Letter: T

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.

Urinary incontinence, defined as the involuntary leakage of urine, has multiple causes which may require different management strategies. Stress incontinence is common during pregnancy, caused by the hormonal changes of pregnancy and pressure on the bladder from the expanding uterus. Pharmacological treatment is not routinely indicated for urinary stress incontinence that has occurred due to pregnancy.

Women with pre-existing conditions that cause urinary frequency, enuresis and incontinence may require ongoing treatment during pregnancy under specialist supervision. Human pregnancy safety data is limited or lacking for most of the drug options, and the risks and benefits should therefore be considered on a case-by-case basis, taking into account the severity of the woman’s condition and likely effects on her health and quality of life if an established medication regimen is altered.

Oxybutynin is the best studied treatment for urinary frequency during pregnancy, although data are still very limited. Neither of two studies nor a handful of case reports raise concern that oxybutynin exposure is associated with infant congenital malformation. Increased risks of preterm delivery and low infant birth weight were noted in one of the studies but may be related to the underlying maternal condition. These findings require confirmation.

There are no further published human pregnancy exposure data for drugs to treat urinary frequency, enuresis and/or incontinence. A small number of pregnancy outcomes have been reported to UKTIS following prenatal exposure to oxybutynin, solifenacin, tolterodine, fesoterodine, mirabegron, propantheline, and trospium, with no major congenital malformations described. Data are absent for darifenacin, flavoxate, and propiverine.

Adverse fetal effects have been observed in preclinical (animal) studies of darifenacin, propiverine, fesoterodine, mirabegron, oxybutynin, and tolterodine; however, some exposures were at maternally toxic doses.

Exposure to drugs used to reduce symptoms of urinary frequency, enuresis and incontinence at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy; however, due to the lack of data, additional fetal monitoring may be warranted. Other risk factors may also 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.

Urinary incontinence, defined as the involuntary leakage of urine, has multiple causes which may require different management strategies. Stress incontinence is common during pregnancy, caused by the hormonal changes of pregnancy and pressure on the bladder from the expanding uterus. Pharmacological treatment is not routinely indicated for urinary stress incontinence that has occurred due to pregnancy.

Women with pre-existing conditions that cause urinary frequency, enuresis and incontinence may require ongoing treatment during pregnancy under specialist supervision. Human pregnancy safety data is limited or lacking for most of the drug options, and the risks and benefits should therefore be considered on a case-by-case basis, taking into account the severity of the woman’s condition and likely effects on her health and quality of life if an established medication regimen is altered.

Oxybutynin is the best studied treatment for urinary frequency during pregnancy, although data are still very limited. Neither of two studies nor a handful of case reports raise concern that oxybutynin exposure is associated with infant congenital malformation. Increased risks of preterm delivery and low infant birth weight were noted in one of the studies but may be related to the underlying maternal condition. These findings require confirmation.

There are no further published human pregnancy exposure data for drugs to treat urinary frequency, enuresis and/or incontinence. A small number of pregnancy outcomes have been reported to UKTIS following prenatal exposure to oxybutynin, solifenacin, tolterodine, fesoterodine, mirabegron, propantheline, and trospium, with no major congenital malformations described. Data are absent for darifenacin, flavoxate, and propiverine.

Adverse fetal effects have been observed in preclinical (animal) studies of darifenacin, propiverine, fesoterodine, mirabegron, oxybutynin, and tolterodine; however, some exposures were at maternally toxic doses.

Exposure to drugs used to reduce symptoms of urinary frequency, enuresis and incontinence at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy; however, due to the lack of data, additional fetal monitoring may be warranted. Other risk factors may also 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.

Tezacaftor is a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator licensed for the treatment of cystic fibrosis.

Typhoid fever is a potentially severe systemic febrile illness endemic in developing countries. The disease is linked to poor sanitation, and faecal contamination of food and water are the main sources of infection. Travel to endemic regions constitutes a major risk for contracting the disease.

