Letter: C

Small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists, also known as gepants, are used in the prevention and acute treatment of migraine. This class includes atogepant, rimegepant, ubrogepant and zavegepant; however, only atogepant and rimegepant are currently licensed for use in the UK.

Human pregnancy exposure data for gepants are extremely limited. Available evidence consists of a small case series, two disproportionality analyses of spontaneous pharmacovigilance reports, and interim results from a cohort study that included 119 rimegepant-exposed pregnancies, of which 47 were exposed during the first trimester. These data are insufficient in both quantity and quality to permit an evidence-based assessment of fetal risk. Although no signal has emerged to suggest that gepants are major human teratogens, evidence with substantial methodological limitations has raised a potential signal for an association with miscarriage. However, the available evidence is insufficient to determine whether this represents a causal association, and further investigation is required.

Migraine is common in women of reproductive age and may occur in pregnancy. It has been estimated that in up to 80% of women who experience migraine, both the frequency and severity of attacks improve during the second and third trimesters of pregnancy; thus, routine prophylaxis is not recommended during pregnancy.  However, in some cases, migraine may fail to improve or may even worsen. In some women, migraine presents for the first time during pregnancy.

Migraine itself does not appear to increase the risk of miscarriage, congenital malformations, or other pregnancy complications. However, if migraine attacks are frequent or severe and left untreated, subsequent maternal effects such as dehydration, inadequate nutrition, and stress may have an adverse effect on the fetus.

If appropriate, non-pharmacological measures, including identification and avoidance of trigger factors, should be tried before drug therapy is considered. Medication may be required for headaches that are severe or associated with nausea and vomiting, and adequate fluid replacement should be provided where dehydration is present. Established treatments such as paracetamol and, where clinically indicated, sumatriptan are generally preferred during pregnancy (see Treatment of Migraine in Pregnancy monograph for more details). Given the paucity of pregnancy safety data, gepants should generally be reserved for situations in which the potential benefit is considered to outweigh the uncertainties regarding fetal risk.

Exposure to gepants at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy. 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. Given the limited pregnancy data available for this class of drug, an additional early anomaly scan around 16 weeks of pregnancy could be considered following first-trimester exposure. UKTIS welcomes reports of gepant exposure during pregnancy.

Clopidogrel is an antiplatelet prodrug, the active metabolite of which inhibits ADP-mediated platelet aggregation through irreversible binding to the platelet P2Y12 receptor. It is indicated for the treatment of transient ischaemic attack, minor ischaemic stroke, and the prevention of atherothrombotic events (including myocardial infarction and stroke) in patients with predisposing factors or after percutaneous coronary intervention.

Maternal cardiovascular conditions (e.g., coronary artery disease, prior stroke, antiphospholipid syndrome) may independently increase the risk of miscarriage, preterm delivery, and impaired fetal growth, particularly when disease control is suboptimal. Low molecular weight heparin (LMWH) is usually the first-line anticoagulation in pregnancy due to limited placental transfer; however, in some circumstances, use of other antithrombotic agents may be necessary. The European Society of Cardiology (ESC) guidelines state that when dual antiplatelet therapy (DAPT) is indicated, clopidogrel is recommended as the P2Y12 inhibitor of choice in combination with low-dose aspirin.

Published data on clopidogrel exposure in pregnancy is limited and consist primarily of case reports and a small cohort study collectively describing fewer than 100 pregnancies (including 74 with confirmed first trimester exposure). UKTIS has prospectively collected outcome data for 15 exposed pregnancies, including 11 exposed in at least the first trimester. The cohort study signalled a possible 4-fold increased risk of overall major congenital malformation; however, this signal arose from a hypothesis-generating analysis without correction for multiple testing and was not specific to any malformation pattern. The findings are therefore inconclusive and require confirmation in higher-quality studies. There were no congenital malformations among the 11 first trimester-exposed pregnancies reported to UKTIS. Data are too limited to assess the risks of other adverse pregnancy outcomes; however, case reports of continued therapy throughout pregnancy mainly describe uneventful outcomes.

Use of clopidogrel in the peripartum period may increase the risk of maternal bleeding complications. Antiplatelet therapy is associated with an increased risk of neuraxial (spinal/epidural) haematoma, and guidelines for neuraxial anaesthesia recommend discontinuation of clopidogrel for approximately 5–7 days prior to procedures such as epidural placement to reduce bleeding risk. Continuation of therapy near delivery may therefore increase the risk of obstetric haemorrhage, including postpartum haemorrhage. Discontinuation of clopidogrel one week before delivery to minimise the risk of bleeding complications has been described in a case report.

