Letter: I

Ixekizumab (Taltz) is a recombinant human monoclonal antibody that selectively binds to the cytokine interleukin-17A (IL-17A) and is used in the treatment of several chronic autoimmune and inflammatory conditions, including plaque psoriasis, psoriatic arthritis, and axial spondyloarthropathies (including axial spondyloarthritis and ankylosing spondylitis).

Published data relating to ixekizumab use during pregnancy are limited and consist of a single case report, two analyses of adverse event reporting data, and pregnancy cases from clinical trials and post-marketing reports, describing a total of 295 exposed pregnancies. Overall, these data do not suggest an increased risk of adverse pregnancy outcome; however, the relatively small number of exposed pregnancies means that small increases in risk, or risk of rare outcomes, cannot be excluded.

Immunoglobulin G (IgG) monoclonal antibodies (mAbs) do not actively cross the placenta in the first trimester and use at this stage is not expected to result in direct fetal exposure; therefore, direct teratogenic or embryotoxic effects are not anticipated.

Although inflammatory autoimmune conditions may improve during pregnancy, active or poorly controlled disease is associated with an increased risk of adverse pregnancy outcomes. The risks and benefits of continuing treatment during pregnancy should therefore be considered on an individual basis and through a shared decision-making process.

Use of immunosuppressant antibodies that actively cross the placenta during pregnancy could result in immunosuppression in the newborn and increase the risk of infection. Data specifically evaluating the effects of in utero ixekizumab exposure on infant immune function are very limited.

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. Please contact UKTIS for an individualised risk assessment where BCG vaccination is indicated in an infant under 6 months of age with prenatal ixekizumab exposure.

Exposure to ixekizumab 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.

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

Intrahepatic cholestasis of pregnancy (ICP), also known as obstetric cholestasis, is a pregnancy-specific liver condition with onset most commonly in the third trimester.

Maternal signs and symptoms of ICP include pruritus and raised serum bile acids; abnormal liver function (ALT/AST) is also a common feature. The pruritus can cause sleep disturbance and can adversely affect quality of life, but ICP is otherwise not detrimental to maternal health. ICP is, however, associated with serious risks to the fetus, including stillbirth, rates of which are thought to be particularly elevated with maternal serum bile acid concentrations >100 micromol/L. Other adverse outcomes associated with ICP include neonatal respiratory distress secondary to meconium aspiration, and preterm delivery (spontaneous and iatrogenic). Fetal monitoring has not been shown to predict or to reduce the risk of adverse perinatal outcomes in pregnancies affected by ICP but may be offered to provide reassurance. Regular monitoring of maternal serum bile acid concentrations and liver function is routine; serum bile acid concentrations may predict the risk of stillbirth and the requirement for early delivery. All women with ICP should be offered consultant-led care and delivery at a hospital unit.

Symptomatic treatments to reduce the sensation of itch include topical emollients (with or without menthol) and sedating antihistamines. The most widely used pharmacological treatment to treat ICP is ursodeoxycholic acid (UDCA); however, the Royal College of Obstetricians and Gynaecologists (RCOG) guidelines (produced in 2022) do not recommend routine use of UDCA for the purpose of reducing adverse perinatal outcomes in women with ICP. Rifampicin is occasionally used on a case-by-case basis as an adjunct to UDCA in women with severe ICP who are not responding to UDCA alone.

ICP may be associated with an increased risk of vitamin K deficiency due to reduced enterohepatic recirculation of bile acids and resultant malabsorption of fats and fat-soluble vitamins. The RCOG guidelines recommend maternal vitamin K supplementation only if there appears to be reduced absorption of dietary fats and/or evidence of abnormal prothrombin time.
Exposure to the medications included in this monograph 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.

Interferon beta is an immunomodulatory therapy used in people with multiple sclerosis.

The available data, although highly limited and potentially confounded for some outcomes, do not suggest an increased risk of congenital malformation, miscarriage, low infant birth weight, stillbirth or impaired neurodevelopment following interferon beta use in pregnancy.

A preconceptual drug review is recommended for all women with multiple sclerosis who are planning a pregnancy. Following confirmation of pregnancy, further clinical review by a neurologist is recommended. In some cases, pregnancy is associated with spontaneous remission of multiple sclerosis. In cases where continued treatment with interferon beta is required, it should not be withheld on account of pregnancy.

Exposure to interferon beta at any stage of pregnancy would not usually be regarded as medical grounds for termination of pregnancy. However, other risk factors which independently increase the risk of adverse pregnancy outcome may be present in individual cases. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.

Iodine 131 (I-131) is a radioactive iodine nuclide that emits beta particles and a small amount of gamma particles. It is widely used in nuclear medicine imaging studies of the thyroid gland and in the management of hyperthyroidism and thyroid cancer.

