Letter: R

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 advice from the manufacturers is that conception should be delayed for four months following discontinuation of therapy. Its intentional use during pregnancy has also generally been restricted or reserved for cases of severe maternal illness. As a result the available data are both highly limited and heavily confounded.

The available data currently consist of uncontrolled case reports/series which document the outcomes of approximately 165 direct maternal exposures, only 18 of which occurred in the first trimester. In addition, there are data from approximately 146 cases of indirect maternal exposure.  Although cases of congenital malformation, miscarriage, stillbirth, preterm delivery and low birth weight have been reported following ribavirin exposure in pregnancy, the data are too limited and not in a format to permit an evidence-based assessment of any increased risk of adverse effects on 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. However, due to a lack of adequately controlled data, it is currently not possible to state conclusively 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. For cases of severe maternal illness, where ribavirin is considered to be the most effective treatment option, ribavirin should not be withheld on the account of pregnancy. 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.

Risperidone is an atypical antipsychotic (AAP) used in the treatment of schizophrenia, mania, and for the short term management of persistent aggression.

Congenital malformation rates specifically following risperidone exposure have been statistically assessed in a collective total of ~2,000 pregnancies. While a meta-analysis of data from 432 exposed pregnancies did not find an increased risk of major malformations, a large cohort study incorporating the remaining exposures identified a statistically significant 1.26-fold increased risk, but no increased rate of heart defects specifically. Rates of other specific malformation subtypes have not been assessed in adequately controlled studies. Data relating to other pregnancy outcomes following maternal risperidone exposure are either extremely limited or are absent, thus precluding evidence-based risk assessments. Potential users should be made aware of the paucity of data, and the decision to prescribe in pregnancy made on a case-by-case basis.

Studies of antipsychotics (APs)/AAPs as therapeutic classes that include a collective total of ~11,500 exposures do not raise concerns of adverse pregnancy outcomes directly related to use, although findings relating to stillbirth and preterm delivery rates are conflicting. Neurodevelopmental outcomes following in utero exposure to APs have not been sufficiently studied to permit any assessment of risk.

In the non-pregnant population, use of AAPs (particularly olanzapine and clozapine) is a risk factor for impaired glucose homeostasis and type 2 diabetes. There are therefore theoretical concerns of an increased risk of maternal gestational diabetes and its sequelae following gestational use of risperidone. A single small study found that women taking risperidone in pregnancy were at ~3-fold increased risk of gestational diabetes, although this finding requires further verification.

Use of risperidone and other APs throughout pregnancy or near delivery has been associated with withdrawal symptoms in the neonate and/or poor neonatal adaptation syndrome (PNAS). These symptoms are likely to be more severe in infants exposed in utero to more than one CNS acting drug. Delivery should therefore be planned in a unit with neonatal intensive care facilities.

It is important to ensure that maternal mental health conditions are treated appropriately. Where a woman’s illness is well-controlled on risperidone, either prior to conception or during pregnancy, the risk of discontinuing or changing medication, or reducing the dose, should be carefully weighed against the risk of relapse. Where clinically appropriate, clinicians are encouraged to discuss the advantages and disadvantages of continued risperidone use during pregnancy with the patient. Where the benefit of continued treatment is considered to outweigh any potential or known risks, risperidone may be prescribed for use in pregnancy.

Rituximab is a chimeric human-murine IgG1 monoclonal antibody produced by recombinant DNA technology administered in the treatment of non-Hodgkin’s lymphoma, chronic lymphocytic leukaemia, rheumatoid arthritis, and granulomatosis with polyangiitis and microscopic polyangiitis. Rituximab acts via CD20⁺ B-cell depletion.

Data specific to rituximab use during pregnancy are limited to case reports and uncontrolled case series. There are extremely limited data available for first trimester-exposed pregnancies (n=14), but data from these and a larger number of preconceptual exposures (<6 months prior to conception) mainly describe healthy outcomes. Although data from uncontrolled studies and case reports do not indicate that rituximab use during pregnancy is associated with adverse pregnancy outcomes, the data are too limited to rule out any risks. Rituximab is not expected to cross the placenta during the first trimester, therefore direct teratogenic effects are not anticipated.

Maternal autoimmune/inflammatory conditions are known to be associated with certain adverse pregnancy outcomes, such as miscarriage, preterm delivery and low birth weight. Ensuring adequate control of the maternal condition may therefore decrease the risk of certain adverse pregnancy outcomes.

Rituximab exposure in utero has been demonstrated to deplete neonatal B-cells. Guidance from Public Health England (PHE) [issued 2017] specifies that live vaccines should not be used until the infant is six months old following in utero biologic immunosuppressant exposure.

Due to the lack of data, additional fetal monitoring may be warranted on a case-by-case basis. 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.

Ricin is a highly toxic, bi-chain polypeptide which can be extracted from the castor bean, Ricinus communis.

Toxicity may arise from ingestion of either the seed itself or through ingestion, inhalation or injection of the extracted protein. Being non-volatile, an aerosolised preparation of the protein has high potential for use in chemical warfare.

There are few available case reports of ricin exposure in human pregnancy, therefore it is not currently possible to assess the risk exposure poses to a developing fetus. Following ricin exposure in a pregnant patient, maternal toxicity is likely to be a major determinant of risk to the fetus.

There are no guidelines regarding the treatment of ricin poisoning during pregnancy. Owing to the severity of complications associated with ricin exposure, treatment of the pregnant patient should be the same as for the non-pregnant patient.

Where exposure to ricin has occurred, even in cases which did not result in maternal toxicity, enhanced fetal monitoring may be warranted. Discussion with UKTIS is recommended.