Pregnant women may be at increased risk of contracting typhoid fever and of experiencing complications such as gastrointestinal bleeding, hepatic dysfunction and intestinal perforation, compared to non-pregnant patients. Typhoid fever may also increase the risk of miscarriage.

Two types of typhoid vaccine are available in the United Kingdom: an inactivated Vi polysaccharide vaccine and a live attenuated oral vaccine. Data regarding pregnancy outcomes following maternal typhoid vaccination are extremely limited.

Pregnant women are advised to avoid travel to areas where typhoid fever is endemic wherever possible. When travel cannot be avoided, UK guidance recommends that typhoid vaccination should be considered following an individualised risk assessment if the risk of exposure is high. The inactivated Vi polysaccharide vaccine is preferred in pregnancy, as the live oral Ty21a vaccine is contraindicated due to a theoretical risk of fetal infection.

Exposure to typhoid vaccine at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy or for additional fetal monitoring. However, other maternal or fetal risk factors may be present in individual cases which independently increase the risk of adverse pregnancy outcome, and these should be considered when undertaking case-specific risk assessment.

Tranexamic acid is an antihaemorrhagic agent which inhibits the breakdown of fibrin clots. It is licensed for the prevention and treatment of haemorrhage due to general or local fibrinolysis, with specific indications including menorrhagia, epistaxis, conisation of the cervix, traumatic hyphaema, hereditary angioneurotic oedema, and to minimise blood loss following bladder surgery and dental extraction in patients with haemophilia.

The available data regarding the fetal effects of prenatal tranexamic acid exposure are highly limited. These data consist of 22 case reports/series and three small clinical trials which describe the outcomes of 363 exposed pregnancies, the majority of which are thought to have been exposed acutely in late pregnancy.

No cases of congenital malformation have been reported among the small number of pregnancies exposed in early pregnancy, and no cases of intrauterine death have been reported among those exposed in later pregnancy. Miscarriage, preterm delivery, low infant birth weight, and neonatal complications have been sporadically described following tranexamic acid exposure. However, the underlying maternal illness which necessitated tranexamic acid use may have contributed to these outcomes.

There are theoretical concerns regarding an increased risk of venous thrombosis following tranexamic acid use in pregnancy, and maternal thrombosis and/or pulmonary embolism have been reported occasionally. However, controlled epidemiological studies do not suggest an increased risk of maternal thrombosis.

Exposure to tranexamic acid 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 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.

Triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan) are 5HT1-receptor agonists used in the treatment of acute migraine and cluster headache and the prophylaxis of premenstrual migraine.

The available data do not raise concern of an increased risk of congenital malformation following in utero exposure to triptans. However, evidence for individual triptans apart from sumatriptan is extremely limited or lacking, and specific assessment of malformation risk for these drugs is therefore not currently possible.

There is no robust evidence of increased risk of miscarriage following use of triptans as a group or of sumatriptan specifically. Data also do not raise concerns of low infant birth weight or preterm delivery with gestational use of triptans as a group, although data for these outcomes are more limited and no conclusions can be drawn about specific triptans. Because triptans cause vasoconstriction, there are theoretical concerns about effects on placental perfusion and fetal growth. Isolated case reports have noted IUGR following triptan overuse in pregnancy. A single study has assessed the rate of stillbirth after exposure to sumatriptan or naratriptan and, although these data do not raise concern, they are not sufficient to make a robust evidence-based assessment of the risk of stillbirth following triptan exposure. Studies have not provided robust evidence of altered neurodevelopment in children exposed in utero to triptans.

Where triptan use in pregnancy is clinically indicated, use of sumatriptan in preference to the other triptans, for which there are a lack of data, is advised. Where treatment with a different triptan has been established preconceptually, an individual risk-benefit analysis of continuing therapy needs to be undertaken, and the available data considered and discussed with the patient.

Exposure to triptans at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy or additional fetal monitoring. Use of large quantities of a triptan (such as very frequent or extended use) may be an indication for additional fetal growth monitoring. Other risk factors may also 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.