I-131 therapy potentially exposes the fetus to ionising radiation and is therefore contraindicated in pregnancy. Given that the fetal thyroid begins functioning at approximately 8-10 weeks post-conception (gestational weeks 10 to 12), a delay between I-131 treatment and pregnancy is usually suggested to avoid radioactive iodine accumulation in the fetal thyroid. UK guidelines currently recommend that women avoid pregnancy for at least six months following treatment.

The available human pregnancy exposure data consist mainly of uncontrolled studies which describe pregnancy outcomes following pre-conception exposure, with only a small number of uncontrolled studies and case reports describing the outcomes of pregnancies where I-131 exposure occurred during pregnancy.

There is currently no conclusive evidence that exposure to I-131 either prior to conception or during pregnancy is associated with the occurrence of fetal congenital malformation, miscarriage, impaired fetal growth, preterm delivery, or stillbirth. However, the available data are limited and of relatively poor quality; as such, it is recommended that pregnancy is avoided after I-131 treatment in accordance with current guidelines.

There have been a number of case reports of congenital hypothyroidism following I-131 treatment of maternal thyrotoxicosis or thyroid cancer. The absolute risk of congenital hypothyroidism in the offspring following I-131 exposure during pregnancy remains unquantified. Neurodevelopmental impairment with congenital hypothyroidism has also been reported in a small number of infants exposed to I-131 in utero. However, this may have been influenced by delays in the diagnosis of congenital/neonatal hypothyroidism and/or in the administration of neonatal thyroxine supplementation. Monitoring of the neonatal thyroid function is advised for all cases of in utero I-131 exposure.

Rates of thyroid carcinoma were not significantly increased amongst the offspring of women exposed to I-131 during the Chernobyl disaster when compared to an unexposed cohort, and no dose-response relationship between in utero I-131 fallout exposure in pregnancy and thyroid carcinoma in the offspring has been identified. No cases of thyroid cancer have been reported in offspring of women treated with I-131 prior to conception or during pregnancy.

Monitoring of neonatal thyroid function is advisable where inadvertent exposure to I-131 therapy has occurred during pregnancy. Other risk factors may also be present in individual cases which 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.

Oral retinoids and their metabolites are associated with a significant teratogenic risk and should only be prescribed and dispensed to women under a Pregnancy Prevention Programme (PPP).

Isotretinoin is a retinoid (13-cis-retinoic acid) used orally or topically in the treatment of severe acne which has not responded to standard forms of therapy. Oral isotretinoin is a confirmed teratogen associated with major structural and neurodevelopmental anomalies (isotretinoin embryopathy). Use during pregnancy is contraindicated. A negative pregnancy test and confirmation that effective contraception (preferably two forms) is used prior to, during, and for at least one month after the last dose is required before isotretinoin can be prescribed to women of childbearing potential.

Malformations associated with isotretinoin embryopathy include central nervous system abnormalities (hydrocephalus, cerebellar abnormalities, microcephaly), facial dysmorphia, cleft palate, external ear abnormalities (absence of external ear, small or absent external auditory canals), eye abnormalities (microphthalmia), cardiovascular abnormalities (conotruncal malformations such as tetralogy of Fallot, transposition of great vessels, septal defects), renal, thymus gland abnormality and parathyroid gland abnormalities.

The absolute risk of congenital malformation following oral isotretinoin therapy is currently unclear. Overall malformation incidence in live-born infants from prospectively reported pregnancies ranges from 5% to 28%, but risk estimation is generally hampered by the small sample sizes, due to the rarity of the exposure, and the fact that frequency of elective pregnancy termination is high following gestational isotretinoin exposure, potentially leading to an underestimation of malformation risk. The only (small) study to have attempted to quantify structural malformation risk in different exposure periods found no statistically significant difference in likelihood of malformation between infants exposed before two weeks’ gestation and those exposed in the period from 2-9 weeks’ gestation, with data also suggesting that even brief exposure (less than one week’s duration) may carry a high risk. No minimum dose or duration of treatment has therefore been specified as without risk for congenital malformation. Because of the long half-life of the drug, women are advised to avoid conception for at least one month following discontinuation of therapy. The currently available data are too limited to facilitate assessment of the absolute risk of infant congenital malformation following conception within this period.

Neurodevelopmental delay of varying severity has been reported following in utero isotretinoin exposure, both in association with congenital anomalies and in exposed infants without structural malformation. The period of risk for impaired neurodevelopment is undetermined and may hypothetically extend throughout gestation, as central nervous system development continues to term. Miscarriage risk appears to be increased above those commonly reported in observational studies, with estimates from prospective datasets of up to 30%. An increased incidence of ectopic pregnancy has also been reported.