No additional fetal monitoring is required solely due to clopidogrel exposure. However, given the paucity of pregnancy safety data, women should be encouraged to attend their routine anomaly scan (at 18-22 weeks of pregnancy). As maternal cardiovascular pathology independently increases adverse pregnancy outcome risks, individualised risk assessment is essential when counselling and managing pregnant women requiring antiplatelet therapy. Discussion of individual cases with UKTIS is recommended.

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators (CFTRm), including deutivacaftor, elexacaftor, ivacaftor, lumacaftor, tezacaftor and vanzacaftor, are licensed as various single and combination products for the treatment of cystic fibrosis (CF). A combination product containing elexacaftor-tezacaftor-ivacaftor (ETI) is available as Kaftrio^®.

Poorly controlled CF in pregnancy can result in exacerbation of maternal pulmonary disease and poor nutritional status, increasing the risk of adverse pregnancy outcomes, including premature delivery and impaired fetal growth. Maternal clinical decline has been described following modulator therapy cessation during pregnancy. CF must be well-controlled during pregnancy to prevent complications.

Treatment with elexacaftor-tezacaftor-ivacaftor (ETI) combination therapy forms most of the available safety data on CFTRm use in pregnancy.

CFTRm use in pregnancy does not appear to be associated with increased risks of malformation, miscarriage, intrauterine fetal death or stillbirth, altered fetal growth, or preterm delivery. However, studies with larger sample size and higher quality methodology are required to confirm these findings. Uncontrolled case reports have documented cases of neonatal complications and neurodevelopmental impairments. Again, higher quality studies are required to determine whether these events occur with greater incidence following in utero CFTRm exposure.

Non-congenital lens opacities have been observed in children treated with ivacaftor-containing regimens, and consequently, several uncontrolled studies have reported formal cataract assessments in children exposed to CFTRm in utero. Three cases of small bilateral cataracts have been reported in the literature, all following in utero exposure to ETI combination treatment. Although these data are too limited to establish a causal relationship between CFTRm use in pregnancy and congenital cataract development, formal eye assessment is recommended following in utero CFTRm exposure. Elevated transaminases have been observed among patients treated with CFTRm. Liver function tests (LFTs) are recommended for children born following in utero CFTRm exposure.

There are a small number of cases of CFTRm exposure in the second and third trimester, where treatment was initiated following fetal CF diagnosis. These data provide some preliminary evidence of the possible benefits of CFTRm use in women who are CFTR carriers and pregnant with a fetus with CF. Treatment of the fetus with CFTRm requires multidisciplinary specialist care from a Fetal Medicine Unit and neonatal services.

CFTRm use in pregnancy can lower the immunoreactive trypsinogen concentration in the offspring, resulting in false-negative newborn blood spot CF screening results. CFTR genetic testing should be considered for all infants born to mothers on CFTR modulators to avoid delayed diagnosis.

Exposure to CFTRm 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.

Synthetic cannabinoid receptor agonists (SCRA) are full CB1 and CB2 receptor agonists with a higher potency than delta-9-trans-tetrahydrocannabinol found in cannabis. Street names include Annihilation, Bonzai, King B, K2, Magic Gold, Spice, Spice Arctic, Spice Diamond, Spice Gold, Spice Tropical Synergy, Spicey Ultra Strong XXX, and Spicey XXX Regular Smoke.

Synthetic cathinones are a derivative of cathinone, an active ingredient in Khat (Cathula edulis Forsk). Common names include methcathinone, ephedrone, ethylcathinone, M-CAT, white magic, meow meow, and cat.

Clarithromycin is a macrolide antibiotic, indications include sinusitis, otitis media, pharyngitis, tonsillitis, bronchitis, pneumonia, skin and soft tissue infections, and Helicobacter pylori eradication.

The majority of studies investigating malformation risk following clarithromycin use in pregnancy do not provide evidence of an association. A single study has described increased risks of specific malformations, including atrioventricular septal defects, gastroschisis, and orofacial clefts; however, these findings may have been impacted by methodological biases and/or confounding by indication, and therefore do not provide compelling evidence of a causal association and require further investigation

The available data relating to risk of miscarriage are conflicting. Three studies included in meta-analyses have described increased risks; however, these data may have been impacted by methodological biases and/or confounding by indication. Further research is therefore required.

