Letter: C

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.

Codeine is an opioid analgesic used in the treatment of mild-to-moderate pain and as an antitussive. Dihydrocodeine is a semisynthetic opioid also used in the treatment of mild-to-moderate pain and as an antitussive. There are no published pregnancy safety data specifically for dihydrocodeine; however, any fetal or neonatal effects are expected to be similar to those for codeine. UKTIS has collected prospective data on 99 pregnancies with therapeutic exposure to dihydrocodeine (including 23 live-born infants with first trimester exposure). When genetic conditions were excluded, no major malformations were observed among 82 live-born infants exposed at any time during pregnancy.

The available data do not provide robust evidence of an increase in risk of malformation with gestational codeine use but are conflicting and potentially confounded. The majority of the available prospective cohort studies (greater than 4,300 first trimester exposures) have not identified significant increased risks of congenital anomaly overall following fetal codeine exposure. While single studies have identified increased risks of specific malformations, most are methodologically limited and these findings require further confirmation.

Data regarding other pregnancy outcomes are limited. A prospective cohort study described small increased risks of stillbirth, small for gestational age and preterm delivery with gestational codeine exposure in early pregnancy. However, these results may have been impacted by unmeasured co-variable risk factors that were not adequately considered in the analysis. As such, these findings remain unconfirmed. There are no data regarding the risk of miscarriage or abnormal neurodevelopment following in utero codeine exposure. Increased use of codeine in pregnancy among mothers of children with neuroblastoma was found in a single study. However, this finding is heavily biased and the association requires further investigation.

There are theoretical concerns that maternal use of codeine near term may be associated with respiratory depression in the neonate. However, the only study which has investigated the risk of neonatal respiratory depression found no increased risk. There are a small number of published case reports of perinatal arterial stroke and neonatal withdrawal in infants of women who used codeine in the weeks before delivery. However, no epidemiological studies have investigated these associations. Neonatal monitoring for symptoms of withdrawal may be warranted following maternal use of codeine near term.

The Medicines and Healthcare products Regulatory Agency (MHRA) advise that the use of codeine by lactating mothers is contraindicated due to concerns of infant opiate toxicity following exposure to codeine or its metabolite, morphine, through breast milk. For further guidance on the use of codeine in breastfeeding we advise contact with the UK Drugs in Lactation Advisory Service (UKDILAS).

Exposure to codeine at any stage in pregnancy would not usually be regarded as an indication for 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.

Colchicine is licensed for the treatment of acute gout and prophylaxis of gout attack, but is also used off-licence for the prophylaxis of familial Mediterranean fever (FMF; recurrent polyserositis). Colchicine is a mitotic spindle fibre inhibitor which induces metaphase arrest in cells undergoing mitosis.

Data regarding exposure to colchicine during pregnancy are mainly derived from its use to treat familial Mediterranean fever (FMF) and Behçet’s disease (BD), and consist of approximately 1,000 colchicine-exposed pregnancies described in controlled studies and larger case series.

The available data do not provide evidence of an increased risk of congenital malformation, miscarriage or stillbirth. One of two studies investigating karyotype anomaly described a 2.2-fold increased risk in abnormal fetal karyotype in infants exposed to colchicine during pregnancy (combined maternal and paternal exposures) compared to unexposed controls. However, the authors emphasised that the absolute risk of fetal aneuploidy was low in the colchicine-exposed group (0.66% vs. 0.15% in the control group). No adjustment for co-variable risk factors, other than maternal age, was performed, therefore data confounding cannot be excluded. Additionally, maternal and paternal exposures were not analysed separately, so it is difficult to determine whether maternal exposure during early pregnancy/pre-conception is a risk (in contrast to paternal exposure). Another three studies investigating karyotype anomaly rates (one also combined maternal and paternal exposures, two investigated maternal exposure only) did not identify an association. The evidence for an increased risk of karyotype anomaly following maternal and/or paternal exposure is unclear.

Data regarding the risk of low birth weight (LBW)/small for gestational age (SGA) infants and preterm delivery following colchicine exposure in pregnancy are limited and conflicting. However, FMF and BD are both independent risk factors for these outcomes, therefore confounding by indication is possible. Further studies controlling for indication are required. There are no data on which to assess the risk of neonatal complications or neurodevelopmental impairment.

Exposure to colchicine 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.

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 cirrhosis. In pregnancy the drug has been used for relief from pruritus associated with intrahepatic cholestasis of pregnancy (ICP; also known as obstetric cholestasis), although current Royal College of Obstetricians and Gynaecologists (RCOG) guidelines state that colestyramine is ‘not in clinical use’ for this purpose. Colestyramine is also used in pregnancy as washout therapy for leflunomide and teriflunomide.

There are currently insufficient data to permit a meaningful risk assessment of the potential effects of colestyramine exposure in pregnancy and women should be made aware of this lack of information. However, because colestyramine is not absorbed systemically, it is not expected to have direct effects, although colestyramine may cause maternal deficiencies of fat-soluble vitamins which may lead to adverse fetal effects. In particular, maternal vitamin K deficiency (a recognised complication of ICP itself) 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. Current RCOG guidelines on the management of ICP recommend checking prothrombin time, even in the absence of colestyramine treatment.

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.

Cocaine is a tropane alkaloid with local anaesthetic and CNS stimulant properties.  Cocaine is legitimately (though rarely) used as a topical local anaesthetic and illicitly as a drug of abuse.  Cocaine is mainly abused by insufflation (snorting) but it can also be injected, smoked or ingested.  It causes acute vasoconstriction which may cause fetal haemorrhage and hypoxia.  Its use is contraindicated in pregnancy.

