Letter: T

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 its associated 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 typhoid vaccine. Very little information is available regarding pregnancy outcomes following typhoid vaccination in human pregnancy.

Pregnant women are advised to avoid travel to areas where typhoid fever is endemic wherever possible. When travel during pregnancy cannot be avoided, the United Kingdom Department of Health recommends that maternal typhoid vaccination should be considered if there is a high risk of infection. The inactivated Vi polysaccharide vaccine may be preferable in pregnancy due to the theoretical risk of fetal infection from live vaccines. Exposure to typhoid vaccine 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.

Tretinoin (all-trans retinoic acid, ATRA) is an endogenous metabolite of vitamin A which is normally present in plasma. Tretinoin is used topically in the treatment of acne, hyperpigmentation, and repair of dermal photodamage, and orally for the induction of remission in acute promyelocytic leukaemia.

Topical tretinoin
Although sporadic case reports have described malformations, including cardiovascular defects, limb defects, ear defects and CNS defects following maternal use of topical tretinoin during the first trimester of pregnancy, no increased risk of congenital malformation has been shown in subsequent larger cohort studies of topical first trimester tretinoin exposure. There is currently no good evidence that topical tretinoin exposure is associated with increased risks of miscarriage, low birth weight, preterm delivery or intrauterine death. These data are, however, too limited to definitively exclude a fetal risk and use during pregnancy is therefore not generally recommended. An individual risk assessment is advised where exposure to supratherapeutic doses of topical tretinoin has occurred, or risk factors which increase absorption of the drug are present in association with pregnancy. 

Systemic tretinoin
The manufacturer advises that there is a high risk of severe malformations and that effective contraception (progesterone-only pills are not considered to be an effective measure of contraception during treatment with tretinoin) must be used for the duration of oral treatment and for one month afterwards. There are insufficient data (particularly relating to first trimester exposure) to quantify the risks posed to a developing fetus following oral exposure to tretinoin. Case reports have described miscarriage, intrauterine fetal death, low birth weight, and preterm delivery following oral tretinoin exposure; however, an impact of the underlying condition cannot be excluded. The risk-benefit balance between maternal and fetal wellbeing must be addressed on an individual basis. Other retinoids are known to be teratogenic at therapeutic doses and the likelihood of an increased risk of structural malformation and neurodevelopmental impairment with tretinoin use in the first trimester should therefore be considered and discussed with the patient.

Data regarding the risk of adverse neurodevelopmental effects following in utero tretinoin exposure are limited, but adverse effects are well described for other retinoids. Clinicians and patients should, therefore, be aware of the potential risk of neurodevelopmental impairment following tretinoin exposure in utero at any stage of pregnancy, and that such effects cannot be screened for antenatally. 

Exposure to oral, or in some cases topical, tretinoin during pregnancy may warrant additional fetal ultrasound assessment. Other risk factors may also be present in individual cases which may independently increase the risk of adverse pregnancy outcomes. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments. Due to the known teratogenicity of retinoids, enhanced fetal ultrasound may be warranted following exposure to tretinoin in pregnancy by any route. Discussion with UKTIS is recommended.

Tricyclic antidepressants (TCAs) block the re-uptake of both serotonin and noradrenaline and are used in the management of depression, anxiety disorders and neuropathic pain. Currently available TCAs include amitriptyline, clomipramine, dosulepin, doxepin, imipramine, lofepramine, nortriptyline and trimipramine. 

The available data provides no strong evidence of an association between maternal use of TCAs as a class during pregnancy and an increased risk of congenital malformation overall, or of any specific malformations. There is limited or no information on use of specific TCAs, therefore an increased risk of malformations cannot be ruled out. A possible association between in utero clomipramine exposure and cardiac malformations has been suggested but remains to be confirmed. Other findings are conflicting; however possible associations with spontaneous abortion, preterm delivery, preeclampsia, and autism spectrum disorder have been identified.

An increased incidence of neonatal complications has been reported in the offspring of women with psychiatric illnesses; however the relative contributions of the underlying maternal condition and specific drug treatments have not been clearly defined. Use of TCAs throughout pregnancy or near delivery may be 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.

It is important to ensure that maternal mental health disorders are treated appropriately during pregnancy. Where a patient is stabilised on a TCA, 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 of the maternal condition.

The currently available data do not support the need for any additional fetal monitoring following in utero exposure to TCAs; however data on individual TCAs is limited and the need for additional monitoring should therefore be determined on a case-by-case basis. 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.

There is a separate UKTIS monograph on Use of amitriptyline in pregnancy.

