Letter: R

Direct oral anticoagulants (DOACs) include Factor Xa inhibitors (apixaban, rivaroxaban, edoxaban) and the direct thrombin inhibitor (dabigatran). These drugs act on specific components of the coagulation cascade, resulting in reduced thrombin generation and inhibition of fibrin clot formation. They are widely used for stroke prevention in atrial fibrillation, and the treatment and prevention of venous thromboembolism.

Small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists, also known as gepants, are used in the prevention and acute treatment of migraine.

Six biologic monoclonal antibody (mAb) therapies are licensed for the management of severe asthma: mepolizumab, reslizumab, benralizumab, omalizumab, dupilumab, and tezepelumab. This monograph summarises the available data for mepolizumab, benralizumab, tezepelumab, and reslizumab. For further information on omalizumab and dupilumab, please see the separate UKTIS monographs.

There are limited published human pregnancy data relating to mepolizumab and benralizumab. Data regarding reslizumab are very limited. No published human pregnancy exposures to tezepelumab have been identified. Data are derived from case reports (mepolizumab-exposed n=3; benralizumab-exposed n=6) and a pharmacovigilance analysis including 154 mepolizumab exposed, 774 benralizumab exposed, and 25 reslizumab-exposed pregnancies. The nature and size of these datasets limit the assessment of the risk of adverse pregnancy outcomes. mAbs do not actively cross the placenta in the first trimester and are therefore not expected to result in direct fetal exposure; this may lead to a lower risk of teratogenic/embryotoxic effects.

It is critically important to ensure that maternal asthma is well-controlled in pregnancy. Where a woman’s asthma is well-controlled with a mAb, particularly when conventional treatments have been ineffective, the risks and benefits of continuing treatment during pregnancy should be assessed on a case-by-case basis and discussed with the patient as part of a shared decision-making process.

Guidance from the UK Health Security Agency (UKHSA) [issued 2017] advises that live vaccines should be avoided until the infant is at least 6 months of age following in utero exposure to biologic immunosuppressant therapies. While mAbs used to treat asthma are not broadly immunosuppressant, the effects of in utero exposure on the neonatal or infant immune system are largely unknown. Please contact UKTIS for an individualised risk assessment where BCG vaccination is indicated in an infant under 6 months of age with prenatal asthma mAb exposure.

Exposure to asthma mAbs at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy or any additional fetal monitoring. However, other risk factors which could independently increase the risk of adverse pregnancy outcome may be present in individual cases. Such factors are important to consider when performing case-specific risk assessments.

Recreational drugs derive from several classes and most commonly include cannabis, cocaine, opioids, amphetamines, MDMA, LSD, khat, synthetic cathinones, synthetic cannabinoids, kratom, ketamine, GHB, and nitrous oxide. Numerous prescription drugs are also used recreationally, such as benzodiazepines, some opioid painkillers, and gabapentinoids.

Recreational drug use should be avoided during pregnancy due to the largely unknown effects on fetal development and wellbeing, as well as childhood neurodevelopment.

It is not uncommon for women to report recreational drug use that occurred prior to recognition of pregnancy. Occasional recreational drug users are advised to avoid further exposure and to seek advice from a healthcare professional regarding the possible need for additional fetal monitoring. Pregnant women with chronic drug exposure or substance use disorder require careful specialist management which may include a supervised withdrawal programme.

Data on fetal and childhood outcomes following prenatal recreational drug exposure are confounded by numerous factors that are more prevalent among recreational drug users and that can independently increase the risk of adverse pregnancy outcome. These may include co-exposure to other substances (in particular, alcohol and tobacco), socioeconomic factors, and particularly with heavy drug use, health problems, including vitamin deficiencies, malnutrition, blood borne viruses and mental health conditions. Assessment of outcomes is also complicated by the fact that street drugs are commonly mixed with other substances and/or are not the substance that the user believes they are consuming.

Exposure to any centrally acting substance around the time of delivery can cause neonatal withdrawal symptoms and/or neonatal toxicity. Infants perinatally exposed to recreational drugs should be delivered in a hospital with facilities for neonatal monitoring and supportive treatment as required.

Exposure to recreational drugs may be an indication for additional fetal monitoring depending on the substance involved, the timing and duration of use, and the pregnant woman’s general health. Other risk factors which could independently increase the risk of adverse pregnancy outcome may also be present in individual cases and are important to consider when performing a risk assessment.

Ribavirin is a synthetic nucleoside antiviral agent available in oral and aerosolised formulations. It is currently licensed to treat chronic hepatitis C in combination with interferon alfa-2b or peginterferon alfa-2b (oral), and for the treatment of respiratory syncytial virus (RSV) bronchiolitis in infants and children (aerosol). Unlicensed indications for ribavirin include influenza, severe acute respiratory syndrome (SARS), and adenoviral pneumonia.

Ribavirin is known to accumulate within cells and is eliminated slowly from non-plasma compartments. As it has been shown to be teratogenic, embryotoxic, and mutagenic in various animal species at doses within the human therapeutic range, the manufacturer advises that conception should be delayed for nine months following discontinuation of therapy. Its intentional use during pregnancy has generally been restricted to cases of severe maternal illness. The available data are therefore highly limited and confounded.

The available data consist of uncontrolled case reports/series which document the outcomes of approximately 204 direct maternal exposures, only 25 of which occurred in the first trimester. In addition, there are data from approximately 150 cases of indirect maternal exposure. Although cases of congenital malformation, miscarriage, stillbirth, preterm delivery and low birth weight have been reported, causality cannot be assigned to ribavirin exposure. Additionally, the data are too limited and not in a format to permit an assessment of the magnitude of any possible risk to the developing fetus.

No published studies have investigated maternal or fetal outcomes of pregnant women occupationally exposed to ribavirin. Exposure estimation data suggest that only a small amount of ribavirin would ever reach the maternal systemic circulation, and therefore the fetus, following occupational exposure. While this is reassuring, the lack of adequately controlled data means it is not possible to confirm that there is no increased risk of adverse pregnancy outcomes. If occupational exposure is unavoidable, then adequate precautions should be taken to minimise exposure.

Ribavirin exposure at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy. However, other risk factors may be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments. Given the limited data, the possibility of an increased risk of adverse pregnancy outcomes following maternal ribavirin exposure cannot be excluded, and the need for additional fetal monitoring should be considered on a case-by-case basis.

Rifampicin is a semisynthetic antibacterial drug used in the treatment of tuberculosis, leprosy, brucellosis, Legionnaire’s disease, Haemophilus influenza, and serious staphylococcal infections. Rifampicin is also used as prophylaxis against meningococcal meningitis, and off-license for pruritis caused by intrahepatic cholestasis of pregnancy.

There are very limited data relating to fetal risks following exposure to rifampicin during pregnancy. No increased risks of miscarriage, congenital malformation, preterm delivery or low birth weight have been attributed to rifampicin exposure, although the underlying maternal infections requiring rifampicin treatment have known independent risks during pregnancy.

Neonatal haemorrhage has been reported following exposure to rifampicin in late pregnancy; therefore, both maternal supplementation with vitamin K and neonatal intramuscular vitamin K at birth is recommended when rifampicin is administered in the weeks preceding delivery.

Due to the increased risk to both mother and fetus of an untreated maternal illness, if clinically indicated, rifampicin should not be withheld in pregnancy. Exposure to rifampicin at any stage of pregnancy would not usually be regarded as medical grounds for termination of pregnancy. Other risk factors may be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.