The limited data available do not suggest an increased risk of intrauterine death following gestational exposure to clarithromycin. There are no studies investigating the risk of low birth weight, preterm delivery, neonatal complications, or neurodevelopmental impairment following the use of clarithromycin during pregnancy; however, data do not suggest increased risks of these outcomes following gestational exposure to macrolide antibiotics as a class.

At the time of writing, the Royal College of Obstetricians and Gynaecologists (RCOG) advise routine intrapartum antibiotic prophylaxis for all women in preterm labour, with or without premature rupture of membranes (PROM). Benzylpenicillin should be used preferentially but substituted for a cephalosporin in patients with a non-severe penicillin allergy, or vancomycin where the allergy is severe. The National Institute for Health and Care Excellence (NICE) guidelines also state that women with pre-labour PROM should be offered oral erythromycin (250mg, 4 times a day) for a maximum of 10 days or until the woman is in established labour (whichever is sooner), with oral penicillin offered to patients who cannot tolerate erythromycin.

It is important to effectively treat infections in pregnancy as adverse maternal and fetal effects may result from uncontrolled infection or pyrexia.

Where possible, the results of culture and sensitivity tests should guide treatment choice in accordance with local prescribing guidelines. If a macrolide is indicated, erythromycin has historically been preferred during pregnancy because there is more documented experience of its use than for other macrolides. However, treatment choices should be made on a case-by-case basis accounting for likely efficacy and tolerability, as well as possible fetal effects.

Exposure to clarithromycin 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.

Topical corticosteroids reduce inflammation and suppress the immune system in the treatment of atopic and auto-immune conditions affecting the skin, eyes and nasal mucosa. Topical corticosteroids available in the UK include hydrocortisone, alclometasone, beclometasone, clobetasone, diflucortolone, fludroxycortide, fluocinolone, fluocinonide, fluocortolone, fluticasone, mometasone and triamcinolone.

Appropriate use of topical corticosteroids should, in general, not lead to high systemic levels and is therefore unlikely to pose significant risks during pregnancy. However, a number of factors can lead to increased exposure levels, such as use of higher potency preparations, use on broken skin or large areas of skin, use for prolonged periods, and use outside of the manufacturer’s instructions (particularly regarding frequency and quantity of application). This should be borne in mind when carrying out risk assessments.

Systemic exposure to corticosteroids in pregnancy has been associated in some, but not all studies, with increased rates of orofacial clefts in the infant. Overall, the available data do not demonstrate that use of topical corticosteroids in pregnancy increases the risk of congenital malformation, including orofacial clefts, although information on some specific malformations is limited.

Data do not demonstrate that use of topical corticosteroids as a group in pregnancy is associated with miscarriage, intrauterine death, preterm delivery, or reduced fetal growth. However, where data have been stratified by exposure type, there is a suggestion of an increased risk of lower birth weight with use of high potency preparations or large cumulative doses. Ongoing research is required to confirm these findings and to clarify whether higher potency preparations or large cumulative doses may also pose increased risks of other adverse fetal outcomes.

If the use of topical corticosteroids is indicated at any stage of pregnancy, treatment should not be withheld. Exposure to topical corticosteroids 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.

Systemic corticosteroids available in the UK include prednisolone, prednisone, hydrocortisone, betamethasone, dexamethasone, deflazacort, methylprednisolone and triamcinolone.

Corticosteroids are used to reduce inflammation, suppress the immune system, and replace hormones where a deficiency exists. The British Society for Rheumatology (BSR) states that prednisolone is compatible with pregnancy and is the preferred corticosteroid for treatment of rheumatological disease in pregnancy. Guidelines from the Royal College of Obstetricians and Gynaecologists (RCOG) state that where premature delivery is anticipated, intramuscular dexamethasone or betamethasone should be offered to women to reduce the risk of neonatal respiratory distress syndrome. Systemic corticosteroids are also used in the treatment of severe COVID-19 infection, including during pregnancy.

