199. PMID: 27242802.
27. UK Department of Health and Social Care. Interim clinical commissioning policy: Remdesivir for patients hospitalised with COVID-19 (adults and children 12 years and older). 2021; Available from: www.england.nhs.uk/coronavirus/wp-content/uploads/sites/52/2020/07/C1322-interim-cc-policy-remdesivir-for-people-hospitalised-with-covid-19-v3.pdf.
28. Gottlieb, R.L., C.E. Vaca, R. Paredes, J. Mera, B.J. Webb, G. Perez, G. Oguchi, P. Ryan, B.U. Nielsen, M. Brown, A. Hidalgo, Y. Sachdeva, S. Mittal, O. Osiyemi, J. Skarbinski, K. Juneja, R.H. Hyland, A. Osinusi, S. Chen, G. Camus, M. Abdelghany, S. Davies, N. Behenna-Renton, F. Duff, F.M. Marty, M.J. Katz, A.A. Ginde, S.M. Brown, J.T. Schiffer, J.A. Hill, and G.-U.-. Investigators, Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients. N Engl J Med, 2021. PMID: 34937145.
29. UK Department of Health and Social Care. Interim Clinical Commissioning Policy: Neutralising monoclonal antibodies and intravenous antivirals in the treatment of COVID-19 in hospitalised patients. 2021; Available from: www.england.nhs.uk/coronavirus/wp-content/uploads/sites/52/2021/09/C1529-interim-clinical-comm-policy-neutralising-monoclonal-antibodies-and-intravenous-antivirals.pdf.
30. Mulangu, S., L.E. Dodd, R.T. Davey, Jr., O. Tshiani Mbaya, M. Proschan, D. Mukadi, M. Lusakibanza Manzo, D. Nzolo, A. Tshomba Oloma, A. Ibanda, R. Ali, S. Coulibaly, A.C. Levine, R. Grais, J. Diaz, H.C. Lane, J.-J. Muyembe-Tamfum, B. Sivahera, M. Camara, R. Kojan, R. Walker, B. Dighero-Kemp, H. Cao, P. Mukumbayi, P. Mbala-Kingebeni, S. Ahuka, S. Albert, T. Bonnett, I. Crozier, M. Duvenhage, C. Proffitt, M. Teitelbaum, T. Moench, J. Aboulhab, K. Barrett, K. Cahill, K. Cone, R. Eckes, L. Hensley, B. Herpin, E. Higgs, J. Ledgerwood, J. Pierson, M. Smolskis, Y. Sow, J. Tierney, S. Sivapalasingam, W. Holman, N. Gettinger, D. Vallee, and J. Nordwall, A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics. The New England journal of medicine, 2019. 381(24): p. 2293-2303.
31. Anderson, J., J. Schauer, S. Bryant, and C.R. Graves, The use of convalescent plasma therapy and remdesivir in the successful management of a critically ill obstetric patient with novel coronavirus 2019 infection: A case report. Case Reports in Women’s Health, 2020. 27: p. e00221.
32. Maldarelli, G.A., M. Savage, S. Mazur, C. Oxford-Horrey, M. Salvatore, and K.M. Marks, Remdesivir Treatment for Severe COVID-19 in Third-Trimester Pregnancy: Case Report and Management Discussion. Open Forum Infectious Diseases, 2020. 7(9).
33. Naqvi, M., P. Zakowski, L. Glucksman, S. Smithson, and R.M. Burwick, Tocilizumab and Remdesivir in a Pregnant Patient With Coronavirus Disease 2019 (COVID-19). Obstetrics & Gynecology, 2020. 136(5): p. 1025-1029.