Trimethoprim is an antibiotic used to treat a variety of bacterial infections, but most commonly in the treatment or prophylaxis of urinary tract infections. It acts as a selective inhibitor of dihydrofolate reductase to prevent folic acid synthesis, thereby inhibiting DNA replication. It is available for use as a single agent and in combination with sulfamethoxazole (co-trimoxazole), which also inhibits folate metabolism, producing a synergistic antimicrobial effect.

Much of the available pregnancy exposure safety data are provided from studies which have investigated gestational co-trimoxazole use and, as such, do not assess the risk of trimethoprim exposure alone. The available data are limited by small study sample sizes, the possibility of data confounding from the underlying maternal illness for which trimethoprim/co-trimoxazole was prescribed, and study design methodologies which may have increased the possibility of chance findings.

As trimethoprim is a folic acid antagonist, there are concerns that periconceptual/perinatal use may limit the availability of folic acid and impact the developing fetus. Several studies investigating overall malformation risks have demonstrated possible associations with both first trimester and pre-conception trimethoprim exposure, however data are conflicting. A larger number of studies are available which have investigated specific anomalies following periconceptual/perinatal trimethoprim use, with several providing evidence of associations with neural tube defects, cardiac defects and facial clefts. Studies have also described increased risks of spontaneous miscarriage, low birth weight and preterm delivery. However, there are conflicting results for all of these findings, and given the limitations described above, any causal association with trimethoprim use remains unconfirmed.

Where trimethoprim use during the first trimester is considered necessary, there may be an advantage to taking high dose (5mg) folic acid, although no UK guideline currently recommends this and any benefit over standard dose supplementation is theoretical and scientifically unproven. Women prescribed trimethoprim who are trying to conceive or who are not using a reliable form of contraception should be made aware of the available data regarding possible fetal risk and advised to delay conception until treatment is completed. Pre-conceptual folic acid supplementation should also be discussed. 

Trimethoprim is frequently used in combination with the sulphonamide, sulfamethoxazole. There have been concerns that use of sulphonamide-containing medicines near delivery may increase the risk of hyperbilirubinemia and neonatal haemolysis in the neonate, particularly in premature infants or infants with glucose-6-phosphate dehydrogenase (G6PD) deficiency. However, the majority of population studies do not show an increased risk of neonatal hyperbilirubinemia following in utero sulphonamide exposure and this may therefore only be a concern in neonates with other risk factors (preterm/G6PD deficiency).

The treatment of infection in pregnancy should be guided by the results of culture and sensitivity tests, in accordance with local prescribing guidelines. Data concerning the safety of first trimester use of trimethoprim are conflicting and, as such, increased risks of congenital malformation or other adverse pregnancy outcomes cannot be excluded. An earlier detailed anomaly ultrasound (from 12-16 weeks onwards) may be considered following inadvertent use in the first trimester to exclude major structural problems. 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.

‘Triptans’ (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan) are 5HT1-receptor agonists used in the treatment of acute migraine and cluster headache. They are not used for migraine prophylaxis. 

The available data (including a collective total of ~11,000 pregnancies with exposure to any triptan and >9,000 sumatriptan-exposed pregnancies) do not raise concern of an increased risk of congenital malformation following in utero exposure. However, evidence for other triptans is extremely limited or lacking and 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. 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 an evidence-based assessment of the risk of stillbirth following triptan exposure. No studies have assessed rates of neurodevelopmental outcomes following in utero triptan exposure.

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 another triptan has been established preconceptually, an individual risk benefit analysis of continuing therapy for that patient 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. 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.

Tranexamic acid is an antihaemorrhagic agent which inhibits the breakdown of fibrin clots. It is licensed for the prevention and treatment of haemorrhages 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 concerning the fetal effects of gestational tranexamic acid exposure are highly limited. These data currently consist of 12 case reports/series and two small randomised controlled trials which describe the outcomes of 230 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.

Theoretical concerns exist regarding an increased risk of venous thrombosis following tranexamic acid use in pregnancy, and maternal thrombosis and/or pulmonary embolism have been reported in a small number of exposed pregnancies. However, controlled epidemiological studies do not currently provide supportive evidence of an increased risk of maternal thrombosis following tranexamic acid exposure in pregnancy.

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.

Trastuzumab is a recombinant humanised IgG1 monoclonal antibody against the human epidermal growth factor receptor 2 (HER2). Trastuzumab is indicated in the treatment of HER2 positive early breast cancer, metastatic breast cancer, and metastatic gastric cancer, where tumours have either HER2 overexpression or HER2 gene amplification.