A detailed fetal anomaly scan is recommended following all first trimester exposures to isotretinoin. Women should be made aware of the limitations of this investigation and that impaired neurodevelopment may occur in the absence of structural anomalies. When counselling women regarding the teratogenic risk of isotretinoin, possible synergistic effects of other exposures and the effects of prolonged exposure, high dose regimes or inter-individual variation in isotretinoin metabolism should be considered. 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 are inadequate data to assess fetal risk following exposure during pregnancy to topical isotretinoin. Use during pregnancy can therefore not be recommended; however, women who are inadvertently exposed during or within the month prior to pregnancy should be reassured that systemic absorption of the drug is generally low and that existing studies show no evidence of a teratogenic risk for topical retinoids as a group. The risk of isotretinoin embryopathy remains unquantified where exposure to supratherapeutic doses of topical isotretinoin occurs, or risk factors which increase absorption of the drug are present.

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) used to treat acute and chronic pain, and in the management of arthritis.

The use of NSAIDs in pregnancy has been associated with increased risks of miscarriage, malformation (including specific defects, such as cardiovascular defects, septal cardiac defects, and orofacial clefts), preterm delivery and fetal growth impairment. However, the available evidence is often conflicting, is likely confounded, and findings may have also been influenced by methodological limitations. Causal relationships between NSAID use in pregnancy and these outcomes are therefore unproven.

Twenty-two studies collectively including more than 75,000 ibuprofen-exposed pregnancies have investigated the risk of adverse fetal effects following in utero exposure. There is no robust evidence of associations with intrauterine death/stillbirth, preterm delivery or neurodevelopmental impairment. The data relating to other pregnancy outcomes are conflicting, with a small number of individual studies describing increased risks of miscarriage, overall and specific malformations, and low infant birth weight. However, it is possible that confounding has affected these data. Further studies are required before robust conclusions can be drawn.

Exposure to NSAIDs after 20 weeks of gestation has been associated with an increased risk of premature closure of the ductus arteriosus (DA) and oligohydramnios. These effects are thought to be mediated by the inhibitory effect of NSAIDs on prostaglandin production. There are conflicting findings regarding the risks of persistent pulmonary hypertension of the newborn (PPHN) following antenatal use of NSAIDs. Further evidence is required before this possible association can be confirmed. A possible class effect for these associations should be considered for all NSAIDs.

All NSAIDs should, where possible, be avoided after 20 weeks of pregnancy. In circumstances where the maternal clinical condition requires short-term treatment with ibuprofen (such as acute short-lived pain), treatment should be limited to the shortest duration possible. There is currently no evidence-based guidance about how long use should be restricted for but pragmatic advice is to limit use to no longer than three days. Longer term use at any stage of pregnancy, for example for treatment of chronic arthritis, or any use in the third trimester (28 weeks of gestation or beyond), should be avoided. As fetal urine production begins at approximately 10 weeks’ gestational age, UKTIS recommends referral to a Fetal Medicine Unit for monitoring of DA patency and oligohydramnios following prolonged NSAID use after the first trimester.

Please refer to the NSAID overview monograph for more information. 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.

Imatinib mesylate is a tyrosine kinase inhibitor used in the treatment of haematological malignancies (specifically Philadelphia chromosome positive chronic myeloid leukaemia (CML) or acute lymphoblastic leukaemia (ALL)), Kit (CD117) positive gastrointestinal stromal tumours, and other malignancies. Imatinib inhibits signalling and proliferation of cells driven by dysregulated platelet-derived growth factor receptor (PDGFR) and ABL kinase activity.

Inadequately treated haematological malignancies in pregnancy may be associated with increased risks for miscarriage, thromboembolism, fetal growth restriction, preterm birth (and associated sequelae) and perinatal mortality, in addition to severe maternal illness and, potentially, death.

Data regarding imatinib use in human pregnancy are limited to retrospective case reports and case series describing approximately 368 pregnancies, 252 of which were exposed in the first trimester. No controlled epidemiological studies have assessed the risk of congenital malformation, miscarriage, intrauterine death (IUD), low birth weight (LBW), preterm delivery, neonatal complications or adverse neurodevelopmental outcomes following in utero imatinib exposure.

Both animal studies and human case reports have described malformations in fetuses exposed to imatinib during organogenesis. Certain specific anomalies (combinations of exomphalos, renal agenesis, scoliosis and hemivertebrae) have been reported in four infants in the published literature and in one infant reported retrospectively to UKTIS. Although duplicate reporting of the same malformed child is possible, and investigation for a genetic cause was not undertaken for any of these cases, further investigation is warranted to determine if these reports signal a pattern of malformation attributable to in utero imatinib exposure.