34. Burwick, R.M., S. Yawetz, K.E. Stephenson, A.-R.Y. Collier, P. Sen, B.G. Blackburn, E.M. Kojic, A. Hirshberg, J.F. Suarez, M.E. Sobieszczyk, K.M. Marks, S. Mazur, C. Big, O. Manuel, G. Morlin, S.J. Rose, M. Naqvi, I.T. Goldfarb, A. DeZure, L. Telep, S.K. Tan, Y. Zhao, T. Hahambis, J. Hindman, A.P. Chokkalingam, C. Carter, M. Das, A.O. Osinusi, D.M. Brainard, T.A. Varughese, O. Kovalenko, M.D. Sims, S. Desai, G. Swamy, J.S. Sheffield, R. Zash, and W.R. Short, Compassionate Use of Remdesivir in Pregnant Women With Severe Coronavirus Disease 2019. Clinical Infectious Diseases, 2020.
35. Swedish Orphan Biovitrum Ltd. SmPC: Kineret 100 mg solution for injection in a pre-filled syringe. 2020.
36. Berger, C.T., M. Recher, U. Steiner, and T.M. Hauser, A patient’s wish: anakinra in pregnancy. Annals of the Rheumatic Diseases, 2009. 68(11): p. 1794-1795.
37. Chang, Z., C.Y. Spong, A.A. Jesus, M.A. Davis, N. Plass, D.L. Stone, D. Chapelle, P. Hoffmann, D.L. Kastner, K. Barron, R.T. Goldbach-Mansky, and P. Stratton, Brief Report: Anakinra Use During Pregnancy in Patients With Cryopyrin-Associated Periodic Syndromes. Arthritis & Rheumatology, 2014. 66(11): p. 3227-3232.
38. Duman, N.Ç., M.Z. Gören, and A. Karaalp, #20 Anakinra use during pregnancy and lactation: A case report. Reproductive Toxicology, 2019. 88: p. 139-140.
39. Smith, C.J.F. and C. Chambers, FRI0107 Five successful pregnancies with antenatal anakinra exposure, in FRIDAY, 15 JUNE 2018. 2018, BMJ Publishing Group Ltd and European League Against Rheumatism.
40. Youngstein, T., P. Hoffmann, A. Gül, T. Lane, R. Williams, D.M. Rowczenio, H. Ozdogan, S. Ugurlu, J. Ryan, L. Harty, S. Riminton, A.P. Headley, J. Roesler, N. Blank, J.B. Kuemmerle-Deschner, A. Simon, A.S. Woolf, P.N. Hawkins, and H.J. Lachmann, International multi-centre study of pregnancy outcomes with interleukin-1 inhibitors. Rheumatology, 2017. 56(12): p. 2102-2108.
41. Bazzani, C., R. Scrivo, L. Andreoli, E. Baldissera, M. Biggioggero, V. Canti, M. Gerosa, I. Pontikaki, V. Ramoni, L. Trespidi, S. Zatti, R. Caporali, R. Gorla, F. Iannone, A. Lojacono, P. Meroni, C. Montecucco, M. Motta, M.G. Sabbadini, G. Valesini, and A. Tincani, Prospectively-followed pregnancies in patients with inflammatory arthritis taking biological drugs: an Italian multicentre study. Clin Exp Rheumatol, 2015. 33(5): p. 688-93. PMID: 26311348.
42. Fischer-Betz, R., C. Specker, and M. Schneider, Successful outcome of two pregnancies in patients with adult-onset Still’s disease treated with IL-1 receptor antagonist (anakinra). Clin Exp Rheumatol, 2011. 29(6): p. 1021-3. PMID: 22153586.
43. Mahase, E., Covid-19: FDA authorises neutralising antibody bamlanivimab for non-admitted patients. BMJ, 2020: p. m4362.
44. Chen, P., A. Nirula, B. Heller, R.L. Gottlieb, J. Boscia, J. Morris, G. Huhn, J. Cardona, B. Mocherla, V. Stosor, I. Shawa, A.C. Adams, J. Van Naarden, K.L. Custer, L. Shen, M. Durante, G. Oakley, A.E. Schade, J. Sabo, D.R. Patel, P. Klekotka, and D.M. Skovronsky, SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19. New England Journal of Medicine, 2021. 384(3): p. 229-237.