Systemic administration of corticosteroids during organogenesis has been associated with an increase in rates of cleft lip and palate in some animal models. Although the majority of human data do not demonstrate that gestational exposure to systemic corticosteroids increases the risk of orofacial clefts, a small number of studies have suggested an association and further research is therefore required. The available data do not support an association between in utero exposure to systemic corticosteroids and cardiac defects in the offspring. Data on other specific malformations are too limited to confirm or refute associations. Studies assessing birth weight outcomes following gestational exposure to systemic corticosteroids (low birth weight, intrauterine growth restriction, small for gestational age) do not provide robust evidence of an association but are limited. The currently available data suggest that preterm delivery may be associated with gestational exposure to systemic corticosteroids. However, they do not rule out that this may be due to confounding as a consequence of the underlying maternal illness, rather than to steroid exposure itself, and further well-controlled studies are required to address this question. Due to limited data, it is not currently possible to conduct an evidence-based assessment of the risks of miscarriage or intrauterine death following corticosteroid use but prescribers should be aware that uncontrolled inflammation has been linked to fetal demise. The data on neurodevelopmental outcomes in the child following gestational exposure to systemic corticosteroids are generally highly confounded by the fact that these drugs are commonly used in the setting of premature rupture of membranes and/or preterm or very preterm delivery.

It should also be noted that many of the studies reporting pregnancy outcomes following gestational exposure to systemic corticosteroids are limited by a lack of stratification to account for differing doses, treatment duration, and steroid potencies. An increased risk of adverse fetal effects following use of high dose/potency corticosteroids, or use for extended periods, can therefore not be ruled out.

Where use of systemic corticosteroids is clinically indicated for the mother or fetus, treatment should not be withheld on account of pregnancy. Exposure to corticosteroids 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.

Inhaled corticosteroids are commonly used in the treatment of asthma. Inhaled corticosteroids available in the UK include: beclometasone, budesonide, ciclesonide, fluticasone and mometasone.

Good control of asthma during pregnancy is crucial. Inhaled corticosteroids should not be withheld if clinically indicated. Pregnant women with asthma should be counselled about the importance of maintaining control of their asthma, including continued use of prescribed medication.

Systemic exposure to corticosteroids in pregnancy has been associated in some (but not all) studies with an increased rate of orofacial clefts in the infant. Overall, the available evidence does not demonstrate that use of inhaled corticosteroids in early pregnancy causes orofacial clefts or cardiovascular malformations in the offspring. Data on other specific malformations are too limited to confirm or refute associations. The current data on intrauterine death rates following in utero exposure to inhaled corticosteroids are reassuring but require confirmation with further research. The available data do not suggest that gestational exposure to inhaled corticosteroids increases the risk of pathological birth weight outcomes (low birth weight, intrauterine growth restriction, small for gestational age) or preterm delivery. Due to limited data, it is not currently possible to conduct an evidence-based assessment of the risks of miscarriage or adverse neurodevelopmental outcomes in the child following gestational exposure to inhaled corticosteroids.

Exposure to inhaled corticosteroids 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.

Colestyramine (cholestyramine) is an anion exchange resin that is not absorbed from the gastro-intestinal tract. Colestyramine forms an insoluble complex with bile acids in the intestine, preventing their reabsorption and resulting in a decrease in serum cholesterol and low-density lipoprotein concentrations. It is licensed for the treatment of diarrhoeal disorders, hypercholesterolaemia, and pruritus associated with partial biliary obstruction and primary biliary cholangitis. Colestyramine is also used in pregnancy as washout therapy for leflunomide and teriflunomide.

Colestyramine has also been used for relief from pruritus associated with intrahepatic cholestasis of pregnancy (ICP; also known as obstetric cholestasis), although the Royal College of Obstetricians and Gynaecologists (RCOG) does not recommend its use for this purpose.

There are currently insufficient data to permit a meaningful risk assessment of the potential effects of colestyramine exposure in pregnancy. Colestyramine is not absorbed systemically, and use is therefore not expected to result in direct fetal exposure. However, its use may cause deficiencies of fat-soluble vitamins which may lead to adverse fetal effects. In particular, maternal vitamin K deficiency may lead to hypoprothrombinaemia, and thus, bleeding disorders in the fetus and neonate. Assessment of maternal prothrombin time, appropriate maternal vitamin K supplementation, and administration of vitamin K to the neonate should be considered if treatment with colestyramine is needed in pregnancy.

Exposure to colestyramine 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 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.