Cases of miscarriage, stillbirth, preterm delivery, intrauterine growth restriction (IUGR)/LBW and neonatal complications following in utero imatinib exposure have been described in the literature. Due to the lack of controlled studies and the potential for these outcomes to be influenced by the underlying conditions for which imatinib is used to treat, it is not currently possible to assess the direct impact imatinib use in pregnancy may have on these outcomes.

The potential teratogenicity of imatinib and other tyrosine kinase inhibitors requires that their use in pregnancy be carefully considered against the need to prevent deterioration of the maternal disease. Patients wishing to interrupt therapy to become pregnant should also be informed of the risk of relapse, even where complete molecular remission was achieved, and of the possibility of a suboptimal response on restarting therapy. Imatinib should only be used during the first trimester of pregnancy where benefits of treatment clearly outweigh the potential risk of congenital malformation, and where these risks and benefits have been fully discussed with the patient.

Due to the lack of data, additional fetal monitoring for structural malformation and growth may be warranted 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.

Infliximab is a chimeric human-murine IgG1 monoclonal antibody produced by recombinant DNA technology. It is administered in the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, psoriasis, Crohn’s disease and ulcerative colitis where other systemic therapies are ineffective or unsuitable.

The available human pregnancy exposure and outcome data are mainly provided by uncontrolled studies which together describe more than 2,400 infliximab-exposed pregnancies, with more than 1,200 exposed in at least the first trimester. Although the total number of exposed pregnancies is quite large, the available data for specific pregnancy outcomes can be limited and evidence from controlled studies is often lacking.

There is currently no convincing evidence of an association between infliximab and an overall increased risk of congenital malformation, or any specific malformation or pattern of malformations. The available evidence also does not suggest increased risks of miscarriage, intrauterine death, preterm delivery or neurodevelopmental impairment. Although some studies have suggested associations between infliximab exposure and impaired fetal growth, the available data are conflicting and likely confounded by the underlying maternal condition.

Use of immunosuppressant antibodies that actively cross the placenta during pregnancy could result in immunosuppression in the newborn and increase the risk of infection. Rare cases of fatal infection following BCG vaccination after in utero infliximab exposure have been described in the literature. General guidance has been provided from a number of authorities around avoiding/deferring live vaccine use in infants exposed to infliximab in utero. Although the manufacturer of infliximab recommends avoiding live vaccine use until the child is 12 months old, other recommendations vary depending on both the circumstances of infliximab exposure and infant infection risk. UKTIS recommend a case-specific risk assessment approach when considering the use of live vaccines following in utero infliximab exposure. Discussion with UKTIS is recommended in all cases where use of a live vaccine is being considered in an infant <12 months of age where there has been in utero exposure to infliximab.

Pregnant women treated with infliximab are likely to have additional fetal growth monitoring due to their underlying medical condition; no additional fetal monitoring is required as a result of infliximab exposure specifically. 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.

Insect repellents are applied to the skin and clothing to deter biting insects, such as mosquitos and ticks. They are important in the prevention of mosquito-borne infections, such as malaria, Zika virus, dengue fever and yellow fever, and tick-borne infections including Lyme disease and tick-borne encephalitis.

Pregnant women should be advised against travel to areas where there is a risk of mosquito-borne infection and should be aware that transmission of Lyme disease and other tick-borne illnesses vary locally and globally.

When exposure to environments where insect bites may lead to serious illness is unavoidable, non-pharmacological preventative measures are important. These include staying indoors at the times of day when mosquitos are most active, using bed nets impregnated with insecticide, and minimising skin exposure when outdoors by wearing long sleeves and trousers (including tucking trousers into socks where there is a risk of mosquito/tick exposure). Insect repellent should be applied to clothing and exposed skin according to the manufacturer’s instructions and washed off once returning indoors. Ticks should be removed from the skin intact as soon as possible to reduce the risk of transmission of tick-borne disease.

The use of diethyl-m-toluamide (DEET) 50% is recommended first-line for all pregnant women, at any stage of pregnancy, travelling to a malarial area. The available data on the use of DEET in human pregnancy do not raise concern of adverse effects but are too limited to formally rule these out. However, the benefits of using DEET to prevent malaria and other insect-borne disease are likely to outweigh any risk of harm.

If DEET is not tolerated, an icaridin (20%), or hydrated, cyclized eucalyptus citriodora oil, or 3-ethlyaminopropionate (also called IR3535)-containing repellent can be considered as possible alternatives. There are no data relating to exposure to these agents in human pregnancy; however, animal studies have not demonstrated any features of developmental toxicity.

Exposure to insect repellents, according to the manufacturer’s instructions, at any stage of 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.

Note: Where travel to a malarial area during pregnancy is unavoidable, additional prophylaxis will be necessary. Please consult the Malaria Prophylaxis monograph or contact UKTIS on 0344 892 0909 for more information.