USE OF TYPHOID VACCINE IN PREGNANCY

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.

USE OF TRIPTANS IN PREGNANCY

‘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.

USE OF TRIMETHOPRIM 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 and potentially confounded. A larger number of studies 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 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 regarding the safety of first trimester trimethoprim use are conflicting and, as such, increased risks of congenital malformation or other adverse pregnancy outcomes cannot be excluded. Where trimethoprim exposure has occurred during the first trimester, an earlier anomaly ultrasound (from 12-16 weeks onwards) may be considered 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.

USE OF TRICYCLIC ANTIDEPRESSANTS IN PREGNANCY

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 provide 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 (including cardiac defects). 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 malformation has been suggested but remains to be confirmed. Other findings are conflicting; however possible associations with miscarriage, preterm delivery, preeclampsia, and autism spectrum disorder have been identified, though data confounding is likely.

An increased risk 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.

A small number of studies have described associations between maternal TCA use and adverse maternal outcomes. Maternal TCA use in pregnancy may be a prognostic risk factor for gestational diabetes and pre-eclampsia.

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.

USE OF TRETINOIN IN PREGNANCY

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.

USE OF TRAZODONE IN PREGNANCY

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.

USE OF TRASTUZUMAB IN PREGNANCY

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.

USE OF TRANEXAMIC ACID IN PREGNANCY

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.

USE OF TOCILIZUMAB IN PREGNANCY

Tocilizumab is a recombinant humanized, anti-human monoclonal antibody of the IgG1 subclass directed against soluble and membrane-bound receptors of interleukin 6. It is licensed to treat giant cell arteritis and as second line therapy for rheumatoid arthritis in adults and juvenile idiopathic (poly)arthritis. It is also used off-license as an acutely administered treatment for severe COVID-19.

While preclinical animal studies have not demonstrated that tocilizumab exposure in pregnancy is associated with fetal structural anomalies, a possible increase in the crude rate of embryo/fetal deaths has been described. However, this increase in embryo/fetal demise was only observed following high-dose maternal exposure (>100 times the human therapeutic dose). Given the lack of dose equivalence, this finding is not considered relevant to human pregnancy exposure.

Human pregnancy safety data are provided by case reports/series which collectively describe 367 pregnancies among women with chronic conditions who were receiving regular treatment with tocilizumab, mainly from the time of conception. Where details were provided, most women discontinued tocilizumab use early in pregnancy; as such, evidence is generally lacking regarding the safety of longer-term use in pregnancy. An additional 51 cases of late gestational tocilizumab exposure have been reported in case reports/series which describe acute tocilizumab treatment of severe COVID-19. Few controlled studies exist and have only been conducted using non-denominator-based adverse drug event datasets. These studies include 357 adverse reaction reports where maternal tocilizumab use was used in pregnancy.

Due to minimal placental transfer of IgG antibodies prior to approximately 14 weeks’ gestation, direct fetal exposure following maternal use in early pregnancy is not anticipated. Studies using non-denominator-based adverse drug event datasets found no signal of adverse fetal or pregnancy outcomes. Although adverse pregnancy outcomes have been described following in utero exposure to tocilizumab, including cases of congenital anomaly, miscarriage, low birth weight and preterm delivery, the crude rates of these events do not appear notably increased above their expected background rates and no pattern of malformation has been observed. Furthermore, these observations are based on small numbers of exposed and affected pregnancies/infants which produced imprecise risk estimates. Of note, no adverse events considered attributable to tocilizumab exposure were described among the small number of women with acute treatment of severe COVID-19.

There is a theoretical concern that immunosuppressant antibodies which actively cross the placenta during pregnancy could result in neonatal/infant immunosuppression and an increased risk of infection. There are currently no data regarding the effect of in utero tocilizumab exposure on the neonatal/infant immune system. Guidance from Public Health England (PHE), issued 2017, specified that live vaccines should not be used until the infant is 6 months old following in utero biologic immunosuppressant exposure. It is unclear if an acute exposure to tocilizumab, such as in the treatment of severe COVID-19, could sufficiently impact neonatal immune function. In cases where there are clear risks with leaving a child unvaccinated, it may be important to consider the potential benefits of live vaccine exposure.

There is currently no compelling evidence that tocilizumab is teratogenic or fetotoxic. However, owing to the limited evidence currently available, all first trimester-exposed patients should have their 20-week ultrasound scan conducted by a clinician experienced in the prenatal detection of malformations. There is currently no evidence to indicate that any additional fetal monitoring is required. 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.

USE OF TRAMADOL IN PREGNANCY

SUMMARY: Tramadol is an opioid receptor agonist with serotonergic and noradrenergic activity used in the management of moderate-to-severe pain.

Published data concerning gestational tramadol exposure describe the outcomes of approximately 9,200 exposed infants, with the majority of the data considering the risk of congenital malformation and miscarriage. There are limited data regarding the risk of other adverse pregnancy outcomes.

The majority of data regarding risks of congenital malformation following first trimester tramadol exposure are reassuring. A single study has identified modest increased risks of specific malformations; however, this has not been supported by the largest study to date and confounding factors may have been contributory. The available data do not currently provide convincing evidence to suggest that first trimester tramadol use is associated with an increased risk of malformation overall, or of any specific malformation. While the majority of data regarding tramadol use in the first trimester are reassuring, tramadol use in pregnancy should be reserved for cases where adequate pain management has not been achieved using alternative analgesics.

The available data regarding risk of miscarriage following gestational tramadol exposure, although conflicting, are largely reassuring. The largest and most methodologically robust study available does not indicate an increased risk of miscarriage following gestational tramadol exposure. A single cohort study found no increased risk of preterm delivery within 146 pregnancies exposed to tramadol in at least the first trimester. There are no controlled data regarding the risk of intrauterine fetal death, low birth weight, infant neurodevelopmental impairment or cancer following intrauterine tramadol exposure.

Use of tramadol near term may cause neonatal respiratory depression and long-term use may be associated with neonatal abstinence syndrome. Where exposure has occurred in the weeks preceding delivery, monitoring of the neonate in a unit with neonatal facilities is advised.

Exposure to tramadol 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.

Related documents: Pain Management in Pregnancy