Data on cocaine use is heavily confounded, however cocaine use during pregnancy has been associated with increased risk of spontaneous abortion, placental abruption, premature labour, intrauterine growth retardation and Sudden Infant Death Syndrome (SIDS).  The teratogenicity of cocaine is not confirmed, however malformations observed in infants after prenatal cocaine exposure include microcephaly and malformations of the skeletal system, nervous system, gastrointestinal tract, genitourinary system and cardiovascular system.  Exposure in late pregnancy may lead to neonatal withdrawal in the infant.

Exposure to cocaine at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy but may warrant enhanced antenatal surveillance of fetal growth and development.

Chloroquine is used for chemoprophylaxis and treatment of malaria. It is also used in the treatment of amoebic hepatitis/abscess, lupus erythematosus and rheumatoid arthritis. This document covers data relating to use of chloroquine as an antimalarial only.

Travel to areas where malaria is endemic should be avoided during pregnancy wherever possible. If travel to such areas is unavoidable, insect repellents, bed nets, appropriate clothing to prevent mosquito bites and adequate chemoprophylaxis should be used.

Human pregnancy data relating to both prophylaxis and treatment with chloroquine provide no evidence that exposure to the medication itself increases the risk of miscarriage, congenital malformation or stillbirth/IUD, prematurity, growth restriction or neonatal complications, and no conclusive evidence of an increased risk of low birth weight. However, data for some of these outcomes is limited, particularly those related to first trimester/early pregnancy exposure. Due to the limitations of the available data, increased risks of congenital malformation or miscarriage cannot be completely excluded.

Where use of chloroquine is clinically indicated, it should not be withheld on account of the pregnancy as the known risks of maternal malaria infection are likely to be far greater than any potential risks to the fetus from the drug.

Exposure to chloroquine at any stage of pregnancy in the absence of maternal malaria infection would not usually be regarded as an indication for additional fetal monitoring. However, other risk factors may be present in individual cases which independently increase the risk of an adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.

Important: Please ensure that the selected antimalarial will provide appropriate prophylaxis for the area of travel. Advice is available from a number of sources (e.g. UKHSA^[1], WHO^[2], BNF,^[3] Fit For Travel,^[4] Travel Health Pro,^[5] and TRAVAX^[6]).

For further advice on malaria prevention in pregnancy please refer to the relevant UKTIS document below.

Chlorphenamine (chlorpheniramine) is a first-generation sedating antihistamine used for the symptomatic relief of allergic disorders.

The available data do not show that chlorphenamine use in pregnancy is associated with an increase in the overall rate of congenital malformation. Associations between first trimester in utero chlorphenamine exposure and various specific malformations have been described in a small number of case-control studies. These have included eye and ear anomalies, neural tube defects, specific cardiac defects and facial clefting. However, these findings are generally considered limited by the study methodologies which may have introduced risks of chance findings. Further prospective studies investigating these associations are therefore required.

The limited published data do not suggest an increased risk of spontaneous abortion after in utero chlorphenamine exposure. No studies have investigated the incidence of intrauterine death, low infant birth weight, preterm delivery or neonatal complications with use of chlorphenamine during pregnancy. Studies in which antihistamines have been analysed as a therapeutic class have not shown any increased risk of these outcomes. There are no data regarding infant neurodevelopment after in utero exposure to chlorphenamine or other antihistamines.

Where use of chlorphenamine in pregnancy is being considered, the available pregnancy safety data and its limitations should be discussed with the patient. Exposure to chlorphenamine 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.

Ciclosporin (cyclosporin, cyclosporine, cyclosporine A) is a calcineurin inhibitor used systemically for graft rejection prophylaxis and management, and in the treatment of ulcerative colitis, rheumatoid arthritis, atopic dermatitis, psoriasis, nephrotic syndrome, and endogenous uveitis. It is also used topically as an eye drop solution for severe keratitis in adults with dry eye disease.

A guideline produced by the British Society for Rheumatology (BSR) and British Health Professionals in Rheumatology (BHPR) states that ciclosporin is compatible for use throughout pregnancy (and breastfeeding) at the lowest effective dose.

The available data relating to the safety of maternal ciclosporin use in human pregnancy mainly consist of uncontrolled case series and a smaller number of controlled studies, which collectively describe the pregnancy outcomes of approximately 4,000 unique pregnancies in women with solid organ transplants or immune mediated diseases. Around 2,000 of these relate to exposure in the first trimester. Uncontrolled data are likely limited by reporting bias and confounding resulting from concomitant medication exposures and associated maternal medical conditions.

The available data do not currently provide evidence that systemic use of ciclosporin during pregnancy increases the risk of congenital malformation. Increased rates of preterm delivery and intrauterine growth restriction have been identified among women receiving systemic treatment; however, it is unclear to what extent these findings are confounded by the underlying maternal medical condition.

The currently available data do not suggest an increased risk of miscarriage, intrauterine death, neonatal complications, or neurodevelopmental impairment following ciclosporin use in pregnancy.

There are no pregnancy exposure data relating specifically to topical administration of ciclosporin. However, given the mode of administration, it is unlikely that significant systemic absorption will occur. Topical ciclosporin treatment can therefore be considered when there is no alternative with a better established pregnancy safety profile.

Women being treated with ciclosporin who are planning a pregnancy or who become pregnant should be offered a medication review by their specialist. Regular clinical review and monitoring of maternal whole blood ciclosporin concentration is recommended both during and after pregnancy due to the risk of subtherapeutic or toxic blood concentrations as a consequence of the pharmacokinetic changes which may be associated with pregnancy. Close monitoring of the maternal graft function and immunosuppressive status, with regular observations of the maternal obstetric condition and fetal growth, is advised.

Exposure to ciclosporin at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy. However, other risk factors present in individual cases 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.