There are very limited data on use of trastuzumab in pregnancy, therefore an evidence-based assessment of risk to the fetus is not currently possible. Only one case of congenital malformation (renal agenesis) has been observed following first trimester exposure to trastuzumab; however, data are limited to 25 exposed pregnancies. Oligohydramnios/anhydramnios has been observed in >60% of case reports documenting exposure during pregnancy, and 100% of pregnancies where trastuzumab exposure continued in the second or third trimester. Effects on miscarriage, fetal growth, preterm delivery, stillbirth, neonatal complications, neurodevelopment and carcinogenicity risk in offspring have not been adequately studied. The manufacturer advises that effective contraception should be used during treatment with trastuzumab and for seven months after treatment has concluded.

Trastuzumab has been associated with an increased risk of reversible cardiac dysfunction in the non-pregnant patient, which may be exacerbated during pregnancy by the additional strain placed on maternal cardiac function.

Enhanced monitoring of maternal cardiac function and amniotic fluid volume is recommended if trastuzumab treatment is ongoing during pregnancy. 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.

Trazodone is a triazolopyridine antidepressant drug used in the treatment of anxiety and depressive disorders, particularly where sedation is required.

Data are limited to a small number of trazodone-exposed pregnant women and providing an estimate on the likelihood of adverse outcomes following exposure during pregnancy is not currently possible. However, there is currently no evidence to suggest that exposure to trazodone is associated with an increased risk of congenital malformation, miscarriage or stillbirth/intrauterine death, preterm delivery or low infant birth weight.

It is important to ensure that maternal mental health disorders are treated appropriately during pregnancy. Where a patient is stabilised on trazodone, 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 of the maternal condition. Where use of trazodone in pregnancy is considered clinically necessary, patients should be made aware of the limitations of the existing pregnancy safety data and the lowest effective dose used.

Studies have suggested that use of antidepressants for the treatment of depression during pregnancy may be associated with an increased risk of miscarriage, low birth weight and intrauterine growth restriction. However, there is also evidence to suggest that maternal depression may independently contribute to these findings and a causal link to antidepressant medications is thus unconfirmed.

An increased risk of poor neonatal adaptation syndrome (PNAS) has been reported following chronic use or use near the time of delivery of other antidepressants; monitoring of the neonate for symptoms suggestive of withdrawal is therefore advised. These symptoms are likely to be more severe in infants exposed in utero to more than one CNS acting drug.

Exposure to trazodone at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy or an indication for 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.

Tamsulosin is an alpha 1A selective adrenoceptor-blocking drug used in the treatment of benign prostatic hypertrophy. While the drug is not licensed for use in women, it is used off-license in the treatment of renal calculi, renal colic, glomerulonephritis, and other disorders of the urinary tract.

The published data relating to gestational exposure to tamsulosin are limited to two small studies which collectively describe 94 exposed pregnancies, the majority of which were exposed in the second or third trimester. Due to the lack of safety data, it is not currently possible to provide an evidence-based risk assessment for exposure during the first trimester of pregnancy. Where such exposure has occurred, women should be strongly encouraged to attend their routine detailed fetal anomaly scan.

Exposure to tamsulosin in the second or third trimester of pregnancy has not been associated with miscarriage, stillbirth, preterm delivery, impaired fetal growth or neonatal complications. However, the data are absent or too limited to exclude such associations.

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.

UKTIS are currently collecting pregnancy outcome data for tamsulosin. If you have a pregnant patient who has been exposed to tamsulosin please telephone UKTIS on 0344 892 0909 or download a reporting form to inform us of this exposure.

In the UK the Td-IPV vaccine Revaxis® is indicated for use in individuals over 10 years of age who require vaccination against tetanus, diphtheria and/or polio. Monovalent vaccines for these conditions are not available in the UK.

There are currently no published studies specifically regarding use of Td-IPV vaccines, such as Revaxis® in pregnancy. Tetanus/diphtheria/pertussis/polio (Tdap-IPV) vaccines have however been widely used in the UK maternal pertussis vaccination programme. Data from over 6,600 Tdap-IPV-exposed pregnancies do not suggest increased risk to the fetus of stillbirth, low birth weight/intrauterine growth restriction, or reduced gestational length. There are insufficient first trimester exposure data to permit an evidence-based assessment of the risk of congenital malformations.

UK guidelines state that tetanus-containing vaccines can be given to pregnant women when protection is required without delay. If a woman with unknown or incomplete vaccination status requires immunisation against tetanus after week 16 of pregnancy, the Department of Health suggests that an initial dose of tetanus/diphtheria/pertussis/polio (Tdap-IPV) vaccine be given in place of Td-IPV vaccine, and that Td/IPV vaccine is then given at appropriate intervals to complete the course of immunisation against tetanus.

Exposure to tetanus/diphtheria/polio vaccine at any stage in pregnancy would not 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.