45. Pan, H., R. Peto, Q.A. Karim, M. Alejandria, A.M. Henao-Restrepo, C.H. García, M.-P. Kieny, R. Malekzadeh, S. Murthy, M.-P. Preziosi, S. Reddy, M.R. Periago, V. Sathiyamoorthy, J.-A. Røttingen, and S. Swaminathan, Repurposed antiviral drugs for COVID-19 –interim WHO SOLIDARITY trial results. 2020, Cold Spring Harbor Laboratory.
46. Furtado, R.H.M., O. Berwanger, H.A. Fonseca, T.D. Correa, L.R. Ferraz, M.G. Lapa, F.G. Zampieri, V.C. Veiga, L.C.P. Azevedo, R.G. Rosa, R.D. Lopes, A. Avezum, A.L.O. Manoel, F.M.T. Piza, P.A. Martins, T.C. Lisboa, A.J. Pereira, G.B. Olivato, V.C.S. Dantas, E.P. Milan, O.C.E. Gebara, R.B. Amazonas, M.B. Oliveira, R.V.P. Soares, D.D.F. Moia, L.P.A. Piano, K. Castilho, R. Momesso, G.P.P. Schettino, L.V. Rizzo, A.S. Neto, F.R. Machado, A.B. Cavalcanti, and C.C.-B.I. Investigators, Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial. Lancet, 2020. 396(10256): p. 959-967. PMID: 32896292.
47. Shephard’s, Lopinavir and ritonavir. 2020.
48. Biogen Idec Ltd. SmPC: AVONEX 30 micrograms/0.5 ml solution for injection. 2019.
49. Reprotox, Colchicine. 2020.
50. Ben-Chetrit, E., S. Bergmann, and R. Sood, Mechanism of the anti-inflammatory effect of colchicine in rheumatic diseases: a possible new outlook through microarray analysis. Rheumatology (Oxford, England), 2006. 45(3): p. 274-282.
51. Novartis Pharmaceuticals UK Ltd. SmPC: Glivec 100 mg film-coated tablets. 2019.
52. Aman, J. COUNTER-COVID Trial Protocol. 2020; Available from: www.clinicaltrialsregister.eu/ctr-search/trial/2020-001236-10/NL.
53. Reprotox, Imatinib. 2020.
54. Jain, N., D. Sharma, R. Agrawal, and A. Jain, A Newborn with Teratogenic Effect of Imatinib Mesylate: A Very Rare Case Report. Medical Principles and Practice, 2015. 24(3): p. 291-293.
55. Pye, S.M., J. Cortes, P. Ault, A. Hatfield, H. Kantarjian, R. Pilot, G. Rosti, and J.F. Apperley, The effects of imatinib on pregnancy outcome. Blood, 2008. 111(12): p. 5505-5508.
56. Costanzo, G., D. Firinu, F. Losa, M. Deidda, M.P. Barca, and S. Del Giacco, Baricitinib exposure during pregnancy in rheumatoid arthritis, in Therapeutic advances in musculoskeletal disease. 2020. p. 1759720X19899296-1759720X19899296.
57. Mahadevan, U., M.C. Dubinsky, C. Su, N. Lawendy, T.V. Jones, A. Marren, H. Zhang, D. Graham, M.E.B. Clowse, S.R. Feldman, and D.C. Baumgart, Outcomes of Pregnancies With Maternal/Paternal Exposure in the Tofacitinib Safety Databases for Ulcerative Colitis. Inflammatory Bowel Diseases, 2018. 24(12): p. 2494-2500.
58. Reprotox, Tofacitinib. 2020.
59. Fernández-Sánchez, M., Ribes-Artero, H., Romá-Sánchez, E., Gómez-Portero, M.R., Guerrero-Hurtado, E., García-Pellicer, J. and Poveda-Andrés, J.L. Fetal exposure to tofacitinib during the first trimester: A healthy newborn case report. Birth Defects Res. 2021 Oct 15;113(17):1275-1279 PMID: 34309233.